An area of the brain involved in the planning and production of spoken and signed language in humans plays a similar role in chimpanzee communication, researchers report online on February 28th in the journal Current Biology, a publication of Cell Press.
"Chimpanzee communicative behavior shares many characteristics with human language," said Jared Taglialatela of the Yerkes National Primate Research Center. "The results from this study suggest that these similarities extend to the way in which our brains produce and process communicative signals."
The results also suggest that the "neurobiological foundations" of human language may have been present in the common ancestor of modern humans and chimpanzees, he said.
Scientists had identified Broca's area, located in part of the human brain known as the inferior frontal gyrus (IFG), as one of several critical regions that light up with activity when people plan to say something and when they actually talk or sign. Anatomically, Broca's area is most often larger on the left side of the brain, and imaging studies in humans had shown left-leaning patterns of brain activation during language-related tasks, the researchers said.
"We didn't know if or to what extent other primates, and particularly humans' closest ancestor, the chimpanzees, possess a comparable region involved in the production of their own communicative signals," Taglialatela said.
In the new study, the researchers non-invasively scanned the brains of three chimpanzees as they gestured and called to a person in request for food that was out of their reach. Those chimps showed activation in the brain region corresponding to Broca's area and in other areas involved in complex motor planning and action in humans, the researchers found.
The findings might be interpreted in one of two ways, Taglialatela said.
"One interpretation of our results is that chimpanzees have, in essence, a 'language-ready brain,' " he said. "By this, we are suggesting that apes are born with and use the brain areas identified here when producing signals that are part of their communicative repertoire.
"Alternatively, one might argue that, because our apes were captive-born and producing communicative signals not seen often in the wild, the specific learning and use of these signals 'induced' the pattern of brain activation we saw. This would suggest that there is tremendous plasticity in the chimpanzee brain, as there is in the human brain, and that the development of certain kinds of communicative signals might directly influence the structure and function of the brain."
The researchers include Jared P. Taglialatela, Yerkes National Primate Research Center, Atlanta, GA, Department of Natural Sciences, Clayton State University, Morrow, GA; Jamie L. Russell, Yerkes National Primate Research Center, Atlanta, GA; Jennifer A. Schaeffer, Yerkes National Primate Research Center, Atlanta, GA; and William D. Hopkins, Yerkes National Primate Research Center, Atlanta, GA, Department of Psychology, Agnes Scott College, Decatur, GA.
Source: Cathleen Genova
Cell Press
среда, 1 июня 2011 г.
Hair Cells Act As Biological Wound Dressing
A new study in Artificial Organs tested the effects of a wound dressing created with hair follicular cells. The findings reveal that skin substitutes using living hair cells can increase wound healing.
Researchers applied the technique to wound surfaces on mice. Subjects that were administered this biological dressing produced two times better wound closure than the control set.
The technique not only provides the proper environment for cell attachment and growth, but also serves as an effective biodressing to keep wounds moist and maintain structural strength during healing. "This technique shows promise as a biological dressing that is not only efficient and strong but also can be produced with less time and effort," says Jung Chul Kim, lead author of the study.
The use of skin substitutes for wound healing has suffered setbacks in recent years due to the expensive price. However, this method of wound dressing improves early-stage wound healing and reduces the time between preparation and patient use.
This study is published in the November 2007 issue of Artificial Organs.
Dr. Jung Chul Kim is affiliated with Kyungpook National University in Daegu, Korea.
Since 1977, Artificial Organs has been publishing original articles featuring the studies of design, performance, and evaluation of the biomaterials and devices for the international medical, scientific, and engineering communities involved in the research and clinical application of artificial organ development.
Wiley-Blackwell was formed in February 2007 as a result of the acquisition of Blackwell Publishing Ltd. by John Wiley & Sons, Inc., and its merger with Wiley's Scientific, Technical, and Medical business. Together, the companies have created a global publishing business with deep strength in every major academic and professional field. Wiley-Blackwell publishes approximately 1,400 scholarly peer-reviewed journals and an extensive collection of books with global appeal. For more information on Wiley-Blackwell, please visit blackwellpublishing/ or interscience.wiley/.
Source: Amy Molnar
Blackwell Publishing Ltd.
Researchers applied the technique to wound surfaces on mice. Subjects that were administered this biological dressing produced two times better wound closure than the control set.
The technique not only provides the proper environment for cell attachment and growth, but also serves as an effective biodressing to keep wounds moist and maintain structural strength during healing. "This technique shows promise as a biological dressing that is not only efficient and strong but also can be produced with less time and effort," says Jung Chul Kim, lead author of the study.
The use of skin substitutes for wound healing has suffered setbacks in recent years due to the expensive price. However, this method of wound dressing improves early-stage wound healing and reduces the time between preparation and patient use.
This study is published in the November 2007 issue of Artificial Organs.
Dr. Jung Chul Kim is affiliated with Kyungpook National University in Daegu, Korea.
Since 1977, Artificial Organs has been publishing original articles featuring the studies of design, performance, and evaluation of the biomaterials and devices for the international medical, scientific, and engineering communities involved in the research and clinical application of artificial organ development.
Wiley-Blackwell was formed in February 2007 as a result of the acquisition of Blackwell Publishing Ltd. by John Wiley & Sons, Inc., and its merger with Wiley's Scientific, Technical, and Medical business. Together, the companies have created a global publishing business with deep strength in every major academic and professional field. Wiley-Blackwell publishes approximately 1,400 scholarly peer-reviewed journals and an extensive collection of books with global appeal. For more information on Wiley-Blackwell, please visit blackwellpublishing/ or interscience.wiley/.
Source: Amy Molnar
Blackwell Publishing Ltd.
The Complexity Of Disease Phenotypes
Animal models have been invaluable in understanding how gene mutations physically affect a complex organism. However, as vividly illustrated in a new research study examining mice with a metabolic disease, the same mutation in the same species can produce wildly variable results.
Niemann-Pick type C (NPC) disease is a rare genetic condition brought on by a mutation in one protein, NPC1, which helps shuttle cholesterol out of a cell compartment called the lysosome. As a result, cholesterol accumulates in virtually every tissue in the body, causing widespread organ dysfunction and death.
John Dietschy and colleagues evaluated how factors like genetic background, additional mutations, and environmental influences affected the lifespan of a mouse model of NBC. Overall, the lifespan of different npc1-/- mice ranged from 50-130 days, and even simple differences such as the host colony (same strain, just different location of breeding), or slight alterations in diet affected the average lifespan.
These studies highlight just how complex a 'simple' genetic disease really is, and that such variability should be carefully considered when designing animal experiments or interpreting results. It is particularly important, Dietschy and colleagues note, to use these animal models to carefully differentiate the non-specific environmental and genetic effects on lifespan from treatments that have a direct effect on the genetic abnormality present in the disease and thus may promote survival.
The Journal of Lipid research
Corresponding Author: John M. Dietschy, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX
Source: Nick Zagorski
American Society for Biochemistry and Molecular Biology
Niemann-Pick type C (NPC) disease is a rare genetic condition brought on by a mutation in one protein, NPC1, which helps shuttle cholesterol out of a cell compartment called the lysosome. As a result, cholesterol accumulates in virtually every tissue in the body, causing widespread organ dysfunction and death.
John Dietschy and colleagues evaluated how factors like genetic background, additional mutations, and environmental influences affected the lifespan of a mouse model of NBC. Overall, the lifespan of different npc1-/- mice ranged from 50-130 days, and even simple differences such as the host colony (same strain, just different location of breeding), or slight alterations in diet affected the average lifespan.
These studies highlight just how complex a 'simple' genetic disease really is, and that such variability should be carefully considered when designing animal experiments or interpreting results. It is particularly important, Dietschy and colleagues note, to use these animal models to carefully differentiate the non-specific environmental and genetic effects on lifespan from treatments that have a direct effect on the genetic abnormality present in the disease and thus may promote survival.
The Journal of Lipid research
Corresponding Author: John M. Dietschy, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX
Source: Nick Zagorski
American Society for Biochemistry and Molecular Biology
New Method To Overcome Multiple Drug Resistant Diseases Developed By Stanford Researchers
Many drugs once considered Charles Atlases of the pharmaceutical realm have been reduced to the therapeutic equivalent of 97-pound weaklings as the diseases they once dispatched with ease have developed resistance to them.
The problem is well documented for antibiotics, although not confined to them. Chemotherapy drugs that were once highly effective when first used against a particular cancer now are often rendered near powerless when a patient's cancer resurges.
Even more devastating, when an organism develops resistance to one drug, it often becomes resistant to other drugs (known as multi-drug resistance), rendering not just one medication but a whole class of therapeutics useless against it.
But researchers at Stanford University have developed a method to get around one of the most common forms of resistance, thereby opening up some if not many resistant diseases to the reinvigorated fury of the medications that once laid them low. To do it, they took a tip from nature.
"Nature has developed all of this firepower for getting things into cells, and one of the ways is to create entities that are arginine-rich," said Paul Wender, the Bergstrom Professor of Chemistry at Stanford University. Arginine is an amino acid, the building block of proteins, and as such is found in virtually every cell in the human body, as well as other mammalian bodies.
Using such a common transporter to ferry a potent medication inside a resistant cell is a bit like recruiting your grandmother to cart a load of switchblade knives through customs. Indeed, Wender said, "Arginine-rich sequences appear to figure in the mechanisms by which many pathogens invade cells." Wender's team used a necklace of eight arginine molecules to surround the medication they worked with.
Wender and his colleagues figured out that a particular molecular subunit within arginine, called a guanidinium group, was what nature actually exploits to get foreign substances through cell membranes. Working with Taxol(r), a widely used chemotherapeutic agent, they attached a series of arginines with their associated guanidinium groups and tried it out against Taxol-resistant ovarian cancer cells implanted in mice. It worked.
"It's an exciting result to be able to take a drug known to work against cancer, but stymied by resistant cells, and restore it to effectiveness using an arginine transporter," Wender said. "This bodes well for use with other drugs that succumb to resistance."
A paper describing the work is scheduled to be published next week in the online Early Edition of the Proceedings of the National Academy of Sciences. Wender's group collaborated with that of Chris Contag, a professor of pediatrics and of microbiology and immunology at Stanford's School of Medicine, who is a co-author on the paper.
"Overcoming Taxol resistance is big. It's huge," said Nelson Teng, professor of obstetrics and gynecology at the Medical School. "In essence, the technology can be used to overcome one of the most challenging types of problems of drug resistance."
The type of drug resistance that Wender's work has overcome develops when pumps located in the membrane that encloses a cell become sensitized to a medication. It is one of the most common ways in which resistance manifests. The pumps, which normally capture and eject foreign material from a cell, are produced at higher levels in certain resistant cells and, because of their increased number, become more effective at tossing the drug molecules out.
"It is kind of like a bouncer," Wender said. "If you're not recognized as being part of the club, then you're kicked out." Resistant cells also create a lot more of the pumps than a normal cell would have.
Some researchers have tried dealing with this situation by adding another molecule to the mix to inhibit the pump, keeping it busy so the medication can slip in while the pumps are occupied with the decoy molecule. But if any of the molecules make their way into healthy cells, they can gum up the proper functioning of the pumps in those cells, too, adding to the litany of undesirable side effects that generally accompany chemotherapy.
Wender's group decided to see if they could take drugs to which diseases had become resistant and, by combining them with what they call "molecular transporters," get them in around the pump.
"If we think of the pump as being a bouncer for the cellular club, then effectively what we're doing is disguising one of these therapeutic agents to get it in through the back door or the side door," Wender said. "We're not even going to deal with the bouncer."
Therein lies what may be the greatest value of the work. The basic approach of bonding a medication to an arginine-rich transporter to slip it past the cellular sentries could, in theory, be used to get any of a host of medications into any cell that has developed the type of resistance involving increased numbers of export pumps.
"This could potentially be used with any drug which is effective but has a delivery problem," Teng said. "Not just Taxol."
That could include medications for diseases caused by antibiotic resistant bacteria, such as multi-drug resistant tuberculosis, or by drug resistant parasites such as malaria, as well as other types of cancer.
The arginine transporter manages to avoid ejection by slipping through the membrane of the cell in between the pumps. The key is the ability of arginine to form weak, temporary bonds with some of the molecules that reside in the membrane.
"As the transporter, with all these arginine guanidinium groups, approaches the cell, it basically does a handshake using hydrogen bonds with cell surface constituents that are in the membrane," Wender said. "In essence, it changes its physical properties by shaking hands with all these cell membrane components."
That change in physical properties effectively cloaks the arginine-Taxol complex, allowing it to slip past the sentries and into the cell. As it passes into the cell, the weak bonds it formed with the membrane components break and the transporter, with its therapeutic load, is free to roam inside the cell.
But after getting into the cell, the arginine-Taxol complex still has to break apart for the Taxol to do its job against the cancer cell. Wender's group achieved this by taking advantage of the presence of a molecule called glutathione, which is generally abundant inside cells and which in cancer cells tends to be present in higher levels than usual.
Glutathione is predisposed to attacking sulphur-sulphur bonds, so that is the bond the researchers used to hold the arginine and Taxol together. Once the arginine-Taxol complex is inside the cell, the glutathione can get to work hacking away at the sulphur bonds, and in the process, unwittingly release the compound that will spell its doom.
Because glutathione is relatively scarce outside of cells, the arginine transporter is effectively inert in that environment, so there are no side effects from having the arginine-Taxol complex moving through the patient's body. This is in stark contrast to the present situation, as many patients are extremely sensitive to the molecular vehicle that is currently used to administer ferried Taxol to the cancer cells.
The researchers achieved another breakthrough by tinkering with the form of the arginine used in their transporter. By altering certain aspects of the arginine, the researchers were able to control the rate at which glutathione slices and dices the arginine-Taxol complex.
This gives them an unprecedented ability to regulate the amount of medication that is active inside the patient at any point in time. To date, doctors have had to be content with injecting as high a dose of medication as patients can tolerate and then waiting as the effective amount in the patients slowly dwindled until they could safely inject more. This approach results in a repeated pattern of rapid spikes in the amount of medication in the system, followed by slow declines until the next spike. Ideally, doctors would like the patient to be continually experiencing the maximum tolerable dosage to keep the pressure on the cancer cells, killing them off as quickly and as thoroughly as possible. The arginine transporter makes this possible.
Ovarian cancer was chosen as the subject cancer for this study in part because it commonly develops resistance to Taxol, but also because of a low long-term success rate in treating it. The American Cancer Society estimates that in the United States alone there will be 21,650 diagnoses of ovarian cancer this year and 15,500 deaths from it.
"Ovarian cancer has a drug [Taxol] that works pretty well in the beginning. Seventy or eighty percent of the patients have a response," Teng said. "But it fails at the end because drug resistance develops."
Further studies need to be done to demonstrate the safety of arginine transporters before they can be used in this application in humans, Wender and Teng said. But the researchers already have positive safety data from tests of arginine-transporter technology in another application, one that does not involve drug resistance, so they are optimistic. The discovery of effective arginine transporters could be the key to treating ovarian cancer, as well as other diseases that develop drug resistance, more effectively.
Other co-authors of the paper in PNAS are Elena Dubikovskaya, a graduate student at the time this work was done and now a postdoctoral fellow at University of California-Berkeley; Steve Thorne, a postdoctoral fellow at the time this work was done and now on a faculty member at the University of Pittsburgh; and Thomas Pillow, a graduate student in chemistry.
Teng is working with Wender on other projects stemming from the work with Taxol but was not involved in the research described in this paper.
Source: Louis Bergeron
Stanford University
View drug information on Taxol.
The problem is well documented for antibiotics, although not confined to them. Chemotherapy drugs that were once highly effective when first used against a particular cancer now are often rendered near powerless when a patient's cancer resurges.
Even more devastating, when an organism develops resistance to one drug, it often becomes resistant to other drugs (known as multi-drug resistance), rendering not just one medication but a whole class of therapeutics useless against it.
But researchers at Stanford University have developed a method to get around one of the most common forms of resistance, thereby opening up some if not many resistant diseases to the reinvigorated fury of the medications that once laid them low. To do it, they took a tip from nature.
"Nature has developed all of this firepower for getting things into cells, and one of the ways is to create entities that are arginine-rich," said Paul Wender, the Bergstrom Professor of Chemistry at Stanford University. Arginine is an amino acid, the building block of proteins, and as such is found in virtually every cell in the human body, as well as other mammalian bodies.
Using such a common transporter to ferry a potent medication inside a resistant cell is a bit like recruiting your grandmother to cart a load of switchblade knives through customs. Indeed, Wender said, "Arginine-rich sequences appear to figure in the mechanisms by which many pathogens invade cells." Wender's team used a necklace of eight arginine molecules to surround the medication they worked with.
Wender and his colleagues figured out that a particular molecular subunit within arginine, called a guanidinium group, was what nature actually exploits to get foreign substances through cell membranes. Working with Taxol(r), a widely used chemotherapeutic agent, they attached a series of arginines with their associated guanidinium groups and tried it out against Taxol-resistant ovarian cancer cells implanted in mice. It worked.
"It's an exciting result to be able to take a drug known to work against cancer, but stymied by resistant cells, and restore it to effectiveness using an arginine transporter," Wender said. "This bodes well for use with other drugs that succumb to resistance."
A paper describing the work is scheduled to be published next week in the online Early Edition of the Proceedings of the National Academy of Sciences. Wender's group collaborated with that of Chris Contag, a professor of pediatrics and of microbiology and immunology at Stanford's School of Medicine, who is a co-author on the paper.
"Overcoming Taxol resistance is big. It's huge," said Nelson Teng, professor of obstetrics and gynecology at the Medical School. "In essence, the technology can be used to overcome one of the most challenging types of problems of drug resistance."
The type of drug resistance that Wender's work has overcome develops when pumps located in the membrane that encloses a cell become sensitized to a medication. It is one of the most common ways in which resistance manifests. The pumps, which normally capture and eject foreign material from a cell, are produced at higher levels in certain resistant cells and, because of their increased number, become more effective at tossing the drug molecules out.
"It is kind of like a bouncer," Wender said. "If you're not recognized as being part of the club, then you're kicked out." Resistant cells also create a lot more of the pumps than a normal cell would have.
Some researchers have tried dealing with this situation by adding another molecule to the mix to inhibit the pump, keeping it busy so the medication can slip in while the pumps are occupied with the decoy molecule. But if any of the molecules make their way into healthy cells, they can gum up the proper functioning of the pumps in those cells, too, adding to the litany of undesirable side effects that generally accompany chemotherapy.
Wender's group decided to see if they could take drugs to which diseases had become resistant and, by combining them with what they call "molecular transporters," get them in around the pump.
"If we think of the pump as being a bouncer for the cellular club, then effectively what we're doing is disguising one of these therapeutic agents to get it in through the back door or the side door," Wender said. "We're not even going to deal with the bouncer."
Therein lies what may be the greatest value of the work. The basic approach of bonding a medication to an arginine-rich transporter to slip it past the cellular sentries could, in theory, be used to get any of a host of medications into any cell that has developed the type of resistance involving increased numbers of export pumps.
"This could potentially be used with any drug which is effective but has a delivery problem," Teng said. "Not just Taxol."
That could include medications for diseases caused by antibiotic resistant bacteria, such as multi-drug resistant tuberculosis, or by drug resistant parasites such as malaria, as well as other types of cancer.
The arginine transporter manages to avoid ejection by slipping through the membrane of the cell in between the pumps. The key is the ability of arginine to form weak, temporary bonds with some of the molecules that reside in the membrane.
"As the transporter, with all these arginine guanidinium groups, approaches the cell, it basically does a handshake using hydrogen bonds with cell surface constituents that are in the membrane," Wender said. "In essence, it changes its physical properties by shaking hands with all these cell membrane components."
That change in physical properties effectively cloaks the arginine-Taxol complex, allowing it to slip past the sentries and into the cell. As it passes into the cell, the weak bonds it formed with the membrane components break and the transporter, with its therapeutic load, is free to roam inside the cell.
But after getting into the cell, the arginine-Taxol complex still has to break apart for the Taxol to do its job against the cancer cell. Wender's group achieved this by taking advantage of the presence of a molecule called glutathione, which is generally abundant inside cells and which in cancer cells tends to be present in higher levels than usual.
Glutathione is predisposed to attacking sulphur-sulphur bonds, so that is the bond the researchers used to hold the arginine and Taxol together. Once the arginine-Taxol complex is inside the cell, the glutathione can get to work hacking away at the sulphur bonds, and in the process, unwittingly release the compound that will spell its doom.
Because glutathione is relatively scarce outside of cells, the arginine transporter is effectively inert in that environment, so there are no side effects from having the arginine-Taxol complex moving through the patient's body. This is in stark contrast to the present situation, as many patients are extremely sensitive to the molecular vehicle that is currently used to administer ferried Taxol to the cancer cells.
The researchers achieved another breakthrough by tinkering with the form of the arginine used in their transporter. By altering certain aspects of the arginine, the researchers were able to control the rate at which glutathione slices and dices the arginine-Taxol complex.
This gives them an unprecedented ability to regulate the amount of medication that is active inside the patient at any point in time. To date, doctors have had to be content with injecting as high a dose of medication as patients can tolerate and then waiting as the effective amount in the patients slowly dwindled until they could safely inject more. This approach results in a repeated pattern of rapid spikes in the amount of medication in the system, followed by slow declines until the next spike. Ideally, doctors would like the patient to be continually experiencing the maximum tolerable dosage to keep the pressure on the cancer cells, killing them off as quickly and as thoroughly as possible. The arginine transporter makes this possible.
Ovarian cancer was chosen as the subject cancer for this study in part because it commonly develops resistance to Taxol, but also because of a low long-term success rate in treating it. The American Cancer Society estimates that in the United States alone there will be 21,650 diagnoses of ovarian cancer this year and 15,500 deaths from it.
"Ovarian cancer has a drug [Taxol] that works pretty well in the beginning. Seventy or eighty percent of the patients have a response," Teng said. "But it fails at the end because drug resistance develops."
Further studies need to be done to demonstrate the safety of arginine transporters before they can be used in this application in humans, Wender and Teng said. But the researchers already have positive safety data from tests of arginine-transporter technology in another application, one that does not involve drug resistance, so they are optimistic. The discovery of effective arginine transporters could be the key to treating ovarian cancer, as well as other diseases that develop drug resistance, more effectively.
Other co-authors of the paper in PNAS are Elena Dubikovskaya, a graduate student at the time this work was done and now a postdoctoral fellow at University of California-Berkeley; Steve Thorne, a postdoctoral fellow at the time this work was done and now on a faculty member at the University of Pittsburgh; and Thomas Pillow, a graduate student in chemistry.
Teng is working with Wender on other projects stemming from the work with Taxol but was not involved in the research described in this paper.
Source: Louis Bergeron
Stanford University
View drug information on Taxol.
The Tongue Is The Start Of The Route To Obesity
Obesity gradually numbs the taste sensation of rats to sweet foods and drives them to consume larger and ever-sweeter meals, according to neuroscientists. Findings from the Penn State study could uncover a critical link between taste and body weight, and reveal how flab hooks the brain on sugary food.
"When you have a reduced sensitivity to palatable foods, you tend to consume it in higher amounts," said Andras Hajnal, associate professor of neural and behavioral sciences at Penn State College of Medicine. "It is a vicious circle."
Previous studies have suggested that obese persons are less sensitive to sweet taste and crave sweet foods more than lean people. However, little is known about the specific differences between obese and lean individuals in their sense of taste and the pleasure they derive from sweet foods.
Hajnal and his Penn State colleague Peter Kovacs, a post-doctoral fellow, investigated these differences by studying the taste responses of two strains -- OLETF and LETO rats.
Compared to the lean and healthy LETO rats, the taste responses in OLETF rats mirror those in obese humans. These rats have normal body weight at first, but they tend to chronically overeat due to a missing satiety signal, become obese and develop diabetes. The obese rats also show an increased preference for sweet foods and also are willing to work harder to obtain sweet solutions as a reward for their learning.
"When you have excess body weight, the brain is supposed to tell you not to eat more, or not choose high caloric meals" said Hajnal. "But this control apparently fails and thus the obesity epidemic is rising, and we want to find out how the sense of taste drives up food intake."
The researchers implanted electrodes in the rodents' brains to record the firing of nerve cells when the rats' tongues were exposed to various tastes -- salt, citric acid, plain water and six different concentrations of sucrose.
Hajnal and Kovacs specifically looked at differences in processing taste in the pontine parabrachial nucleus (PBN), a part of the brain that uses nerve cells to relay information from the surface of the tongue to the brain.
"We found that compared to the LETO rats, the OLETF rats had about 50 percent fewer neurons firing when their tongues were exposed to sucrose, suggesting that obese rats are overall less sensitive to sucrose," explained Hajnal, whose findings appeared in a recent issue of the Journal of Neurophysiology. The response to salt was the same for both strains.
However, when the obese rats were fed a stronger concentration of sucrose, their nerve cells fired more vigorously than in the lean rats. In other words, obese rats have a weaker response to weak concentrations and a stronger response to strong concentrations.
"These findings tell us that there is a difference in activation of neurons between lean and obese rats when they are exposed varying concentrations of sucrose," noted Hajnal. "If you sense sweetness less, you may be inclined to eat sweeter foods."
The Penn State researchers believe that the increased consumption of sweet foods over time could be influencing the brain's reward center by relaying progressively weaker nerve signals, which affects the perception of taste of the meals through the PBN.
In obese humans, an increase in the weight-height ratio is usually accompanied by a decrease in dopamine, which is a neurotransmitter associated with the brain's pleasure system.
"In these obese rats, like in humans, the dopamine system is suppressed and it is very possible that the obese rats are seeking a hedonistic experience or reward by eating larger meals and when they have a chance they also eat more sweets," Hajnal added.
The findings linking taste responses and obesity could hold an important message for a condition that affects more than 60 percent of adult Americans.
For instance, Hajnal points to an ever-increasing amount of fat and sugar in processed foods. The enhanced taste of these foods, he says, stimulates our taste and food reward neurons on a chronic basis, making them less sensitive over time. And what do we do when this happens?
"Instead of eating less, we seek out higher palatability," Hajnal explained. "We simply start putting an extra spoonful of sugar in our coffee."
Source: Amitabh Avasthi
Penn State
"When you have a reduced sensitivity to palatable foods, you tend to consume it in higher amounts," said Andras Hajnal, associate professor of neural and behavioral sciences at Penn State College of Medicine. "It is a vicious circle."
Previous studies have suggested that obese persons are less sensitive to sweet taste and crave sweet foods more than lean people. However, little is known about the specific differences between obese and lean individuals in their sense of taste and the pleasure they derive from sweet foods.
Hajnal and his Penn State colleague Peter Kovacs, a post-doctoral fellow, investigated these differences by studying the taste responses of two strains -- OLETF and LETO rats.
Compared to the lean and healthy LETO rats, the taste responses in OLETF rats mirror those in obese humans. These rats have normal body weight at first, but they tend to chronically overeat due to a missing satiety signal, become obese and develop diabetes. The obese rats also show an increased preference for sweet foods and also are willing to work harder to obtain sweet solutions as a reward for their learning.
"When you have excess body weight, the brain is supposed to tell you not to eat more, or not choose high caloric meals" said Hajnal. "But this control apparently fails and thus the obesity epidemic is rising, and we want to find out how the sense of taste drives up food intake."
The researchers implanted electrodes in the rodents' brains to record the firing of nerve cells when the rats' tongues were exposed to various tastes -- salt, citric acid, plain water and six different concentrations of sucrose.
Hajnal and Kovacs specifically looked at differences in processing taste in the pontine parabrachial nucleus (PBN), a part of the brain that uses nerve cells to relay information from the surface of the tongue to the brain.
"We found that compared to the LETO rats, the OLETF rats had about 50 percent fewer neurons firing when their tongues were exposed to sucrose, suggesting that obese rats are overall less sensitive to sucrose," explained Hajnal, whose findings appeared in a recent issue of the Journal of Neurophysiology. The response to salt was the same for both strains.
However, when the obese rats were fed a stronger concentration of sucrose, their nerve cells fired more vigorously than in the lean rats. In other words, obese rats have a weaker response to weak concentrations and a stronger response to strong concentrations.
"These findings tell us that there is a difference in activation of neurons between lean and obese rats when they are exposed varying concentrations of sucrose," noted Hajnal. "If you sense sweetness less, you may be inclined to eat sweeter foods."
The Penn State researchers believe that the increased consumption of sweet foods over time could be influencing the brain's reward center by relaying progressively weaker nerve signals, which affects the perception of taste of the meals through the PBN.
In obese humans, an increase in the weight-height ratio is usually accompanied by a decrease in dopamine, which is a neurotransmitter associated with the brain's pleasure system.
"In these obese rats, like in humans, the dopamine system is suppressed and it is very possible that the obese rats are seeking a hedonistic experience or reward by eating larger meals and when they have a chance they also eat more sweets," Hajnal added.
The findings linking taste responses and obesity could hold an important message for a condition that affects more than 60 percent of adult Americans.
For instance, Hajnal points to an ever-increasing amount of fat and sugar in processed foods. The enhanced taste of these foods, he says, stimulates our taste and food reward neurons on a chronic basis, making them less sensitive over time. And what do we do when this happens?
"Instead of eating less, we seek out higher palatability," Hajnal explained. "We simply start putting an extra spoonful of sugar in our coffee."
Source: Amitabh Avasthi
Penn State
'Fusion' Protein Found By Johns Hopkins Researchers - Without It, Muscle Cells 'refuse To Fuse'
Working with fruit flies, scientists at Johns Hopkins have discovered a protein required for two neighboring cells to fuse and become one "super cell."
Most cells enjoy their singular existence, but the strength and flexibility of muscles relies on hundreds or even thousands of super cells that make large-scale motion smooth and coordinated, such as flexion of a bicep.
The newly discovered protein, dubbed Solitary, coordinates the movement of tiny molecular delivery trucks to a cell's surface. Cells that lack Solitary stay, well, solitary. "They refuse to fuse," says Hopkins assistant professor of molecular biology and genetics Elizabeth Chen, Ph.D., whose report on the work is online this week in Developmental Cell.
Chen and her team studied fruit fly embryo muscles to find the molecular signals that tell two neighboring cells to join as one, plucking out for further study those embryos containing cells that refused to fuse.
They then compared the genetic sequences from healthy embryos with sequences from defective embryos to locate differences and identify the genes responsible for unfused muscle cells. In the process, they identified Solitary.
Chen's team next made a tool to see the Solitary protein, enabling them to track its localization under a fluorescent microscope. At each future fusion point between cells that they examined in the fly muscles, they saw concentrations of glowing clumps of Solitary protein.
"As we uncover more of the players in cell fusion, we get closer to manipulating fusion for our benefit," Chen adds. Muscular dystrophy, for example, might be treated by injecting into patients healthy muscle cells that are designed to fuse efficiently with the diseased muscles, saving the diseased cells from deteriorating.
They also discovered that Solitary protein is attached to the cell's skeleton. "It was so bizarre to see Solitary - something meant to regulate the cell's internal structure - to be involved in the external events of cell fusion," says Chen.
But in addition to structural support, the cell's "skeleton" provides an internal railway of sorts, along which other proteins and molecules can move. Indeed, the researchers saw that while normal cells were able to shuttle tiny storage compartments within the cell - presumably holding important molecular tools needed for cell fusion - to the fusion site, these storage compartments were scattered haphazardly, seemingly lost in the cellular wilderness, in cells lacking Solitary.
When two neighboring cells fuse, they need to break down the barrier between them, explains Chen. It turns out that the Solitary protein marks where that break is happening and subsequently tells the cell where to build its skeleton railway. "In this role, Solitary acts not like the delivery truck, but more like a construction site foreman," says Chen. "It's told where the cell barrier needs to be broken, then directs the building of a delivery road so that the molecular supplies can be brought to the fusion site."
The research was funded by the National Institutes of Health, the American Heart Association, the Edward Mallinckrodt Jr. Foundation, March of Dimes, Packard Foundation and Searle Scholars Program.
Authors on the paper are Sangjoon Kim, Khurts Shilagardi, Shiliang Zhang, Sabrina Hong, Kristen Sens, Jinyan Bo, Guillermo Gonzalez and Elizabeth Chen, all of Johns Hopkins.
On the Web:
developmentalcell/
mbg.jhmi/
Contact: Audrey Huang
Johns Hopkins Medical Institutions
Most cells enjoy their singular existence, but the strength and flexibility of muscles relies on hundreds or even thousands of super cells that make large-scale motion smooth and coordinated, such as flexion of a bicep.
The newly discovered protein, dubbed Solitary, coordinates the movement of tiny molecular delivery trucks to a cell's surface. Cells that lack Solitary stay, well, solitary. "They refuse to fuse," says Hopkins assistant professor of molecular biology and genetics Elizabeth Chen, Ph.D., whose report on the work is online this week in Developmental Cell.
Chen and her team studied fruit fly embryo muscles to find the molecular signals that tell two neighboring cells to join as one, plucking out for further study those embryos containing cells that refused to fuse.
They then compared the genetic sequences from healthy embryos with sequences from defective embryos to locate differences and identify the genes responsible for unfused muscle cells. In the process, they identified Solitary.
Chen's team next made a tool to see the Solitary protein, enabling them to track its localization under a fluorescent microscope. At each future fusion point between cells that they examined in the fly muscles, they saw concentrations of glowing clumps of Solitary protein.
"As we uncover more of the players in cell fusion, we get closer to manipulating fusion for our benefit," Chen adds. Muscular dystrophy, for example, might be treated by injecting into patients healthy muscle cells that are designed to fuse efficiently with the diseased muscles, saving the diseased cells from deteriorating.
They also discovered that Solitary protein is attached to the cell's skeleton. "It was so bizarre to see Solitary - something meant to regulate the cell's internal structure - to be involved in the external events of cell fusion," says Chen.
But in addition to structural support, the cell's "skeleton" provides an internal railway of sorts, along which other proteins and molecules can move. Indeed, the researchers saw that while normal cells were able to shuttle tiny storage compartments within the cell - presumably holding important molecular tools needed for cell fusion - to the fusion site, these storage compartments were scattered haphazardly, seemingly lost in the cellular wilderness, in cells lacking Solitary.
When two neighboring cells fuse, they need to break down the barrier between them, explains Chen. It turns out that the Solitary protein marks where that break is happening and subsequently tells the cell where to build its skeleton railway. "In this role, Solitary acts not like the delivery truck, but more like a construction site foreman," says Chen. "It's told where the cell barrier needs to be broken, then directs the building of a delivery road so that the molecular supplies can be brought to the fusion site."
The research was funded by the National Institutes of Health, the American Heart Association, the Edward Mallinckrodt Jr. Foundation, March of Dimes, Packard Foundation and Searle Scholars Program.
Authors on the paper are Sangjoon Kim, Khurts Shilagardi, Shiliang Zhang, Sabrina Hong, Kristen Sens, Jinyan Bo, Guillermo Gonzalez and Elizabeth Chen, all of Johns Hopkins.
On the Web:
developmentalcell/
mbg.jhmi/
Contact: Audrey Huang
Johns Hopkins Medical Institutions
Industry Teams Receive Awards From Michael J. Fox Foundation
As part of its ongoing efforts to do whatever it takes to speed delivery of transformative treatments and a cure for Parkinson's disease, The Michael J. Fox Foundation for Parkinson's Research has awarded up to $3 million in total funding to four industry teams seeking to push potential new PD treatments closer to the clinic. The awards were granted under MJFF's Therapeutics Development Initiative (TDI) program. Open exclusively to industry researchers, TDI is the cornerstone of the Foundation's efforts to expand industry investment in PD drug development. Through TDI, the Foundation shares the risk of drug development, thus helping to speed companies abilities to reach critical decision points for Parkinson's disease projects. Each of the four TDI grant awardees listed below will undertake research aimed at solving critical gaps in the development of new PD treatments.
"While industry plays a vital role in shepherding new therapeutics through the development process toward clinical trials and patients, competitive pressures and tough allocation decisions too often get in the way of making the kinds of 'big bets' necessary for breakthrough developments" said Katie Hood, CEO of The Michael J. Fox Foundation. "By funding industry partners directly, TDI seeks to advance promising treatments that might otherwise get stuck at the pre-clinical stage. Our capital may be comparatively modest, but it can serve as a 'carrot' to leverage companies expertise and infrastructure and speed the development of therapeutics that could have an immense impact on patients' quality of life."
While the Foundation has funded industry researchers since its inception, the Therapeutics Development Initiative was launched in 2006 as part of a larger initiative to capture the attention and imagination of company decision-makers and encourage them to allocate resources to Parkinson's projects. To date, of the approximately $21 million the Foundation has committed in total funding to industry, almost a third (nearly $8 million) has gone to 14 projects under TDI. The current round of awardees will focus on developing and optimizing new treatments targeting alpha-synuclein toxicity; chronic inflammation; trophic factors; and mitochondrial dysfunction.
Christine Bulawa, PhD, of FoldRx Pharmaceuticals Inc., will work to develop a disease-modifying drug that could block the toxicity associated with clumping of the protein alpha-synuclein, a hallmark of PD pathology. Dr. BulawaВЎ's team has identified chemical compounds that protect neurons from alpha-synuclein toxicity and will now work with the compounds in a rodent model of Parkinson's. The researchers hope to identify promising small molecules that, with further optimization, can be developed into drug candidates to be tested in PD patients in clinical trials.
Chronic inflammation plays a role in the death of the dopamine-producing neurons that are lost in Parkinson's disease. Patrick Flood, PhD, of TheraLogics, Inc., and his group will test compounds that specifically target the inflammatory pathway in a PD animal model to determine whether certain drugs can protect against this neuronal loss. The team will assess whether blocking inflammation reverses destruction of dopamine-producing neurons, and actually leads to regeneration of these cells within the brain, to determine the most effective dose and timing for therapeutic intervention.
The blood-brain barrier is a thin layer of tightly packed cells separating the central nervous system from the body's bloodstream. This layer is crucial to protecting the brain from foreign substances, but also poses a major challenge in delivering potentially therapeutic treatments via orally administered drugs. Antonia Orsi, PhD, and her team from Phytopharm have developed a small orally active molecule that crosses the blood-brain barrier. In vivo and in vitro, the molecule increases levels of trophic factors, specialized proteins that potently promote survival of neurons. The team has already demonstrated that the compound can increase the number of dopaminergic neurons in a mouse model of PD. The goal now is to gain greater understanding of the neurorestorative properties of this compound in mice and, if successful, test the compound in a primate model of Parkinson's disease.
Mitochondria are the "energy factories" of body cells. It is believed that mitochondrial function is decreased in people with Parkinson's disease and that mitochondrial toxins induce parkinsonian symptoms in animal models. Rebecca Pruss, PhD, and her colleagues at Trophos are developing unique compounds that improve mitochondrial function and that are currently being evaluated in patients for the treatment of ALS and diabetic neuropathy. Dr. Pruss will test whether these compounds are neuroprotective in an animal model of Parkinson's disease.
Grant abstracts and researcher bios for all projects are available on the Foundation's Web site, michaeljfox/.
About The Michael J. Fox Foundation
The Michael J. Fox Foundation for Parkinson's Research is dedicated to ensuring the development of a cure for Parkinson's disease through an aggressively funded research agenda. To date, the Foundation has funded more than $115 million in research directly or through partnerships.
Source: Dana Barde
The Michael J. Fox Foundation for Parkinson's Research
"While industry plays a vital role in shepherding new therapeutics through the development process toward clinical trials and patients, competitive pressures and tough allocation decisions too often get in the way of making the kinds of 'big bets' necessary for breakthrough developments" said Katie Hood, CEO of The Michael J. Fox Foundation. "By funding industry partners directly, TDI seeks to advance promising treatments that might otherwise get stuck at the pre-clinical stage. Our capital may be comparatively modest, but it can serve as a 'carrot' to leverage companies expertise and infrastructure and speed the development of therapeutics that could have an immense impact on patients' quality of life."
While the Foundation has funded industry researchers since its inception, the Therapeutics Development Initiative was launched in 2006 as part of a larger initiative to capture the attention and imagination of company decision-makers and encourage them to allocate resources to Parkinson's projects. To date, of the approximately $21 million the Foundation has committed in total funding to industry, almost a third (nearly $8 million) has gone to 14 projects under TDI. The current round of awardees will focus on developing and optimizing new treatments targeting alpha-synuclein toxicity; chronic inflammation; trophic factors; and mitochondrial dysfunction.
Christine Bulawa, PhD, of FoldRx Pharmaceuticals Inc., will work to develop a disease-modifying drug that could block the toxicity associated with clumping of the protein alpha-synuclein, a hallmark of PD pathology. Dr. BulawaВЎ's team has identified chemical compounds that protect neurons from alpha-synuclein toxicity and will now work with the compounds in a rodent model of Parkinson's. The researchers hope to identify promising small molecules that, with further optimization, can be developed into drug candidates to be tested in PD patients in clinical trials.
Chronic inflammation plays a role in the death of the dopamine-producing neurons that are lost in Parkinson's disease. Patrick Flood, PhD, of TheraLogics, Inc., and his group will test compounds that specifically target the inflammatory pathway in a PD animal model to determine whether certain drugs can protect against this neuronal loss. The team will assess whether blocking inflammation reverses destruction of dopamine-producing neurons, and actually leads to regeneration of these cells within the brain, to determine the most effective dose and timing for therapeutic intervention.
The blood-brain barrier is a thin layer of tightly packed cells separating the central nervous system from the body's bloodstream. This layer is crucial to protecting the brain from foreign substances, but also poses a major challenge in delivering potentially therapeutic treatments via orally administered drugs. Antonia Orsi, PhD, and her team from Phytopharm have developed a small orally active molecule that crosses the blood-brain barrier. In vivo and in vitro, the molecule increases levels of trophic factors, specialized proteins that potently promote survival of neurons. The team has already demonstrated that the compound can increase the number of dopaminergic neurons in a mouse model of PD. The goal now is to gain greater understanding of the neurorestorative properties of this compound in mice and, if successful, test the compound in a primate model of Parkinson's disease.
Mitochondria are the "energy factories" of body cells. It is believed that mitochondrial function is decreased in people with Parkinson's disease and that mitochondrial toxins induce parkinsonian symptoms in animal models. Rebecca Pruss, PhD, and her colleagues at Trophos are developing unique compounds that improve mitochondrial function and that are currently being evaluated in patients for the treatment of ALS and diabetic neuropathy. Dr. Pruss will test whether these compounds are neuroprotective in an animal model of Parkinson's disease.
Grant abstracts and researcher bios for all projects are available on the Foundation's Web site, michaeljfox/.
About The Michael J. Fox Foundation
The Michael J. Fox Foundation for Parkinson's Research is dedicated to ensuring the development of a cure for Parkinson's disease through an aggressively funded research agenda. To date, the Foundation has funded more than $115 million in research directly or through partnerships.
Source: Dana Barde
The Michael J. Fox Foundation for Parkinson's Research
Sea Lamprey Research Sheds Light On How Stress Hormones Evolved
Michigan State University researchers are the first to identify a stress hormone in the sea lamprey, using the 500 million-year-old species as a model to understand the evolution of the endocrine system.
Corticosteroid hormones control stress response in animals with backbones, including humans. While scientists have learned quite a bit about these so-called stress hormones in most modern animals, little was known about the hormones' earliest forms in prehistoric creatures such as lamprey.
"By identifying 11-deoxycortisol as a stress hormone in lamprey, it allows us to better understand how the endocrine system in vertebrates evolved into the complex systems we see in humans today," explained Weiming Li, professor of fisheries and wildlife who helped lead the project. Li also is a member of the Michigan Agricultural Experiment Station.
The hormone is the only one the researchers have found so far in the lamprey and Li said the researchers are hypothesizing that it may be the only corticosteroid hormone in the lamprey. Humans, in contrast, have more than 30 corticosteroid hormones.
The research is published in the Proceedings of the National Academy of Sciences.
Native to the Atlantic Ocean, sea lampreys are invasive species in the Great Lakes. They stay alive by attaching themselves to other fish, such as salmon and trout, and then suck out the fish's body fluids. One sea lamprey can kill 40 or more pounds of fish. The U.S. and Canadian governments spend about $10 million to $15 million per year on lamprey control.
Li led the groundbreaking research that identified the pheromone male lampreys use to attract females to their nests to mate. He has made a synthetic version of the pheromone and is testing its effectiveness as a control for the destructive parasites. While the identification of 11-deoxycortisol likely won't directly help his lamprey control work, Li said this new discovery will bolster understanding on how the fish has successfully adapted since the Paleozoic Era.
"Most jawless animals similar to the lamprey didn't survive into the modern era, so they're not available for us to use as we strive to learn more about how human systems developed," Li said. "The sea lamprey, a survivor, gives us a snapshot of what happened as vertebrates evolved into the animals we know today."
Li and his team plan to continue studying the lamprey, possibly investigating how the endocrine and other body systems became more integrated and successfully adapted to the changing environment.
Other paper authors are David Close, former doctoral student in Li's lab, now at the University of British Columbia; Sang-Seon Yun, former post-doctoral researcher now at Kunsan National University in Korea; Stephen McCormick, of U.S. Geological Survey Conte Anadromous Fish Research Center; and Andrews Wildbill, MSU undergraduate student.
The research is supported by the National Science Foundation, the Confederated Tribes of the Umatilla Indian Reservation, the Bonneville Power Administration, the Great Lakes Fishery Commission, the MSU College of Agriculture and Natural Resources, and the National Institute of Mental Health.
Li's research also is supported by the Michigan Agricultural Experiment Station.
Source:
Jamie DePolo
Michigan State University
Corticosteroid hormones control stress response in animals with backbones, including humans. While scientists have learned quite a bit about these so-called stress hormones in most modern animals, little was known about the hormones' earliest forms in prehistoric creatures such as lamprey.
"By identifying 11-deoxycortisol as a stress hormone in lamprey, it allows us to better understand how the endocrine system in vertebrates evolved into the complex systems we see in humans today," explained Weiming Li, professor of fisheries and wildlife who helped lead the project. Li also is a member of the Michigan Agricultural Experiment Station.
The hormone is the only one the researchers have found so far in the lamprey and Li said the researchers are hypothesizing that it may be the only corticosteroid hormone in the lamprey. Humans, in contrast, have more than 30 corticosteroid hormones.
The research is published in the Proceedings of the National Academy of Sciences.
Native to the Atlantic Ocean, sea lampreys are invasive species in the Great Lakes. They stay alive by attaching themselves to other fish, such as salmon and trout, and then suck out the fish's body fluids. One sea lamprey can kill 40 or more pounds of fish. The U.S. and Canadian governments spend about $10 million to $15 million per year on lamprey control.
Li led the groundbreaking research that identified the pheromone male lampreys use to attract females to their nests to mate. He has made a synthetic version of the pheromone and is testing its effectiveness as a control for the destructive parasites. While the identification of 11-deoxycortisol likely won't directly help his lamprey control work, Li said this new discovery will bolster understanding on how the fish has successfully adapted since the Paleozoic Era.
"Most jawless animals similar to the lamprey didn't survive into the modern era, so they're not available for us to use as we strive to learn more about how human systems developed," Li said. "The sea lamprey, a survivor, gives us a snapshot of what happened as vertebrates evolved into the animals we know today."
Li and his team plan to continue studying the lamprey, possibly investigating how the endocrine and other body systems became more integrated and successfully adapted to the changing environment.
Other paper authors are David Close, former doctoral student in Li's lab, now at the University of British Columbia; Sang-Seon Yun, former post-doctoral researcher now at Kunsan National University in Korea; Stephen McCormick, of U.S. Geological Survey Conte Anadromous Fish Research Center; and Andrews Wildbill, MSU undergraduate student.
The research is supported by the National Science Foundation, the Confederated Tribes of the Umatilla Indian Reservation, the Bonneville Power Administration, the Great Lakes Fishery Commission, the MSU College of Agriculture and Natural Resources, and the National Institute of Mental Health.
Li's research also is supported by the Michigan Agricultural Experiment Station.
Source:
Jamie DePolo
Michigan State University
Discovering Diversity In The Tropics
William Gerwick is quite happy to tell you about his scientific expeditions to Fiji. He can expound on the amazing explorations his group has led to Madagascar, Papua New Guinea, and other destinations in search of exotic molecules that could one day lead to new treatments for human diseases.
But broach the subject of Panama and it's time to get comfortable in your seat. The Scripps Institution of Oceanography at UC San Diego professor's palpable enthusiasm is rooted in his laboratory's multifaceted drug discovery and training program that ranges from the Central American country's rain forest jungles to its underwater world.
Just mention a potential drug called "Coibamide" to uncork Gerwick's excitement. The island of Coiba off Panama's Pacific coast was free of human inhabitants for hundreds of years, save for the pirates that occasionally encamped there. A prison was housed in one section of the island for about a century until it closed in 2004. The rest of the island remained an undisturbed wilderness.
It was here, while exploring Coiba's shallow waters in June 2004 that Kerry McPhail, then a postdoctoral scientist working with Gerwick, discovered a cyanobacterium, a primitive photosynthetic organism with features unlike any previously encountered by scientists. Laboratory analysis and testing revealed that the organism naturally produces a potent cancer-fighting compound.
"To the full extent that we can tell, the compound is working by a novel mechanism to kill cancer cells," said Gerwick, a scientist with the Scripps Center for Marine Biotechnology and Biomedicine and the UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences. "It has a very unusual molecular structure unlike any we've seen before."
Undisturbed locations such as Coiba are rare and disappearing around the world. Gerwick's research in Panama is helping to counteract that slide through a unique program that blends drug discovery from the natural world, the conservation of biodiverse sources, training for young scientists, and scientific as well as economic development in economically disadvantaged countries.
The International Cooperative Biodiversity Groups (ICBG) program, the brainchild of Josh Rosenthal and others at the Bethesda, Maryland-based Fogarty International Center, oversees a handful of programs around the world and regards Gerwick's Panamanian research center as a model of success.
"Through ICBG, we are involved in an integrative program of joint discovery that engages the host country, not only in the final rewards of drug discovery, but in the rewards that come from being engaged in the process," said Gerwick.
Hidden Cures Await
When the Panamanian government began moving prisoners off Coiba in 2004 with the idea of closing the prison facility, the picturesque island was initially slated for development as a tourist attraction because of its undisturbed beauty. Gerwick's group and others led counterefforts aimed at preserving the island's rich diversity. Their push helped lead to Coiba's designation as a Panamanian national park and UNESCO (United Nations Educational, Scientific, and Cultural Organization) World Heritage Site, protected by law from commercial development.
Panama's location as a bridge between North and South America and a natural thoroughfare for a diverse assortment of migratory land and water species gives it a unique appeal to scientists. Flora and fauna on the Caribbean side of the isthmus are vastly different from the Pacific side.
"Despite the fact that we all know Panama because of its famous canal, I have been struck by how remote and primitive and relatively unspoiled large stretches of Panama remain today," said Gerwick.
Lena Gerwick, a biologist and fellow Scripps researcher, believes that in addition to cancer, the Panamanian environment could be holding biomedically promising sources for treating malaria and tropical diseases such as Chagas' disease, leishmaniasis, and dengue fever. Such diseases have been labeled as "neglected" afflictions because they impact millions of people but have been largely forgotten by the developed world and pharmaceutical companies due to the anticipation of poor returns, and thus few resources are made available to find new treatments for these diseases.
"If you have a lot of diverse organisms, as you find in the tropics, they produce a large diversity of natural products," said Lena Gerwick, a co-principal investigator for the Gerwick lab's ICBG-sponsored program. "There is high competition for every species to carve out its own niche and survive. With that you find a lot of compounds used in defense and other diverse activities. Within this biodiversity might be the next cure for malaria or the next cure for tuberculosis, so there is a great need to conserve it."
Marcy Balunas, a joint Scripps postdoctoral researcher and Smithsonian Tropical Research Institute (STRI) postdoctoral fellow, attributes the country's rich diversity of organisms to its wealth of geological features, including flatlands, mountainous regions, and distinct coastlines.
"It's one of the biodiversity hotspots in the world," said Balunas, who was born and raised in the United States but is now a full-time resident of Panama City. "It's amazing."
Among her assortment of duties, Balunas coordinates field expeditions off remote islands and lush mangroves, and conducts analyses inside laboratories at Panama's Institute of Advanced Scientific Investigations and High Technology Services (INDICASAT).
She also collaborates with other scientists in Panama such as botanist Alicia IbaГ±ez, a STRI scientist and conservationist from Spain, who is developing a botanical guide to Coiba as well as working on a management plan for the island.
Balunas also spends much of her days in Panama mentoring students. On top of its environmental biodiversity efforts, William Gerwick's group in Panama has added a component that fosters human diversity. Working through the CREO (Conservation, Research, and Educational Opportunities) program, ultimately funded through the National Institutes of Health (NIH), William Gerwick and Balunas have hosted a handful of American minority students at its Panamanian base, where they live and train alongside researchers such as Balunas, IbaГ±ez, and other scientists.
"Panama is a great place to live and to work," said Balunas. "It's given me some really unique opportunities as a scientist but also as a person, living in another country, learning Spanish and becoming part of the Panamanian culture as a U.S. citizen abroad."
Samples extracted from the wilderness are analyzed in Panamanian labs and sometimes shipped to Scripps Oceanography's La Jolla campus for further analysis. Investigations include bioassays, a technique that determines a substance's biological activity (for example, against cancer, malaria, and other diseases) and its potency, DNA analysis for taxonomic identification, and investigations using instruments such as mass and NMR (nuclear magnetic resonance) spectrometers, which can image the structure of organisms down to the molecular level.
Each field expedition yields numerous samples that produce hundreds of compounds that are examined and evaluated. Some candidate compounds have been seen before, while others are new but have nothing to offer for treating diseases. But every so often a candidate compound emerges such as Coibamide-now in preclinical evaluation-revealing a novel structure and amazing potency against a certain disease.
"Working in Panama is a great adventure," said Balunas. "It's an adventure every day. I have adventures in the city and I have them during hiking trips and during marine collection trips. We go to places that are amazingly wonderful-some of which have been protected by the Panamanian government and therefore have really stayed in a pristine condition-so it's really an amazing experience."
Science, Students, And Society
Gerwick's Panama program was recently awarded nearly $5 million by ICBG for its continuation. It is one of eight active ICBG initiatives based elsewhere in Costa Rica, Indonesia, Fiji, Madagascar, Vietnam, Papua New Guinea, and the Philippines.
ICBG was launched in 1992 with a mix of enthusiasm about naturally produced pharmaceutical drugs and a concern that access to many novel compounds would be rapidly disappearing as more and more organisms and habitats around the world fell to extinction. The program is funded by a mix of organizations, including the NIH, National Science Foundation, U.S. Department of Agriculture, Department of Energy, and administered through the Fogarty International Center of the NIH.
"There was a realization in the early '90s that we could combine research-capacity building and benefit sharing in developing countries with natural products drug discovery-and at the same time support conservation-for a win-win-win situation," said Josh Rosenthal, ICBG's program manager.
Cumulatively, researchers across the ICBG's global network have identified more than 1,000 compounds of biological interest -about one-third new to science-and provided training for more than 4,000 scientists. The researchers have generated hundreds of scientific publications.
Beyond core scientific achievements, ICBG's successes have been born in the partnerships forged with governments in developing countries and the resulting scientific infrastructures that have been shaped. The ICBG program not only facilitates short-term needs such as access to remote sites and permits for expedition collections, but also engenders an ongoing trust with the country's scientific community. In Panama this is built upon a long-lasting partnership with STRI and affirmed with the successes of ICBG Panama.
Each newly discovered compound and drug candidate and each newly trained scientist and student pulls the science-government relationship further away from the days of yesteryear when so-called "pirate bioprospectors" would fly into a developing country, pillage its wilderness for biological sources of profitable drugs, and flee without involvement or benefit of the government or the host country's research community.
"ICBG attempts to develop a structure for collaborative research and sharing the benefits of that research with developing country organizations," said Rosenthal.
Rosenthal praises the Gerwicks for establishing a program that integrates all of ICBG's main objectives.
"Most of the ICBG programs have had some success in helping national governments to conserve biological diversity and develop approaches to share that support science, laying the groundwork for future generations of scientists," said Rosenthal, "but the Panama group put it all together in a very successful and innovative way, and demonstrated that this complicated program is compatible with first-class discovery science."
Source
University of California, San Diego
But broach the subject of Panama and it's time to get comfortable in your seat. The Scripps Institution of Oceanography at UC San Diego professor's palpable enthusiasm is rooted in his laboratory's multifaceted drug discovery and training program that ranges from the Central American country's rain forest jungles to its underwater world.
Just mention a potential drug called "Coibamide" to uncork Gerwick's excitement. The island of Coiba off Panama's Pacific coast was free of human inhabitants for hundreds of years, save for the pirates that occasionally encamped there. A prison was housed in one section of the island for about a century until it closed in 2004. The rest of the island remained an undisturbed wilderness.
It was here, while exploring Coiba's shallow waters in June 2004 that Kerry McPhail, then a postdoctoral scientist working with Gerwick, discovered a cyanobacterium, a primitive photosynthetic organism with features unlike any previously encountered by scientists. Laboratory analysis and testing revealed that the organism naturally produces a potent cancer-fighting compound.
"To the full extent that we can tell, the compound is working by a novel mechanism to kill cancer cells," said Gerwick, a scientist with the Scripps Center for Marine Biotechnology and Biomedicine and the UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences. "It has a very unusual molecular structure unlike any we've seen before."
Undisturbed locations such as Coiba are rare and disappearing around the world. Gerwick's research in Panama is helping to counteract that slide through a unique program that blends drug discovery from the natural world, the conservation of biodiverse sources, training for young scientists, and scientific as well as economic development in economically disadvantaged countries.
The International Cooperative Biodiversity Groups (ICBG) program, the brainchild of Josh Rosenthal and others at the Bethesda, Maryland-based Fogarty International Center, oversees a handful of programs around the world and regards Gerwick's Panamanian research center as a model of success.
"Through ICBG, we are involved in an integrative program of joint discovery that engages the host country, not only in the final rewards of drug discovery, but in the rewards that come from being engaged in the process," said Gerwick.
Hidden Cures Await
When the Panamanian government began moving prisoners off Coiba in 2004 with the idea of closing the prison facility, the picturesque island was initially slated for development as a tourist attraction because of its undisturbed beauty. Gerwick's group and others led counterefforts aimed at preserving the island's rich diversity. Their push helped lead to Coiba's designation as a Panamanian national park and UNESCO (United Nations Educational, Scientific, and Cultural Organization) World Heritage Site, protected by law from commercial development.
Panama's location as a bridge between North and South America and a natural thoroughfare for a diverse assortment of migratory land and water species gives it a unique appeal to scientists. Flora and fauna on the Caribbean side of the isthmus are vastly different from the Pacific side.
"Despite the fact that we all know Panama because of its famous canal, I have been struck by how remote and primitive and relatively unspoiled large stretches of Panama remain today," said Gerwick.
Lena Gerwick, a biologist and fellow Scripps researcher, believes that in addition to cancer, the Panamanian environment could be holding biomedically promising sources for treating malaria and tropical diseases such as Chagas' disease, leishmaniasis, and dengue fever. Such diseases have been labeled as "neglected" afflictions because they impact millions of people but have been largely forgotten by the developed world and pharmaceutical companies due to the anticipation of poor returns, and thus few resources are made available to find new treatments for these diseases.
"If you have a lot of diverse organisms, as you find in the tropics, they produce a large diversity of natural products," said Lena Gerwick, a co-principal investigator for the Gerwick lab's ICBG-sponsored program. "There is high competition for every species to carve out its own niche and survive. With that you find a lot of compounds used in defense and other diverse activities. Within this biodiversity might be the next cure for malaria or the next cure for tuberculosis, so there is a great need to conserve it."
Marcy Balunas, a joint Scripps postdoctoral researcher and Smithsonian Tropical Research Institute (STRI) postdoctoral fellow, attributes the country's rich diversity of organisms to its wealth of geological features, including flatlands, mountainous regions, and distinct coastlines.
"It's one of the biodiversity hotspots in the world," said Balunas, who was born and raised in the United States but is now a full-time resident of Panama City. "It's amazing."
Among her assortment of duties, Balunas coordinates field expeditions off remote islands and lush mangroves, and conducts analyses inside laboratories at Panama's Institute of Advanced Scientific Investigations and High Technology Services (INDICASAT).
She also collaborates with other scientists in Panama such as botanist Alicia IbaГ±ez, a STRI scientist and conservationist from Spain, who is developing a botanical guide to Coiba as well as working on a management plan for the island.
Balunas also spends much of her days in Panama mentoring students. On top of its environmental biodiversity efforts, William Gerwick's group in Panama has added a component that fosters human diversity. Working through the CREO (Conservation, Research, and Educational Opportunities) program, ultimately funded through the National Institutes of Health (NIH), William Gerwick and Balunas have hosted a handful of American minority students at its Panamanian base, where they live and train alongside researchers such as Balunas, IbaГ±ez, and other scientists.
"Panama is a great place to live and to work," said Balunas. "It's given me some really unique opportunities as a scientist but also as a person, living in another country, learning Spanish and becoming part of the Panamanian culture as a U.S. citizen abroad."
Samples extracted from the wilderness are analyzed in Panamanian labs and sometimes shipped to Scripps Oceanography's La Jolla campus for further analysis. Investigations include bioassays, a technique that determines a substance's biological activity (for example, against cancer, malaria, and other diseases) and its potency, DNA analysis for taxonomic identification, and investigations using instruments such as mass and NMR (nuclear magnetic resonance) spectrometers, which can image the structure of organisms down to the molecular level.
Each field expedition yields numerous samples that produce hundreds of compounds that are examined and evaluated. Some candidate compounds have been seen before, while others are new but have nothing to offer for treating diseases. But every so often a candidate compound emerges such as Coibamide-now in preclinical evaluation-revealing a novel structure and amazing potency against a certain disease.
"Working in Panama is a great adventure," said Balunas. "It's an adventure every day. I have adventures in the city and I have them during hiking trips and during marine collection trips. We go to places that are amazingly wonderful-some of which have been protected by the Panamanian government and therefore have really stayed in a pristine condition-so it's really an amazing experience."
Science, Students, And Society
Gerwick's Panama program was recently awarded nearly $5 million by ICBG for its continuation. It is one of eight active ICBG initiatives based elsewhere in Costa Rica, Indonesia, Fiji, Madagascar, Vietnam, Papua New Guinea, and the Philippines.
ICBG was launched in 1992 with a mix of enthusiasm about naturally produced pharmaceutical drugs and a concern that access to many novel compounds would be rapidly disappearing as more and more organisms and habitats around the world fell to extinction. The program is funded by a mix of organizations, including the NIH, National Science Foundation, U.S. Department of Agriculture, Department of Energy, and administered through the Fogarty International Center of the NIH.
"There was a realization in the early '90s that we could combine research-capacity building and benefit sharing in developing countries with natural products drug discovery-and at the same time support conservation-for a win-win-win situation," said Josh Rosenthal, ICBG's program manager.
Cumulatively, researchers across the ICBG's global network have identified more than 1,000 compounds of biological interest -about one-third new to science-and provided training for more than 4,000 scientists. The researchers have generated hundreds of scientific publications.
Beyond core scientific achievements, ICBG's successes have been born in the partnerships forged with governments in developing countries and the resulting scientific infrastructures that have been shaped. The ICBG program not only facilitates short-term needs such as access to remote sites and permits for expedition collections, but also engenders an ongoing trust with the country's scientific community. In Panama this is built upon a long-lasting partnership with STRI and affirmed with the successes of ICBG Panama.
Each newly discovered compound and drug candidate and each newly trained scientist and student pulls the science-government relationship further away from the days of yesteryear when so-called "pirate bioprospectors" would fly into a developing country, pillage its wilderness for biological sources of profitable drugs, and flee without involvement or benefit of the government or the host country's research community.
"ICBG attempts to develop a structure for collaborative research and sharing the benefits of that research with developing country organizations," said Rosenthal.
Rosenthal praises the Gerwicks for establishing a program that integrates all of ICBG's main objectives.
"Most of the ICBG programs have had some success in helping national governments to conserve biological diversity and develop approaches to share that support science, laying the groundwork for future generations of scientists," said Rosenthal, "but the Panama group put it all together in a very successful and innovative way, and demonstrated that this complicated program is compatible with first-class discovery science."
Source
University of California, San Diego
Secrets Of Scorpion Venom Revealed By Genetic Analysis
Transcriptomic tests have uncovered the protein composition of venom from the Scorpiops jendeki scorpion. Researchers writing in the open access journal BMC Genomics have carried out the first ever venom analysis in this arachnid, and discovered nine novel poison molecules, never before seen in any scorpion species.
Yibao Ma worked with a team of researchers from Wuhan University, China, to study the sting of S. jendeki, a member of the family Euscorpiidae, which covers Europe, Asia, Africa, and America. He said, "Our work greatly expands the current knowledge of scorpion venoms. We found ten known types and nine novel venom peptides and proteins. These molecules provide a rich, hitherto-unexplored resource for drug development as well as clues into the evolution of the scorpion venom arsenal".
To humans, the sting of scorpions from the Euscorpiidae family tend to be quite mild - about as painful as a mosquito bite. S. jendeki venom has never been studied before. The researchers found that it contains ten known poisons, with markedly diverse modes of action and nine new types of venom peptide, whose biological effects are yet to be determined. The scorpion itself, however, is considered harmless - probably because it cannot deliver enough of the poison to cause any damage to a healthy human. Interestingly, neurotoxins, which are major poisons in the venom of another scorpion species that can kill humans, were not found in the S. jendeki venom.
Ma concludes, "Many types of venom peptides and proteins have been obtained from diverse scorpion species. Some are widely distributed among scorpions from different families, while others, like some of those discovered in our study, appear to be restricted to particular scorpion lineages. The presence of these common and uncommon venom molecules among different lineages reflects the dynamic evolutionary process of the scorpion venom arsenal".
Notes:
Transcriptome analysis of the venom gland of the scorpion Scorpiops jendeki: implication for the evolution of the scorpion venom arsenal
Yibao Ma, Ruiming Zhao, Yawen He, Songryong Li, Jun Liu, Yingliang Wu, Zhijian Cao and Wenxin Li. BMC Genomics (in press) biomedcentral/bmcgenomics/
Contact: Graeme Baldwin
BioMed Central
Yibao Ma worked with a team of researchers from Wuhan University, China, to study the sting of S. jendeki, a member of the family Euscorpiidae, which covers Europe, Asia, Africa, and America. He said, "Our work greatly expands the current knowledge of scorpion venoms. We found ten known types and nine novel venom peptides and proteins. These molecules provide a rich, hitherto-unexplored resource for drug development as well as clues into the evolution of the scorpion venom arsenal".
To humans, the sting of scorpions from the Euscorpiidae family tend to be quite mild - about as painful as a mosquito bite. S. jendeki venom has never been studied before. The researchers found that it contains ten known poisons, with markedly diverse modes of action and nine new types of venom peptide, whose biological effects are yet to be determined. The scorpion itself, however, is considered harmless - probably because it cannot deliver enough of the poison to cause any damage to a healthy human. Interestingly, neurotoxins, which are major poisons in the venom of another scorpion species that can kill humans, were not found in the S. jendeki venom.
Ma concludes, "Many types of venom peptides and proteins have been obtained from diverse scorpion species. Some are widely distributed among scorpions from different families, while others, like some of those discovered in our study, appear to be restricted to particular scorpion lineages. The presence of these common and uncommon venom molecules among different lineages reflects the dynamic evolutionary process of the scorpion venom arsenal".
Notes:
Transcriptome analysis of the venom gland of the scorpion Scorpiops jendeki: implication for the evolution of the scorpion venom arsenal
Yibao Ma, Ruiming Zhao, Yawen He, Songryong Li, Jun Liu, Yingliang Wu, Zhijian Cao and Wenxin Li. BMC Genomics (in press) biomedcentral/bmcgenomics/
Contact: Graeme Baldwin
BioMed Central
MGH Researchers Confirm That Bone Marrow Restores Fertility In Female Mice
A new study from Massachusetts General Hospital (MGH) researchers confirms that female mice that receive bone marrow transplantation after fertility-destroying chemotherapy can go on to have successful pregnancies throughout their normal reproductive life. The report in the August 1 Journal of Clinical Oncology verifies that donor marrow can restore fertility in female mice through an as-yet unidentified mechanism. While donor-derived egg cells or oocytes were observed in the ovaries of marrow recipients, all pups born were from the recipients' own eggs.
"Consistent with our past work, cells derived from the donor bone marrow are getting into the ovaries and developing into immature oocytes," says Jonathan Tilly, PhD, director of the Vincent Center for Reproductive Biology at MGH, the study's senior author. "Although these oocytes derived from marrow cells don't appear competent, at least thus far, to make fertilizable eggs, marrow does contribute something that allows a resumption of fertility in female mice sterilized by chemotherapy."
In a 2005 paper published in the journal Cell, Tilly's group found that the ovaries of female mice that had received bone marrow or blood cell transplants after fertility-destroying doses of chemotherapy appeared normal and contained immature oocytes expressing a marker protein indicating they came from the donor cells. This report followed a 2004 Nature paper, also from Tilly's team, reporting that female mice continued producing eggs well into adulthood, in contrast to the long-held belief that female mammals are born with a finite supply of eggs that is depleted throughout life. Both those papers have been extremely controversial, and the current study was designed to follow up the 2005 paper and to address criticisms raised by other researchers.
In the current study, adult female mice treated with infertility-inducing chemotherapy received bone marrow transplants from non-treated, healthy adult females either one week or two months after chemotherapy. The mice were then housed with healthy adult males and followed for 7 months, a time period in which a group of control females achieved at least five successful pregnancies each. Both the males and the donor females were black in coat color while the recipient females were white-coated. As a result, the coat color of any pups would indicate the source of egg cells used to make the offspring, with tan coats signifying eggs from the recipients and black coats indicating that the eggs had come from marrow donors.
Of the 10 females that received bone marrow transplants one week after chemotherapy, all but one achieved several successful pregnancies during the study period. One gave birth to four litters, one gave birth to five litters, and seven gave birth to six litters of pups. All pups were offspring of the recipients. In a comparison group of 13 females that did not receive marrow after chemotherapy, 10 did become pregnant, but none delivered more than three litters.
Additional experiments indicated that mice receiving transplants one week after chemotherapy had better fertility outcomes than did those transplanted at eight weeks. Similarly, resuming mating sooner after transplantation also improved fertility rates. When chemotherapy doses were increased to levels expected to cause death in half the mice, those that also received bone marrow transplants had improved rates of both survival and long-term fertility.
The coat-color results of the mating trial indicated that the transplanted marrow's contribution to restoring fertility did not involve cells destined to becoming fertilizable eggs. To further investigate this observation, the MGH-Vincent researchers gave chemotherapy-treated females marrow from transgenic females that express a green fluorescent protein (GFP) marker only on germline cells, which are precursor cells involved in producing oocytes. Two months after the transplant, the researchers observed GFP-marked oocytes in immature follicles within recipient ovaries. However, donor-derived oocytes made up less than 2 percent of the total number of oocytes contained within follicles, and no mature follicles contained GFP-marked cells.
Among the published reports raising objections to the previous work of Tilly's group - none of which actually attempted to duplicate those experiments - one theorized that GFP-marked cells observed in recipient ovaries in the 2005 Cell paper might be donor immune cells rather than oocytes. To address that conjecture, the MGH-Vincent team isolated immune cells from normal mice, from the germline-only GFP strain used in their experiments, and from a strain of mice expressing GFP in all cells. Careful analysis confirmed that no immune cells from the germline-only GFP strain contained the marker protein, making it highly unlikely that GFP-labeled cells in the ovaries of females receiving germline-only-labeled marrow were anything other than oocytes. This was further confirmed by experiments showing that isolated immune cells did not express the oocyte-specific marker genes previously used by Tilly's group to identify the marrow-derived oocytes.
Tilly and his colleague note that, since agents that protect fertility most likely would need to be given before chemotherapy to be effective, whatever the donor marrow contributes probably acts by restoring rather than preserving fertility. "Right now, we really don't know exactly what it is in marrow that restores recipient oocyte production and rescues long-term fertility. However, we do know without question that immature oocytes can be generated from cells in adult bone marrow, but they are probably not critical to the fertility rescue observed after the transplants."
Since the 2005 Cell paper, Tilly points out, three studies have been published by other groups showing that, similar to his team's work in females, bone marrow cells from adult male mice or from men can be coaxed to make immature sperm cells, both in lab dishes and after transplantation into the testes. "Clearly, something is going on here regarding the ability of stem cells in bone marrow to produce immature egg and sperm cells, and we need to figure out what it is," he says. Tilly is an associate professor of Obstetrics, Gynecology and Reproductive Biology at Harvard Medical School.
The first author of the study is Ho-Joon Lee, PhD, of the MGH-Vincent Center for Reproductive Biology. Co-authors are Kaisa Selesniemi, PhD, Yuichi Niikura, PhD, and Teruko Niikura, also of MGH-Vincent; and Rachael Klein and David Dombkowski of the MGH Center for Regenerative Medicine. The work was supported by grants from the National Institutes of Health, Sea Breeze Foundation, JM Foundation and Vincent Memorial Research Funds.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine. MGH and Brigham and Women's Hospital are founding members of of Partners HealthCare HealthCare System, a Boston-based integrated health care delivery system.
Massachusetts General Hospital
"Consistent with our past work, cells derived from the donor bone marrow are getting into the ovaries and developing into immature oocytes," says Jonathan Tilly, PhD, director of the Vincent Center for Reproductive Biology at MGH, the study's senior author. "Although these oocytes derived from marrow cells don't appear competent, at least thus far, to make fertilizable eggs, marrow does contribute something that allows a resumption of fertility in female mice sterilized by chemotherapy."
In a 2005 paper published in the journal Cell, Tilly's group found that the ovaries of female mice that had received bone marrow or blood cell transplants after fertility-destroying doses of chemotherapy appeared normal and contained immature oocytes expressing a marker protein indicating they came from the donor cells. This report followed a 2004 Nature paper, also from Tilly's team, reporting that female mice continued producing eggs well into adulthood, in contrast to the long-held belief that female mammals are born with a finite supply of eggs that is depleted throughout life. Both those papers have been extremely controversial, and the current study was designed to follow up the 2005 paper and to address criticisms raised by other researchers.
In the current study, adult female mice treated with infertility-inducing chemotherapy received bone marrow transplants from non-treated, healthy adult females either one week or two months after chemotherapy. The mice were then housed with healthy adult males and followed for 7 months, a time period in which a group of control females achieved at least five successful pregnancies each. Both the males and the donor females were black in coat color while the recipient females were white-coated. As a result, the coat color of any pups would indicate the source of egg cells used to make the offspring, with tan coats signifying eggs from the recipients and black coats indicating that the eggs had come from marrow donors.
Of the 10 females that received bone marrow transplants one week after chemotherapy, all but one achieved several successful pregnancies during the study period. One gave birth to four litters, one gave birth to five litters, and seven gave birth to six litters of pups. All pups were offspring of the recipients. In a comparison group of 13 females that did not receive marrow after chemotherapy, 10 did become pregnant, but none delivered more than three litters.
Additional experiments indicated that mice receiving transplants one week after chemotherapy had better fertility outcomes than did those transplanted at eight weeks. Similarly, resuming mating sooner after transplantation also improved fertility rates. When chemotherapy doses were increased to levels expected to cause death in half the mice, those that also received bone marrow transplants had improved rates of both survival and long-term fertility.
The coat-color results of the mating trial indicated that the transplanted marrow's contribution to restoring fertility did not involve cells destined to becoming fertilizable eggs. To further investigate this observation, the MGH-Vincent researchers gave chemotherapy-treated females marrow from transgenic females that express a green fluorescent protein (GFP) marker only on germline cells, which are precursor cells involved in producing oocytes. Two months after the transplant, the researchers observed GFP-marked oocytes in immature follicles within recipient ovaries. However, donor-derived oocytes made up less than 2 percent of the total number of oocytes contained within follicles, and no mature follicles contained GFP-marked cells.
Among the published reports raising objections to the previous work of Tilly's group - none of which actually attempted to duplicate those experiments - one theorized that GFP-marked cells observed in recipient ovaries in the 2005 Cell paper might be donor immune cells rather than oocytes. To address that conjecture, the MGH-Vincent team isolated immune cells from normal mice, from the germline-only GFP strain used in their experiments, and from a strain of mice expressing GFP in all cells. Careful analysis confirmed that no immune cells from the germline-only GFP strain contained the marker protein, making it highly unlikely that GFP-labeled cells in the ovaries of females receiving germline-only-labeled marrow were anything other than oocytes. This was further confirmed by experiments showing that isolated immune cells did not express the oocyte-specific marker genes previously used by Tilly's group to identify the marrow-derived oocytes.
Tilly and his colleague note that, since agents that protect fertility most likely would need to be given before chemotherapy to be effective, whatever the donor marrow contributes probably acts by restoring rather than preserving fertility. "Right now, we really don't know exactly what it is in marrow that restores recipient oocyte production and rescues long-term fertility. However, we do know without question that immature oocytes can be generated from cells in adult bone marrow, but they are probably not critical to the fertility rescue observed after the transplants."
Since the 2005 Cell paper, Tilly points out, three studies have been published by other groups showing that, similar to his team's work in females, bone marrow cells from adult male mice or from men can be coaxed to make immature sperm cells, both in lab dishes and after transplantation into the testes. "Clearly, something is going on here regarding the ability of stem cells in bone marrow to produce immature egg and sperm cells, and we need to figure out what it is," he says. Tilly is an associate professor of Obstetrics, Gynecology and Reproductive Biology at Harvard Medical School.
The first author of the study is Ho-Joon Lee, PhD, of the MGH-Vincent Center for Reproductive Biology. Co-authors are Kaisa Selesniemi, PhD, Yuichi Niikura, PhD, and Teruko Niikura, also of MGH-Vincent; and Rachael Klein and David Dombkowski of the MGH Center for Regenerative Medicine. The work was supported by grants from the National Institutes of Health, Sea Breeze Foundation, JM Foundation and Vincent Memorial Research Funds.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine. MGH and Brigham and Women's Hospital are founding members of of Partners HealthCare HealthCare System, a Boston-based integrated health care delivery system.
Massachusetts General Hospital
Female Fruit Flies Sick From Mating
Mating can be exhausting. When fruit flies mate, the females' genes are activated to roughly the same extent as when an immune reaction starts. This is shown in a study at Uppsala University that is now appearing in the scientific publication, Journal of Evolutionary Biology.*
Using a combination of behavioral studies and genomic technology, so-called microarrays, researchers at Uppsala University can show how fruit fly females are affected by mating.
"We monitor how genetic expression is impacted by mating and show that the most common process that is affected is the immune defense system," says Ted Morrow at the Department of Ecology and Evolution, Uppsala University.
What's more, the cost of mating turns out to be rather high.
"Previous research findings show that if this cost were not a factor, females would produce 20 percent more offspring," says Ted Morrow.
It is costly for females to mate because competition among males has led to behaviours and adaptations in males that are injurious to females, such as harassment during mating rituals and toxic proteins in their sperm fluid.
"Our results are the strongest evidence that the cost to females is probably tied to the cost of starting an immune reaction. In other words, the males are like a 'sickness' to females," says Ted Morrow.
We can thus conclude the following from the study: the immune defence has developed to combat not only pathogens but also substances produced by males. This lends new meaning to the term 'lovesick.'
Read the full article online at: www3.interscience.wiley/journal/119880717/issue
Article: "Immunogenic males: a genome-wide analysis of reproduction and the cost of mating in Drosophila melanogaster females" P. INNOCENTI & E. H. MORROW Department of Animal Ecology, Evolutionary Biology Center, Uppsala University, Uppsala, Sweden DOI: 10.1111/j.1420-9101.2009.01708.x
Source: Finbar Galligan
Wiley-Blackwell
Using a combination of behavioral studies and genomic technology, so-called microarrays, researchers at Uppsala University can show how fruit fly females are affected by mating.
"We monitor how genetic expression is impacted by mating and show that the most common process that is affected is the immune defense system," says Ted Morrow at the Department of Ecology and Evolution, Uppsala University.
What's more, the cost of mating turns out to be rather high.
"Previous research findings show that if this cost were not a factor, females would produce 20 percent more offspring," says Ted Morrow.
It is costly for females to mate because competition among males has led to behaviours and adaptations in males that are injurious to females, such as harassment during mating rituals and toxic proteins in their sperm fluid.
"Our results are the strongest evidence that the cost to females is probably tied to the cost of starting an immune reaction. In other words, the males are like a 'sickness' to females," says Ted Morrow.
We can thus conclude the following from the study: the immune defence has developed to combat not only pathogens but also substances produced by males. This lends new meaning to the term 'lovesick.'
Read the full article online at: www3.interscience.wiley/journal/119880717/issue
Article: "Immunogenic males: a genome-wide analysis of reproduction and the cost of mating in Drosophila melanogaster females" P. INNOCENTI & E. H. MORROW Department of Animal Ecology, Evolutionary Biology Center, Uppsala University, Uppsala, Sweden DOI: 10.1111/j.1420-9101.2009.01708.x
Source: Finbar Galligan
Wiley-Blackwell
New Light Shed On Memory Loss Following Paradoxical Alzheimer's Finding
Do you remember the seventh song that played on your radio on the way to work yesterday? Most of us don't, thanks to a normal forgetting process that is constantly "cleaning house" - culling inconsequential information from our brains. Researchers at the Buck Institute now believe that this normal memory loss is hyper-activated in Alzheimer's disease (AD) and that this effect is key to the profound memory loss associated with the incurable neurodegenerative disorder.
Last year, this same group of researchers found that they could completely prevent Alzheimer's disease in mice genetically engineered with a human Alzheimer's gene - "Mouzheimer's" - by blocking a single site of cleavage of one molecule, called APP for amyloid precursor protein. Normally, this site on APP is attacked by molecular scissors called caspases, but blocking that process prevented the disease. Now they have studied human brain tissue and found that, just as expected, patients suffering from AD clearly show more of this cleavage process than people of the same age who do not have the disease. However, when they extended their studies to much younger people without Alzheimer's disease, they were astonished to find an apparent paradox: these younger people displayed as much as ten times the amount of the same cleavage event as the AD patients. The researchers now believe they know why.
The Buck Institute study implicates a biochemical "switch" associated with that cleavage of APP, causing AD brains to become stuck in the process of breaking memories, and points to AD as a syndrome affecting the plasticity or malleability of the brain. The study, due to be published in the March 7 issue of the Journal of Alzheimer's Disease, provides new insight into a molecular event resulting in decreased brain plasticity, a central feature of AD.
"Young brains operate like Ferraris - shifting between forward and reverse, making and breaking memories with a facility that surpasses that of older brains, which are less plastic," said Dale Bredesen, MD, Buck Institute faculty member and leader of the research group. "We believe that in aging brains, AD occurs when the 'molecular shifting switch' gets stuck in the reverse position, throwing the balance of making and breaking memories seriously off kilter."
In previous research, lead author Veronica Galvan, PhD, prevented this cleavage in mice genetically engineered to develop the amyloid plaques and deposits associated with AD. These surprising mice had normal memories and showed no signs of brain shrinkage or nerve cell damage, despite the fact that their brains were loaded with the sticky A-beta plaques that are otherwise associated with Alzheimer's disease.
"A-beta is produced throughout the brain throughout life; we believe that it is a normal regulator of the synapses, the connections between neurons," said Galvan, who added that AD, like cancer, is a disease in which imbalanced cell signaling plays an important role.
"The fact that many people develop A-beta plaques yet show no symptoms of AD tells us that the downstream signaling of A-beta - not just A-beta itself - is critical," said Bredesen, "and these pathways can be targeted therapeutically. Simply put, we can restore the balance." Continuing research at the Buck Institute focuses on nerve signaling and efforts to "disconnect" the molecular mechanism that throws memory-making in the reverse direction, as well as understanding mechanisms that support brain cell connections that are crucial to the process of memory making.
AD is an incurable neurodegenerative disease currently affecting 5.1 million Americans. AD results in dementia and memory loss, seriously affecting a person's ability to carry out activities of daily living. AD costs the U.S. $148 billion annually, in addition to untold family suffering.
Joining Bredesen and Galvan as co-authors of the paper, "C-terminal cleavage of the amyloid precursor protein at Asp664: a switch associated with Alzheimer's disease" are Surita Banwait, BA; Junli Zhang, MD; Olivia F. Gorostiza, Marina Ataie, BS; Wei Huang, BS; and Danielle Crippen, BA of the Buck Institute, as well as Edward H. Koo, MD, of the University of California, San Diego, Department of Neuroscience. The work was supported by the Joseph Drown Foundation, The National Institute on Aging, the Bechtel Foundation, and the Alzheimer's Association.
Source: Kris Rebillot
IOS Press
Last year, this same group of researchers found that they could completely prevent Alzheimer's disease in mice genetically engineered with a human Alzheimer's gene - "Mouzheimer's" - by blocking a single site of cleavage of one molecule, called APP for amyloid precursor protein. Normally, this site on APP is attacked by molecular scissors called caspases, but blocking that process prevented the disease. Now they have studied human brain tissue and found that, just as expected, patients suffering from AD clearly show more of this cleavage process than people of the same age who do not have the disease. However, when they extended their studies to much younger people without Alzheimer's disease, they were astonished to find an apparent paradox: these younger people displayed as much as ten times the amount of the same cleavage event as the AD patients. The researchers now believe they know why.
The Buck Institute study implicates a biochemical "switch" associated with that cleavage of APP, causing AD brains to become stuck in the process of breaking memories, and points to AD as a syndrome affecting the plasticity or malleability of the brain. The study, due to be published in the March 7 issue of the Journal of Alzheimer's Disease, provides new insight into a molecular event resulting in decreased brain plasticity, a central feature of AD.
"Young brains operate like Ferraris - shifting between forward and reverse, making and breaking memories with a facility that surpasses that of older brains, which are less plastic," said Dale Bredesen, MD, Buck Institute faculty member and leader of the research group. "We believe that in aging brains, AD occurs when the 'molecular shifting switch' gets stuck in the reverse position, throwing the balance of making and breaking memories seriously off kilter."
In previous research, lead author Veronica Galvan, PhD, prevented this cleavage in mice genetically engineered to develop the amyloid plaques and deposits associated with AD. These surprising mice had normal memories and showed no signs of brain shrinkage or nerve cell damage, despite the fact that their brains were loaded with the sticky A-beta plaques that are otherwise associated with Alzheimer's disease.
"A-beta is produced throughout the brain throughout life; we believe that it is a normal regulator of the synapses, the connections between neurons," said Galvan, who added that AD, like cancer, is a disease in which imbalanced cell signaling plays an important role.
"The fact that many people develop A-beta plaques yet show no symptoms of AD tells us that the downstream signaling of A-beta - not just A-beta itself - is critical," said Bredesen, "and these pathways can be targeted therapeutically. Simply put, we can restore the balance." Continuing research at the Buck Institute focuses on nerve signaling and efforts to "disconnect" the molecular mechanism that throws memory-making in the reverse direction, as well as understanding mechanisms that support brain cell connections that are crucial to the process of memory making.
AD is an incurable neurodegenerative disease currently affecting 5.1 million Americans. AD results in dementia and memory loss, seriously affecting a person's ability to carry out activities of daily living. AD costs the U.S. $148 billion annually, in addition to untold family suffering.
Joining Bredesen and Galvan as co-authors of the paper, "C-terminal cleavage of the amyloid precursor protein at Asp664: a switch associated with Alzheimer's disease" are Surita Banwait, BA; Junli Zhang, MD; Olivia F. Gorostiza, Marina Ataie, BS; Wei Huang, BS; and Danielle Crippen, BA of the Buck Institute, as well as Edward H. Koo, MD, of the University of California, San Diego, Department of Neuroscience. The work was supported by the Joseph Drown Foundation, The National Institute on Aging, the Bechtel Foundation, and the Alzheimer's Association.
Source: Kris Rebillot
IOS Press
Stanford Research Shows New Approach, Old Drug Show Promise Against Hepatitis C
The fight against the liver disease hepatitis C has been at something of an impasse for years, with more than 150 million people currently infected, and traditional antiviral treatments causing nasty side effects and often falling short of a cure. Using a novel technique, medical and engineering researchers at Stanford University have discovered a vulnerable step in the virus' reproduction process that in lab testing could be effectively targeted with an obsolete antihistamine.
The new research was published in the Aug. 31 online version of Nature Biotechnology.
The advance involves two new discoveries. One is that a protein called NS4B is instrumental in binding some of the genetic material, or RNA, and allowing the hepatitis C virus to replicate. The other is that the former anti-itching drug clemizole hydrochloride could hinder that protein, resulting in a tenfold decrease in virus replication with no apparent harm to infected liver-like cells. Because the drug has already been used by people, it is eligible for human testing.
"We're excited about this and we're actively moving forward toward clinical trials," said virology expert Jeffrey Glenn, MD, PhD, associate professor of gastroenterology and hepatology. Glenn is one of two senior authors of the paper. The lead authors are postdoctoral scholars Shirit Einav, MD, in medicine, and Doron Gerber, PhD, in bioengineering.
One of the team's key discoveries used coin-sized microfluidic chips that shrink tabletop biological experiments down to the tiny scale of nanoliters. The paper marks the first time that microfluidic technology has been used to discover a specific drug, said Stephen Quake, PhD, professor of bioengineering and the other senior author of the paper. In fact, the small team was able to screen more than 1,200 drug candidates and find clemizole in just two weeks, Gerber added.
"That's just an example of the power of these microfluidics automation technologies that one or two people working together can actually screen very large numbers of compounds," Quake said. "Big pharmaceutical companies have very large teams and a lot of infrastructure. We're trying to reinvent the whole process."
As director of Stanford's Center for Hepatitis and Liver Tissue Engineering, Glenn focuses his research on trying to expand the number of drug targets for the disease. After using molecular virology techniques to study the NS4B protein, he and Einav began to suspect it could be such a target.
However, like other proteins associated with cellular membranes, NS4B is difficult to purify in large quantities while retaining the protein's natural properties and functionality.
But the advantage of microfludics, Quake said, is that the volumes needed for a successful experiment are quite small, meaning that researchers can get by with very little purified, properly functioning protein. What is insufficient for a benchtop experiment is plenty in microfluidics.
"It lets us redefine the notion of success," Quake said.
Ultimately the researchers discovered that NS4B is an essential player in the virus' process of binding RNA. This is a necessary step in the virus' replication process and, through careful observation, the team determined where it binds and how strongly. That led them to realize which kind of drug - a small-molecule compound - could block that interaction.
Even then, however, the team had to solve another problem, which is the propensity for small-molecule drugs, such as clemizole, to get absorbed into the silicone of the chip itself. Gerber said he worked around that by printing the drug onto the chip directly where the interaction with NS4B would occur. That meant the drug didn't have to move through the chip's plumbing and enough would interact with the protein.
In all, the team found 18 drugs that substantially reduced NS4B binding to its target RNA, but they focused on clemizole because it is already known to be safe in humans. Quake said several of the other compounds were also interesting starting points for developing useful medicines.
Should clemizole prove effective in human trials, Glenn said, it could become an essential component in a new class of multidrug treatments for hepatitis C. Other components could be drugs under development elsewhere that target specific enzymes in the virus. The goal is to improve on the current treatment, a combination of the general antiviral drugs interferon and ribavirin. Those only work about half the time, but have uncomfortable, flulike side effects.
"[Clemizole] does have the potential to be part of a cure, because the idea is not to use it on its own but as a cocktail component," Glenn said.
Similarly it took a cocktail of research expertise to come up with this new assault on the hepatitis C virus, Quake said.
"Neither Jeff's group nor mine could have done this on our own," Quake said. "It was enabled by both of us bringing our pieces to the table: the questions he was asking and the technology we developed."
The other authors of the paper are doctoral student Paul Bryson; postdoctoral scholar Ella Sklan, PhD; research associate Menashe Elazar, PhD, and Sebastian Maerkl, PhD, a former member of Quake's group and now an assistant professor at the Ecole Polytechnique Federale de Lausanne in Switzerland.
The research was funded by a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, the National Institutes of Health, the Fulbright Foundation and an American Liver Foundation Postdoctoral Fellowship Award.
Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at mednews.stanford/.
Source: David Orenstein
Stanford University Medical Center
The new research was published in the Aug. 31 online version of Nature Biotechnology.
The advance involves two new discoveries. One is that a protein called NS4B is instrumental in binding some of the genetic material, or RNA, and allowing the hepatitis C virus to replicate. The other is that the former anti-itching drug clemizole hydrochloride could hinder that protein, resulting in a tenfold decrease in virus replication with no apparent harm to infected liver-like cells. Because the drug has already been used by people, it is eligible for human testing.
"We're excited about this and we're actively moving forward toward clinical trials," said virology expert Jeffrey Glenn, MD, PhD, associate professor of gastroenterology and hepatology. Glenn is one of two senior authors of the paper. The lead authors are postdoctoral scholars Shirit Einav, MD, in medicine, and Doron Gerber, PhD, in bioengineering.
One of the team's key discoveries used coin-sized microfluidic chips that shrink tabletop biological experiments down to the tiny scale of nanoliters. The paper marks the first time that microfluidic technology has been used to discover a specific drug, said Stephen Quake, PhD, professor of bioengineering and the other senior author of the paper. In fact, the small team was able to screen more than 1,200 drug candidates and find clemizole in just two weeks, Gerber added.
"That's just an example of the power of these microfluidics automation technologies that one or two people working together can actually screen very large numbers of compounds," Quake said. "Big pharmaceutical companies have very large teams and a lot of infrastructure. We're trying to reinvent the whole process."
As director of Stanford's Center for Hepatitis and Liver Tissue Engineering, Glenn focuses his research on trying to expand the number of drug targets for the disease. After using molecular virology techniques to study the NS4B protein, he and Einav began to suspect it could be such a target.
However, like other proteins associated with cellular membranes, NS4B is difficult to purify in large quantities while retaining the protein's natural properties and functionality.
But the advantage of microfludics, Quake said, is that the volumes needed for a successful experiment are quite small, meaning that researchers can get by with very little purified, properly functioning protein. What is insufficient for a benchtop experiment is plenty in microfluidics.
"It lets us redefine the notion of success," Quake said.
Ultimately the researchers discovered that NS4B is an essential player in the virus' process of binding RNA. This is a necessary step in the virus' replication process and, through careful observation, the team determined where it binds and how strongly. That led them to realize which kind of drug - a small-molecule compound - could block that interaction.
Even then, however, the team had to solve another problem, which is the propensity for small-molecule drugs, such as clemizole, to get absorbed into the silicone of the chip itself. Gerber said he worked around that by printing the drug onto the chip directly where the interaction with NS4B would occur. That meant the drug didn't have to move through the chip's plumbing and enough would interact with the protein.
In all, the team found 18 drugs that substantially reduced NS4B binding to its target RNA, but they focused on clemizole because it is already known to be safe in humans. Quake said several of the other compounds were also interesting starting points for developing useful medicines.
Should clemizole prove effective in human trials, Glenn said, it could become an essential component in a new class of multidrug treatments for hepatitis C. Other components could be drugs under development elsewhere that target specific enzymes in the virus. The goal is to improve on the current treatment, a combination of the general antiviral drugs interferon and ribavirin. Those only work about half the time, but have uncomfortable, flulike side effects.
"[Clemizole] does have the potential to be part of a cure, because the idea is not to use it on its own but as a cocktail component," Glenn said.
Similarly it took a cocktail of research expertise to come up with this new assault on the hepatitis C virus, Quake said.
"Neither Jeff's group nor mine could have done this on our own," Quake said. "It was enabled by both of us bringing our pieces to the table: the questions he was asking and the technology we developed."
The other authors of the paper are doctoral student Paul Bryson; postdoctoral scholar Ella Sklan, PhD; research associate Menashe Elazar, PhD, and Sebastian Maerkl, PhD, a former member of Quake's group and now an assistant professor at the Ecole Polytechnique Federale de Lausanne in Switzerland.
The research was funded by a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, the National Institutes of Health, the Fulbright Foundation and an American Liver Foundation Postdoctoral Fellowship Award.
Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at mednews.stanford/.
Source: David Orenstein
Stanford University Medical Center
Antibiotic May Be New Stroke Treatment
The antibiotic minocycline may revolutionize the treatment of strokes. A new study, published in the open access journal BMC Neuroscience, describes the safety and therapeutic efficacy of the drug in animal models.
Dr. Cesar V. Borlongan from the University of South Florida, USA worked with a team of researchers to test the treatment in laboratory experiments. He said, "To date, the thrombolytic agent tPA is the only effective drug for acute ischemic stroke; however, only about 2% of ischemic stroke patients benefit from this treatment due to its limited therapeutic window. There is a desperate need to develop additional neuroprotective strategies. This research is an important step in rectifying the treatment issues, presenting a new, more effective treatment for stroke patients".
Every 5 minutes someone in the UK has a stroke and stroke currently accounts for almost 10% of deaths worldwide, claiming more lives than HIV/AIDS. During a stroke, a clot prevents blood flow to parts of the brain, which can have wide ranging short-term and long-term implications. This study recorded the effect of intravenous minocycline in both isolated neurons and animal models after a stroke had been experimentally induced. At low doses it was found to have a neuroprotective effect on neurons by reducing apoptosis of neuronal cells and ameliorating behavioral deficits caused by stroke.
According to Dr. Borlongan, "The safety and therapeutic efficacy of low dose minocycline and its robust neuroprotective effects during acute ischemic stroke make it an appealing drug candidate for stroke therapy. An on-going phase 1 clinical study funded by the National Institutes of Health is exploring the use of intravenous minocycline to treat acute ischemic stroke".
Notes:
Therapeutic targets and limits of minocycline neuroprotection in experimental ischemic stroke
Noriyuki Matsukawa, Takao Yasuhara, Koichi Hara, Lin Xu, Mina Maki, Guolong Yu, Yuji Kaneko, Kosei Ojika, David C Hess and Cesar V Borlongan
BMC Neuroscience (in press)
biomedcentral/bmcneurosci/
Source:
Graeme Baldwin
BioMed Central
Dr. Cesar V. Borlongan from the University of South Florida, USA worked with a team of researchers to test the treatment in laboratory experiments. He said, "To date, the thrombolytic agent tPA is the only effective drug for acute ischemic stroke; however, only about 2% of ischemic stroke patients benefit from this treatment due to its limited therapeutic window. There is a desperate need to develop additional neuroprotective strategies. This research is an important step in rectifying the treatment issues, presenting a new, more effective treatment for stroke patients".
Every 5 minutes someone in the UK has a stroke and stroke currently accounts for almost 10% of deaths worldwide, claiming more lives than HIV/AIDS. During a stroke, a clot prevents blood flow to parts of the brain, which can have wide ranging short-term and long-term implications. This study recorded the effect of intravenous minocycline in both isolated neurons and animal models after a stroke had been experimentally induced. At low doses it was found to have a neuroprotective effect on neurons by reducing apoptosis of neuronal cells and ameliorating behavioral deficits caused by stroke.
According to Dr. Borlongan, "The safety and therapeutic efficacy of low dose minocycline and its robust neuroprotective effects during acute ischemic stroke make it an appealing drug candidate for stroke therapy. An on-going phase 1 clinical study funded by the National Institutes of Health is exploring the use of intravenous minocycline to treat acute ischemic stroke".
Notes:
Therapeutic targets and limits of minocycline neuroprotection in experimental ischemic stroke
Noriyuki Matsukawa, Takao Yasuhara, Koichi Hara, Lin Xu, Mina Maki, Guolong Yu, Yuji Kaneko, Kosei Ojika, David C Hess and Cesar V Borlongan
BMC Neuroscience (in press)
biomedcentral/bmcneurosci/
Source:
Graeme Baldwin
BioMed Central
News From The Journal Of Neuroscience
1. Chromogranins Concentrate Catecholamines
Monica S. Montesinos, J. David Machado, Marcial Camacho, Jesica Diaz, Yezer G. Morales, Diego Alvarez de la Rosa, Emilia Carmona, Agustin CastaГ±eyra, O. Humberto Viveros, Daniel T. O'Connor, Sushil K. Mahata, and Ricardo Borges
The function of chromogranins, a major protein colocalized with catecholamines in dense-core vesicles and chromaffin granules, has been elusive. Montesinos et al. have addressed this mystery and another: how catecholamines are maintained at such high levels in vesicles. The authors used patch amperometry to detect the release of single chromaffin granules from wild-type and chromogranin-A null mouse cells. Because this technique allows discrete, precise measurements of different components of release - formation and expansion of the fusion pore as well as granule and quantal size - it can indicate which component is altered bymutation. In chromogranin-A knock-outs, the quantal size of chromaffin granules was lower, and granules emptied more quickly after fusion compared to controls. Addition of a catecholamine precursor increased quantal size in controls but not knock-outs, suggesting that chromaffin granules from knock-outs could not sequester additional catecholamine. These results strongly suggest that chromogranins help sequester catecholamines in, and slow release from, chromaffin granules.
2. Brn3b Specifies and Suppresses Retinal Cell Fates
Feng Qiu, Haisong Jiang, and Mengqing Xiang
During development, multipotent progenitor cells become committed to a specific fate through expression of cell-specific transcription factors. This week, Qiu et al. present evidence that the transcription factor Brn3b specifies retinal ganglion cell fate and also represses expression of transcription factors that specify alternative fates. The authors used microarrays to find differences in gene expression between Brn3b null and heterozygous mice. They found that many of the most highly upregulated genes in null mice encoded transcription factors known to specify other retinal cell types. Examination of cell-type-specific markers by immunostaining suggested that Brn3b null retinas had fewer ganglion cells and many more amacrine and horizontal cells than controls. On the other hand, overexpression of Brn3b in embryonic retinas increased the proportion of ganglion cells and reduced the number of amacrine and horizontal cells. Thus Brn3b appears to specify retinal ganglion cell fate but also prevents transdifferentiation into other retinal cell types.
3. Adaptation to Curves Affects Perception of Faces
Hong Xu, Peter Dayan, Richard M. Lipkin, and Ning Qian
Are faces perceived holistically or as sums of their parts? Many studies have suggested the former, but experiments reported in this issue suggest that the parts are also perceived individually. To address the question, Xu et al. examined the ability of adaptation to low-level features (curves) to influence perception of high-level features (facial expressions) and vice versa. As shown previously, adaptation to simple curves made human subjects perceive subsequently viewed lines as curving in the opposite direction, and adaptation to sad faces caused subjects to view neutral faces as happy. Additionally, adaptation to concave frown-like curves made subjects perceive neutral faces - cartoons or photographs - as happy. In other words, adaptation to low-level stimuli affected higher-level perception. But the effect of adaptation to curves was smaller than that of adaptation to faces, even for cartoon faces whose mouths were identical to the adapting curve, suggesting that additional holistic components contribute to facial perception.
4. Seizures Disrupt Astrocytic Domain Structure
Nancy Ann Oberheim, Guo-Feng Tian, Xiaoning Han, Weiguo Peng, Takahiro Takano, Bruce Ransom, and Maiken Nedergaard
It was recently discovered that astrocytes tile the brain in nonoverlapping domains that parcel the neuropil into discrete areas infiltrated by single astrocytes. Oberheim et al. now show that this organization is disrupted in mouse models of epilepsy. One week after seizures were induced by ferrous chloride, reactive gliosis appeared, and two types of reactive astrocytes were identified: palisading astrocytes immediately surrounded the injection site and were associated with neurons that had decreased dendritic number, width, and spine density, whereas hypertrophic astrocytes were farther from the site and surrounded neurons that had thicker dendrites with more spines than controls. Both astrocytic types had thicker, longer processes, which were significantly more interdigitated than normal. These changes were also seen in mice that underwent seizures due to kainate injection or genetic mutation, but not in mice that were successfully treated with antiseizure medication or those that showed gliosis due to a non-seizure-inducing mutation.
Please click here for the current table of contents.
Source: Sara Harris
Society for Neuroscience
Monica S. Montesinos, J. David Machado, Marcial Camacho, Jesica Diaz, Yezer G. Morales, Diego Alvarez de la Rosa, Emilia Carmona, Agustin CastaГ±eyra, O. Humberto Viveros, Daniel T. O'Connor, Sushil K. Mahata, and Ricardo Borges
The function of chromogranins, a major protein colocalized with catecholamines in dense-core vesicles and chromaffin granules, has been elusive. Montesinos et al. have addressed this mystery and another: how catecholamines are maintained at such high levels in vesicles. The authors used patch amperometry to detect the release of single chromaffin granules from wild-type and chromogranin-A null mouse cells. Because this technique allows discrete, precise measurements of different components of release - formation and expansion of the fusion pore as well as granule and quantal size - it can indicate which component is altered bymutation. In chromogranin-A knock-outs, the quantal size of chromaffin granules was lower, and granules emptied more quickly after fusion compared to controls. Addition of a catecholamine precursor increased quantal size in controls but not knock-outs, suggesting that chromaffin granules from knock-outs could not sequester additional catecholamine. These results strongly suggest that chromogranins help sequester catecholamines in, and slow release from, chromaffin granules.
2. Brn3b Specifies and Suppresses Retinal Cell Fates
Feng Qiu, Haisong Jiang, and Mengqing Xiang
During development, multipotent progenitor cells become committed to a specific fate through expression of cell-specific transcription factors. This week, Qiu et al. present evidence that the transcription factor Brn3b specifies retinal ganglion cell fate and also represses expression of transcription factors that specify alternative fates. The authors used microarrays to find differences in gene expression between Brn3b null and heterozygous mice. They found that many of the most highly upregulated genes in null mice encoded transcription factors known to specify other retinal cell types. Examination of cell-type-specific markers by immunostaining suggested that Brn3b null retinas had fewer ganglion cells and many more amacrine and horizontal cells than controls. On the other hand, overexpression of Brn3b in embryonic retinas increased the proportion of ganglion cells and reduced the number of amacrine and horizontal cells. Thus Brn3b appears to specify retinal ganglion cell fate but also prevents transdifferentiation into other retinal cell types.
3. Adaptation to Curves Affects Perception of Faces
Hong Xu, Peter Dayan, Richard M. Lipkin, and Ning Qian
Are faces perceived holistically or as sums of their parts? Many studies have suggested the former, but experiments reported in this issue suggest that the parts are also perceived individually. To address the question, Xu et al. examined the ability of adaptation to low-level features (curves) to influence perception of high-level features (facial expressions) and vice versa. As shown previously, adaptation to simple curves made human subjects perceive subsequently viewed lines as curving in the opposite direction, and adaptation to sad faces caused subjects to view neutral faces as happy. Additionally, adaptation to concave frown-like curves made subjects perceive neutral faces - cartoons or photographs - as happy. In other words, adaptation to low-level stimuli affected higher-level perception. But the effect of adaptation to curves was smaller than that of adaptation to faces, even for cartoon faces whose mouths were identical to the adapting curve, suggesting that additional holistic components contribute to facial perception.
4. Seizures Disrupt Astrocytic Domain Structure
Nancy Ann Oberheim, Guo-Feng Tian, Xiaoning Han, Weiguo Peng, Takahiro Takano, Bruce Ransom, and Maiken Nedergaard
It was recently discovered that astrocytes tile the brain in nonoverlapping domains that parcel the neuropil into discrete areas infiltrated by single astrocytes. Oberheim et al. now show that this organization is disrupted in mouse models of epilepsy. One week after seizures were induced by ferrous chloride, reactive gliosis appeared, and two types of reactive astrocytes were identified: palisading astrocytes immediately surrounded the injection site and were associated with neurons that had decreased dendritic number, width, and spine density, whereas hypertrophic astrocytes were farther from the site and surrounded neurons that had thicker dendrites with more spines than controls. Both astrocytic types had thicker, longer processes, which were significantly more interdigitated than normal. These changes were also seen in mice that underwent seizures due to kainate injection or genetic mutation, but not in mice that were successfully treated with antiseizure medication or those that showed gliosis due to a non-seizure-inducing mutation.
Please click here for the current table of contents.
Source: Sara Harris
Society for Neuroscience
Scientists Demonstrate Method For Integrating Nanowire Devices Directly Onto Silicon
Applied scientists at Harvard University in collaboration with researchers from the German universities of Jena, Gottingen, and Bremen, have developed a new technique for fabricating nanowire photonic and electronic integrated circuits that may one day be suitable for high-volume commercial production.
Spearheaded by graduate student Mariano Zimmler and Federico Capasso, Robert L. Wallace Professor of Applied Physics and Vinton Hayes Senior Research Fellow in Electrical Engineering, both of Harvard's School of Engineering and Applied Sciences (SEAS), and Prof. Carsten Ronning of the University of Jena, the findings will be published in Nano Letters. The researchers have filed for U.S. patents covering their invention.
While semiconductor nanowires---rods with an approximate diameter of one-thousandth the width of a human hair---can be easily synthesized in large quantities using inexpensive chemical methods, reliable and controlled strategies for assembling them into functional circuits have posed a major challenge. By incorporating spin-on glass technology, used in Silicon integrated circuits manufacturing, and photolithography, transferring a circuit pattern onto a substrate with light, the team demonstrated a reproducible, high-volume, and low-cost fabrication method for integrating nanowire devices directly onto silicon.
"Because our fabrication technique is independent of the geometrical arrangement of the nanowires on the substrate, we envision further combining the process with one of the several methods already developed for the controlled placement and alignment of nanowires over large areas," said Capasso. "We believe the marriage of these processes will soon provide the necessary control to enable integrated nanowire photonic circuits in a standard manufacturing setting."
The structure of the team's nanowire devices is based on a sandwich geometry: a nanowire is placed between the highly conductive substrate, which functions as a common bottom contact, and a top metallic contact, using spin-on glass as a spacer layer to prevent the metal contact from shorting to the substrate. As a result current can be uniformly injected along the length of the nanowires. These devices can then function as light-emitting diodes, with the color of light determined by the type of semiconductor nanowire used.
To demonstrate the potential scalability of their technique, the team fabricated hundreds of nanoscale ultraviolet light-emitting diodes by using zinc oxide nanowires on a silicon wafer. More broadly, because nanowires can be made of materials commonly used in electronics and photonics, they hold great promise for integrating efficient light emitters, from ultraviolet to infrared, with silicon technology. The team plans to further refine their novel method with an aim towards electrically contacting nanowires over entire wafers.
"Such an advance could lead to the development of a completely new class of integrated circuits, such as large arrays of ultra-small nanoscale lasers that could be designed as high-density optical interconnects or be used for on-chip chemical sensing," said Ronning.
The team's co-authors are postdoctoral fellow Wei Yi and Venkatesh Narayanamurti, John A. and Elizabeth S. Armstrong Professor and dean, both of Harvard's School of Engineering and Applied Sciences; graduate student Daniel Stichtenoth, University of Gottingen; and postdoctoral fellow Tobias Voss, University of Bremen.
The research was supported by the National Science Foundation (NSF) and the German Research Foundation. The authors also acknowledge the support of two Harvard-based centers, the National Science Foundation Nanoscale Science and Engineering Center (NSEC) and the Center for Nanoscale Systems (CNS), a member of the National Nanotechnology Infrastructure Network (NNIN).
Source: Michael Patrick Rutter
Harvard University
Spearheaded by graduate student Mariano Zimmler and Federico Capasso, Robert L. Wallace Professor of Applied Physics and Vinton Hayes Senior Research Fellow in Electrical Engineering, both of Harvard's School of Engineering and Applied Sciences (SEAS), and Prof. Carsten Ronning of the University of Jena, the findings will be published in Nano Letters. The researchers have filed for U.S. patents covering their invention.
While semiconductor nanowires---rods with an approximate diameter of one-thousandth the width of a human hair---can be easily synthesized in large quantities using inexpensive chemical methods, reliable and controlled strategies for assembling them into functional circuits have posed a major challenge. By incorporating spin-on glass technology, used in Silicon integrated circuits manufacturing, and photolithography, transferring a circuit pattern onto a substrate with light, the team demonstrated a reproducible, high-volume, and low-cost fabrication method for integrating nanowire devices directly onto silicon.
"Because our fabrication technique is independent of the geometrical arrangement of the nanowires on the substrate, we envision further combining the process with one of the several methods already developed for the controlled placement and alignment of nanowires over large areas," said Capasso. "We believe the marriage of these processes will soon provide the necessary control to enable integrated nanowire photonic circuits in a standard manufacturing setting."
The structure of the team's nanowire devices is based on a sandwich geometry: a nanowire is placed between the highly conductive substrate, which functions as a common bottom contact, and a top metallic contact, using spin-on glass as a spacer layer to prevent the metal contact from shorting to the substrate. As a result current can be uniformly injected along the length of the nanowires. These devices can then function as light-emitting diodes, with the color of light determined by the type of semiconductor nanowire used.
To demonstrate the potential scalability of their technique, the team fabricated hundreds of nanoscale ultraviolet light-emitting diodes by using zinc oxide nanowires on a silicon wafer. More broadly, because nanowires can be made of materials commonly used in electronics and photonics, they hold great promise for integrating efficient light emitters, from ultraviolet to infrared, with silicon technology. The team plans to further refine their novel method with an aim towards electrically contacting nanowires over entire wafers.
"Such an advance could lead to the development of a completely new class of integrated circuits, such as large arrays of ultra-small nanoscale lasers that could be designed as high-density optical interconnects or be used for on-chip chemical sensing," said Ronning.
The team's co-authors are postdoctoral fellow Wei Yi and Venkatesh Narayanamurti, John A. and Elizabeth S. Armstrong Professor and dean, both of Harvard's School of Engineering and Applied Sciences; graduate student Daniel Stichtenoth, University of Gottingen; and postdoctoral fellow Tobias Voss, University of Bremen.
The research was supported by the National Science Foundation (NSF) and the German Research Foundation. The authors also acknowledge the support of two Harvard-based centers, the National Science Foundation Nanoscale Science and Engineering Center (NSEC) and the Center for Nanoscale Systems (CNS), a member of the National Nanotechnology Infrastructure Network (NNIN).
Source: Michael Patrick Rutter
Harvard University
Hair Formation, Skin Stem Cells And BMP Signaling
The February 15th cover story of G&D reports on the recent discovery by Dr. Elaine Fuchs and colleagues at the Rockefeller University that BMP signaling in dermal papilla cells is important for hair follicle formation.
The dermal papilla (DP) is a small cluster of mesenchymal cells that exist at the base of the hair follicle, and instruct nearby epithelial stem cells to induce hair follicle growth. But because DP cells are so few in number, and loose their hair-inducing potential in culture, the details of this molecular conversation have remained elusive.
Dr. Fuchs' team developed a clever genetic strategy to delete specific genes of interest in DP cells, and then graft these genetically engineered cells onto the backs of immunocompromised (and bald) mice, to study the effect of gene deficiency on hair growth.
The researchers found that deletion of the receptor for the bone morphogenetic protein 1a (BMPR1a) in DP cells prevented the formation of hair follicles in engrafted mice. However, if BMPR1a is intact in DP cells, and a bit more BMP protein is added to the cells, then the DP-stem cell cross-talk is prolonged, and recipient mice grow a tuft of hair on their otherwise bald backs.
"Several years ago, we devised a method to purify the cells and characterize the genes expressed by the DP and its neighboring cells that make hair," says Fuchs. "This gave us clues that BMP signaling might be important in specifying the unique hair-inducing properties of DP cells. We've now succeeded in testing this possibility and our findings are important not only for our understanding of the mesenchymal-epithelial crosstalk that is so critical for hair production, but also for developing new and improved methods for stimulating hair growth."
Source: Heather Cosel
Cold Spring Harbor Laboratory
The dermal papilla (DP) is a small cluster of mesenchymal cells that exist at the base of the hair follicle, and instruct nearby epithelial stem cells to induce hair follicle growth. But because DP cells are so few in number, and loose their hair-inducing potential in culture, the details of this molecular conversation have remained elusive.
Dr. Fuchs' team developed a clever genetic strategy to delete specific genes of interest in DP cells, and then graft these genetically engineered cells onto the backs of immunocompromised (and bald) mice, to study the effect of gene deficiency on hair growth.
The researchers found that deletion of the receptor for the bone morphogenetic protein 1a (BMPR1a) in DP cells prevented the formation of hair follicles in engrafted mice. However, if BMPR1a is intact in DP cells, and a bit more BMP protein is added to the cells, then the DP-stem cell cross-talk is prolonged, and recipient mice grow a tuft of hair on their otherwise bald backs.
"Several years ago, we devised a method to purify the cells and characterize the genes expressed by the DP and its neighboring cells that make hair," says Fuchs. "This gave us clues that BMP signaling might be important in specifying the unique hair-inducing properties of DP cells. We've now succeeded in testing this possibility and our findings are important not only for our understanding of the mesenchymal-epithelial crosstalk that is so critical for hair production, but also for developing new and improved methods for stimulating hair growth."
Source: Heather Cosel
Cold Spring Harbor Laboratory
Molecular Code Broken For Drug Industry's Pet Proteins
All cells are surrounded by protective, fatty membranes.In the cell membrane there are thousands of membrane proteins that transport nutritional substances, ions, and water through the membrane. Membrane proteins are also necessary for cells to recognize each other in the body and for a nervous system, for example, to be formed. Researchers at Stockholm University in Sweden have now managed to reveal the "molecular code" that governs the insertion of proteins in the cell membrane. This work is reported in an article being published on December 13 in the journal Nature.
About 25 percent of all proteins in a cell are found in the cell membrane. Since they regulate all communication between the inside of the cell and the surrounding environment, many membrane proteins are crucial to the life of the cell. Disruptions of their functions often lead to diseases of various kinds. For the drug industry, membrane proteins are high priority "drug targets."
To be suitable for deployment in the fatty cell membrane, all membrane proteins must be lipophiles ("fat-lovers"). All cells have special machinery for producing and dealing with "fatty" proteins and to see to it that they are deployed in proper manner in the cell membrane. The Stockholm University scientists have developed a method for the detailed study of the properties of a membrane protein that are required for it to be recognized by the cell machinery. A couple of years ago the research team published a first article in Nature in which they managed to show that there is a "fat threshold" that determines whether a protein can be deployed to a membrane or not. In this new study they have fully revealed the molecular code that governs the structure of membrane proteins.
"Now that we have deciphered the code, we can determine with a high degree of certainty which parts of a protein will fasten in the membrane." says Gunnar von Heijne.
This new knowledge will help researchers all over the world who are trying to understand more about the cell and its membrane, not least in the drug industry.
"Interest in membrane proteins is at a peak right now, and our findings can be key pieces of the puzzle for pharmaceutical chemists working with drug design, for example," says Gunnar von Hejne.
VETENSKAPSRADET (THE SWEDISH RESEARCH COUNCIL)
Regeringstgatan 56
103 78 Stockholm
vr.se
About 25 percent of all proteins in a cell are found in the cell membrane. Since they regulate all communication between the inside of the cell and the surrounding environment, many membrane proteins are crucial to the life of the cell. Disruptions of their functions often lead to diseases of various kinds. For the drug industry, membrane proteins are high priority "drug targets."
To be suitable for deployment in the fatty cell membrane, all membrane proteins must be lipophiles ("fat-lovers"). All cells have special machinery for producing and dealing with "fatty" proteins and to see to it that they are deployed in proper manner in the cell membrane. The Stockholm University scientists have developed a method for the detailed study of the properties of a membrane protein that are required for it to be recognized by the cell machinery. A couple of years ago the research team published a first article in Nature in which they managed to show that there is a "fat threshold" that determines whether a protein can be deployed to a membrane or not. In this new study they have fully revealed the molecular code that governs the structure of membrane proteins.
"Now that we have deciphered the code, we can determine with a high degree of certainty which parts of a protein will fasten in the membrane." says Gunnar von Heijne.
This new knowledge will help researchers all over the world who are trying to understand more about the cell and its membrane, not least in the drug industry.
"Interest in membrane proteins is at a peak right now, and our findings can be key pieces of the puzzle for pharmaceutical chemists working with drug design, for example," says Gunnar von Hejne.
VETENSKAPSRADET (THE SWEDISH RESEARCH COUNCIL)
Regeringstgatan 56
103 78 Stockholm
vr.se
Social Fish And Single Mothers: Brain Evolution In African Cichlids
How the vertebrate brain has evolved is still a highly debated issue. Using modern analytical tools we studied how ecology, sexual selection and parental care have influenced brain evolution across the highly diverse cichlid fishes of lake Tanganyika.
Our results show that diet and parental care have had an important influence on total brain size. Moreover, by analyzing males and females separately, we show that females caring for offspring alone have larger brains than females sharing care with their partner.
Our results suggest that complex social interactions associated with diet and monoparental female care have favoured the evolution of larger brains.
Proceedings of the Royal Society B: Biological Sciences
Proceedings B is the Royal Society's flagship biological research journal, dedicated to the rapid publication and broad dissemination of high-quality research papers, reviews and comment and reply papers. The scope of journal is diverse and is especially strong in organismal biology.
Proceedings of the Royal Society B: Biological Sciences
Our results show that diet and parental care have had an important influence on total brain size. Moreover, by analyzing males and females separately, we show that females caring for offspring alone have larger brains than females sharing care with their partner.
Our results suggest that complex social interactions associated with diet and monoparental female care have favoured the evolution of larger brains.
Proceedings of the Royal Society B: Biological Sciences
Proceedings B is the Royal Society's flagship biological research journal, dedicated to the rapid publication and broad dissemination of high-quality research papers, reviews and comment and reply papers. The scope of journal is diverse and is especially strong in organismal biology.
Proceedings of the Royal Society B: Biological Sciences
Dynamics Of Conserved Waters In Human HSP 90: Implications For Drug Design
Water is known to be a potential mediator between a drug and its receptor but to what extent must it be considered to be essentially part of the active site and should a putative drug try to expel it.
Here we probe the dynamic behaviour of several water molecules that are predicted to persist in the active site of a potential anti-cancer site.
We find that they are not easily replaced and so further attempts to design drugs against this target must consider the plus-water surface.
Journal of the Royal Society Interface
Journal of the Royal Society Interface is the Society's cross-disciplinary publication promoting research at the interface between the physical and life sciences. It offers rapidity, visibility and high-quality peer review and is ranked fifth in JCR's multidisciplinary category. The journal also incorporates Interface Focus, a peer-reviewed, themed supplement, each issue of which concentrates on a specific cross-disciplinary subject.
Journal of the Royal Society Interface
Here we probe the dynamic behaviour of several water molecules that are predicted to persist in the active site of a potential anti-cancer site.
We find that they are not easily replaced and so further attempts to design drugs against this target must consider the plus-water surface.
Journal of the Royal Society Interface
Journal of the Royal Society Interface is the Society's cross-disciplinary publication promoting research at the interface between the physical and life sciences. It offers rapidity, visibility and high-quality peer review and is ranked fifth in JCR's multidisciplinary category. The journal also incorporates Interface Focus, a peer-reviewed, themed supplement, each issue of which concentrates on a specific cross-disciplinary subject.
Journal of the Royal Society Interface
'Lifestyle' Panel Focus On Avoiding Prostate Cancer And Living Better After Diagnosis
At the Prostate Cancer Foundation's Annual Scientific Retreat, researchers shared new findings on how eating common foods such as tomatoes and fish, maintaining a healthy weight, and avoiding meats cooked at high temperatures may help prevent prostate cancer, and help men live healthier and longer after diagnosis. One in six men will be diagnosed with prostate cancer in their lifetime, and an estimated 218,890 cases will occur in The United States this year.
Since the 1980s, researchers have hypothesized that nutrition choices could be connected to prostate cancer. Today, those ideas are being substantiated by more widespread studies, in combination with newer technologies in gene research.
"There are strong indicators in our research that diet and lifestyle are very important with this particular form of cancer," said Meir Stampfer, M.D., Professor of Epidemiology and Nutrition, Harvard School of Public Health. "When we look at men from other cultures like in Asia, the rates of prostate cancer are significantly lower than in the U.S. Yet when these same men move here, within one generation, the rates increase very rapidly. We believe there is a clear correlation to how we live and eat."
June Chan, ScD, of the University of California San Francisco, has been studying the potential impact of fish oil and tomato extracts on the prostate gland prior to and after exposure. "What we're trying to determine is if men with low grade prostate cancer can manage their disease with these kinds of nutritional interventions and delay or avoid the need for more aggressive treatments, all of which carry a risk of side effects that can adversely affect physical function and quality of life," said Chan. "In combination with other studies, the potential we see for these everyday supplements or foods to help men avoid or delay treatment is promising."
This type of approach, often deemed "active surveillance," is a prostate cancer disease management option that monitors prostate-specific antigen (PSA) levels as well as the grade and stage of the tumor until a more aggressive treatment option may become necessary. One-quarter to one-half of all cases of diagnosed prostate cancer in the U.S. and Europe are considered candidates for this kind of approach, which researchers hope leads to better outcomes for patients with low-risk disease. One aspect of this management approach may include specific dietary modifications such as minimizing intake of red, processed or well-done meats.
Angelo De Marzo, M.D., Ph.D., along with colleague William G. Nelson M.D., Ph.D. of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, have been studying one of the most high profile issues around diet and prostate cancer: don't overheat your meat. "We've known since the 1980s that ingesting meat cooked at very high temperatures can cause cellular mutations, some of which can lead specifically to prostate cancer. What we've found now in the rodent prostate is that the specific areas within the organ that develop cancer after exposure to the meat compounds also first become inflamed and develop a form of atrophy that resembles damaged areas in the human prostate that are likely a very early indicator of a problem." According to De Marzo, if scientists can develop markers of damage and dietary exposures it may be possible for doctors to intervene before cancer ever develops in the prostate.
De Marzo also has some practical advice: "If you're going to eat meat cooked at high temperatures, like I still enjoy, flip your hamburgers more often so the outside does not burn, marinate the meat in ingredients (such as teriyaki sauce) that don't create a crust, precook it in the microwave, or at the least scrape off the charred material." De Marzo also suggests replacing chicken, beef, veal or lamb with soy protein or fish, taking a page from the Asian diet where disease rates are very low. "We need to be realistic: you can help reduce your chance of developing prostate cancer without becoming a vegetarian."
With more widespread testing for prostate cancer using the common PSA test, increasing numbers of new cases are being tracked. The resulting volume of patients, many of whom may have less virulent forms of prostate cancer, is creating a challenge for physicians determined to provide patients with the most appropriate advice -- which may not always include aggressive treatment.
"Thanks to funding from the Prostate Cancer Foundation and others like the National Cancer Institute, we're getting closer every day to developing the best protocols for thousands of men with this diagnosis," said Stampfer. Our goal is that any man with low risk prostate cancer can make simple changes that will extend his life and that healthy men can avoid it altogether."
About the Prostate Cancer Foundation
The Prostate Cancer Foundation (PCF) is the world's largest philanthropic source of support for prostate cancer research. Founded in 1993, the PCF has raised more than $300 million and provided funding for prostate cancer research to more than 1,400 researchers at 100 institutions worldwide. The PCF has a simple, yet urgent goal: to find better treatments and a cure for recurrent prostate cancer. For more information, visit prostatecancerfoundation/.
Source: Sharon Reis
GYMR
Since the 1980s, researchers have hypothesized that nutrition choices could be connected to prostate cancer. Today, those ideas are being substantiated by more widespread studies, in combination with newer technologies in gene research.
"There are strong indicators in our research that diet and lifestyle are very important with this particular form of cancer," said Meir Stampfer, M.D., Professor of Epidemiology and Nutrition, Harvard School of Public Health. "When we look at men from other cultures like in Asia, the rates of prostate cancer are significantly lower than in the U.S. Yet when these same men move here, within one generation, the rates increase very rapidly. We believe there is a clear correlation to how we live and eat."
June Chan, ScD, of the University of California San Francisco, has been studying the potential impact of fish oil and tomato extracts on the prostate gland prior to and after exposure. "What we're trying to determine is if men with low grade prostate cancer can manage their disease with these kinds of nutritional interventions and delay or avoid the need for more aggressive treatments, all of which carry a risk of side effects that can adversely affect physical function and quality of life," said Chan. "In combination with other studies, the potential we see for these everyday supplements or foods to help men avoid or delay treatment is promising."
This type of approach, often deemed "active surveillance," is a prostate cancer disease management option that monitors prostate-specific antigen (PSA) levels as well as the grade and stage of the tumor until a more aggressive treatment option may become necessary. One-quarter to one-half of all cases of diagnosed prostate cancer in the U.S. and Europe are considered candidates for this kind of approach, which researchers hope leads to better outcomes for patients with low-risk disease. One aspect of this management approach may include specific dietary modifications such as minimizing intake of red, processed or well-done meats.
Angelo De Marzo, M.D., Ph.D., along with colleague William G. Nelson M.D., Ph.D. of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, have been studying one of the most high profile issues around diet and prostate cancer: don't overheat your meat. "We've known since the 1980s that ingesting meat cooked at very high temperatures can cause cellular mutations, some of which can lead specifically to prostate cancer. What we've found now in the rodent prostate is that the specific areas within the organ that develop cancer after exposure to the meat compounds also first become inflamed and develop a form of atrophy that resembles damaged areas in the human prostate that are likely a very early indicator of a problem." According to De Marzo, if scientists can develop markers of damage and dietary exposures it may be possible for doctors to intervene before cancer ever develops in the prostate.
De Marzo also has some practical advice: "If you're going to eat meat cooked at high temperatures, like I still enjoy, flip your hamburgers more often so the outside does not burn, marinate the meat in ingredients (such as teriyaki sauce) that don't create a crust, precook it in the microwave, or at the least scrape off the charred material." De Marzo also suggests replacing chicken, beef, veal or lamb with soy protein or fish, taking a page from the Asian diet where disease rates are very low. "We need to be realistic: you can help reduce your chance of developing prostate cancer without becoming a vegetarian."
With more widespread testing for prostate cancer using the common PSA test, increasing numbers of new cases are being tracked. The resulting volume of patients, many of whom may have less virulent forms of prostate cancer, is creating a challenge for physicians determined to provide patients with the most appropriate advice -- which may not always include aggressive treatment.
"Thanks to funding from the Prostate Cancer Foundation and others like the National Cancer Institute, we're getting closer every day to developing the best protocols for thousands of men with this diagnosis," said Stampfer. Our goal is that any man with low risk prostate cancer can make simple changes that will extend his life and that healthy men can avoid it altogether."
About the Prostate Cancer Foundation
The Prostate Cancer Foundation (PCF) is the world's largest philanthropic source of support for prostate cancer research. Founded in 1993, the PCF has raised more than $300 million and provided funding for prostate cancer research to more than 1,400 researchers at 100 institutions worldwide. The PCF has a simple, yet urgent goal: to find better treatments and a cure for recurrent prostate cancer. For more information, visit prostatecancerfoundation/.
Source: Sharon Reis
GYMR
Potential Human Use For New Compound To Prevent Alcoholic Behavior, Relapse In Animals By Blocking Stress Response
A study of alcohol-dependent animals shows that a newly discovered compound that blocks chemical signals active during the brain's response to stress effectively stops excessive drinking and prevents relapse.
The new, synthetic compound, known as MTIP, also muted the anxiety that typically develops in rats experiencing the equivalent of a hangover. Such stress is linked with higher levels of a brain chemical called corticotropin-releasing factor (CRF), which is also thought to trigger relapse in rats that have developed a long-term dependency on alcohol. The research, by Markus Heilig, MD, PhD, at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and his team, appears in the March 7 issue of The Journal of Neuroscience.
"This study shows the activity of a compound that potentially could be used in human subjects," says George Koob, PhD, of the Scripps Research Institute. "It moves the field over another translational barrier, closer to the day when the dark side of addiction is treated."
The new findings build on previous work showing the effectiveness of blocking certain CRF receptors - proteins that bind CRF and make it active - in treating alcohol dependence in animals. CRF levels in the brain rise in the short term after drinking; in subjects that are not dependent, this activation returns to normal within a day or so. The new study shows that the CRF system becomes overactive in the long term in animals with a history of alcohol dependence, increasing the risk for relapse.
Heilig and his team showed that MTIP blocked the activity of CRF in stressful situations without affecting its activity under ordinary circumstances. They studied rats that had been put through several cycles of heavy alcohol consumption and withdrawal to create dependency, as well as animals selectively bred to consume more alcohol. Injections of MTIP prevented excessive drinking of alcohol in both cases and eliminated the rats' susceptibility to relapse under stress. Yet the compound did not affect their native curiosity or lower levels of drinking alcohol in rats that were not alcohol-dependent.
In addition to alcoholism, the compound may prove to be useful in the treatment of depression or anxiety disorders, in which CRF levels can be especially high.
The compound or similar molecules can be given orally, reach the brain in sufficient amounts to block more than 90 percent of certain brain CRF receptors, and do not accumulate in other organs, most importantly the liver, in ways that would cause concerns about potential side effects, says Heilig.
The work was a collaborative project between NIAAA and Eli Lilly and Co.
The Journal of Neuroscience is published by the Society for Neuroscience, an organization of more than 36,500 basic scientists and clinicians who study the brain and nervous system.
Contact: Sara Harris
Society for Neuroscience
The new, synthetic compound, known as MTIP, also muted the anxiety that typically develops in rats experiencing the equivalent of a hangover. Such stress is linked with higher levels of a brain chemical called corticotropin-releasing factor (CRF), which is also thought to trigger relapse in rats that have developed a long-term dependency on alcohol. The research, by Markus Heilig, MD, PhD, at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and his team, appears in the March 7 issue of The Journal of Neuroscience.
"This study shows the activity of a compound that potentially could be used in human subjects," says George Koob, PhD, of the Scripps Research Institute. "It moves the field over another translational barrier, closer to the day when the dark side of addiction is treated."
The new findings build on previous work showing the effectiveness of blocking certain CRF receptors - proteins that bind CRF and make it active - in treating alcohol dependence in animals. CRF levels in the brain rise in the short term after drinking; in subjects that are not dependent, this activation returns to normal within a day or so. The new study shows that the CRF system becomes overactive in the long term in animals with a history of alcohol dependence, increasing the risk for relapse.
Heilig and his team showed that MTIP blocked the activity of CRF in stressful situations without affecting its activity under ordinary circumstances. They studied rats that had been put through several cycles of heavy alcohol consumption and withdrawal to create dependency, as well as animals selectively bred to consume more alcohol. Injections of MTIP prevented excessive drinking of alcohol in both cases and eliminated the rats' susceptibility to relapse under stress. Yet the compound did not affect their native curiosity or lower levels of drinking alcohol in rats that were not alcohol-dependent.
In addition to alcoholism, the compound may prove to be useful in the treatment of depression or anxiety disorders, in which CRF levels can be especially high.
The compound or similar molecules can be given orally, reach the brain in sufficient amounts to block more than 90 percent of certain brain CRF receptors, and do not accumulate in other organs, most importantly the liver, in ways that would cause concerns about potential side effects, says Heilig.
The work was a collaborative project between NIAAA and Eli Lilly and Co.
The Journal of Neuroscience is published by the Society for Neuroscience, an organization of more than 36,500 basic scientists and clinicians who study the brain and nervous system.
Contact: Sara Harris
Society for Neuroscience
Understanding The Role Of Stress In Just About Everything
Stress, to put it bluntly, is bad for you. It can kill you, in fact.
A study now reveals that stress causes deterioration in everything from your gums to your heart and can make you more susceptible to everything from the common cold to cancer. Thanks to new research crossing the disciplines of psychology, medicine, neuroscience, and genetics, the mechanisms underlying the connection are rapidly becoming understood.
The first clues to the link between stress and health were provided in the 1930s by Hans Selye, the first scientist to apply the word "stress"- then simply an engineering term - to the strains experienced by living organisms in their struggles to adapt and cope with changing environments.
One of Selye's major discoveries was that the stress hormone cortisol had a long-term effect on the health of rats.
Cortisol has been considered one of the main culprits in the stress-illness connection, although it plays a necessary role in helping us cope with threats. When an animal perceives danger, a system kicks into gear: A chain reaction of signals releases various hormones - most notably epinephrine ("adrenaline"), norepinephrine, and cortisol - from the adrenal glands above each kidney.
These hormones boost heart rate, increase respiration, and increase the availability of glucose (cellular fuel) in the blood, thereby enabling the famous "fight or flight" reaction.
Because these responses take a lot of energy, cortisol simultaneously tells other costly physical processes - including digestion, reproduction, physical growth, and some aspects of the immune system - to shut or slow down.
When occasions to fight or flee are infrequent and threats pass quickly, the body's stress thermostat adjusts accordingly: Cortisol levels return to baseline (it takes 40-60 minutes), the intestines resume digesting food, the sex organs kick back into gear, and the immune system resumes fighting infections.
But problems occur when stresses don't let up - or when, for various reasons, the brain continually perceives stress even if it isn't really there.
Stress begins with the perception of danger by the brain, and it appears that continued stress can actually bias the brain to perceive more danger by altering brain structures such as those which govern the perception of and response to threat. Prolonged exposure to cortisol inhibits the growth of new neurons, and can cause increased growth of the amygdala, the portion of the brain that controls fear and other emotional responses.
The end result is heightened expectation of and attention to threats in the environment. Stress hormones also inhibit neuron growth in parts of the hippocampus, a brain area essential in forming new memories. In this way, stress results in memory impairments and impairs the brain's ability to put emotional memories in context.
Think of it this way: Too much stress and you forget not to be stressed out.
These brain changes are thought by some researchers to be at the heart of the link between stress and depression - one of stress's most devastating health consequences - as well as posttraumatic stress disorder (PTSD).
Although when we think of stressors we might think of big things like abuse, illness, divorce, grieving, or getting fired, it is now known that the little things - traffic, workplace politics, noisy neighbors, a long line at the bank - can add up and have a similar impact on our well-being and our health.
People who report more minor irritants in their lives also have more mental and physical health problems than those who encounter fewer hassles. And recent research shows that PTSD may be the result of stressors adding up like building blocks, remodeling the plastic brain in a cumulative rather than a once-and-for-all fashion.
But the best known of stress's health impacts are on the heart.
The idea that stress directly causes coronary heart disease has been around since the 1950s; although once controversial, the direct stress-cardiac link is now well-documented by many studies. For instance, men who faced chronic stresses at work or at home ran a 30 percent higher likelihood of dying over the course of a nine-year study; in another study, individuals reporting neglect, abuse, or other stressors in childhood were over three times as likely as nonstressed individuals to develop heart disease in adulthood.
Adding insult to injury, stress may even have a selfperpetuating effect. Depression and heart disease, for example, are not only the results of stress, but also causes of (more) stress. Consequently, the chronically stressed body can appear less like a thermostat than like a wailing speaker placed too close to a microphone - a feedback loop in which the stress response goes out of control, hastening physical decline with age.
Growing evidence shows that our sensitivity to stress as adults is already "tuned," so to speak, in infancy. Specifically, the amount of stress encountered in early life sensitizes an organism to a certain level of adversity; high levels of early life stress may result in hypersensitivity to stress later, as well as to adult depression.
A history of various stressors such as abuse and neglect in early life are a common feature of those with chronic depression in adulthood, for example.
At McGill University in Montreal, Michael J. Meaney and his colleagues have studied mother and infant rats, using rat maternal behavior as a model of early life stress and its later ramifications in humans. The key variable in the world of rat nurturance is licking and grooming. Offspring of rat mothers who naturally lick and groom their pups a lot are less easily startled as adults and show less fear of novel or threatening situations - in other words, less sensitivity to stress - than offspring of less nurturant mothers.
The same thing is true of offspring of naturally less nurturant mothers who are raised (or "cross-fostered") by more nurturant ones. By the same token, low-licking-and-grooming rat mothers are themselves more fearful than the more nurturant rat moms; but again, female offspring of those non-nurturant mothers foster-parented by nurturant mothers show less fear and are themselves more nurturant when they have pups of their own.
This indicates that the connection between maternal nurturance and stress responsiveness is not simply genetic, but that fearfulness and nurturance are transmitted from generation to generation through maternal behavior.
The vicious cycle of stress hormones biasing us to perceive more threat and react with an increased stress response might seem like some kind perverse joke played by nature - or at least a serious design flaw in the brain. But it makes better sense if we take the brain out of its modern, urban, "civilized" context.
The stress response is a necessary response to danger.
For animals, including most likely our hominid ancestors, behavioral transmission of individual differences in stress reactivity from parents to offspring makes sense as an adaptation to fluctuating levels of danger in the environment.
Animals raised in chronically adverse conditions (e.g., high conflict, material deprivation) may expect more of the same in the near future; so in effect, the maternal treatment of offspring attunes them to the level of stress they may expect to encounter in their lives. As such, a response that seems baffling and counterproductive in a modern, civilized context may make more sense in the context of our distant evolutionary past.
Even depression has been theorized as playing an adaptive role in certain contexts.
The inactivity, lack of motivation, loss of interest in pleasurable activities like sex, and withdrawal from social relationships experienced by depressed people closely resemble "sickness behavior" - the energy-saving lethargy activated by the immune system in response to infection.
In a natural setting, the hopeless attitude of depression may be the most adaptive for an organism infected with a pathogen: The best strategy for survival is not to expend energy fruitlessly and become exposed to predators, but to hunker down, hide from threats, and direct energy to immune processes where it's needed.
And it turns out that baboons suffer from depression and other stress-related disorders, just like people do. According to Stanford neuroendocrinologist Robert Sapolsky, who has studied stress in baboon troops, it is the relative safety from predators and high amounts of leisure time enjoyed by some primates - including humans - that has transformed these useful biological coping mechanisms into a source of pointless suffering and illness.
Besides heart disease, PTSD, and depression, chronic stress has been linked to ailments as diverse as intestinal problems, gum disease, erectile dysfunction, adult-onset diabetes, growth problems, and even cancer. Chronic rises in stress hormones have been shown to accelerate the growth of precancerous cells and tumors; they also lower the body's resistance to HIV and cancer-causing viruses like human papilloma virus (the precursor to cervical cancer in women).
The great challenge in stress psychology - and the necessary precursor to developing interventions against stress's harmful effects - has been understanding the mechanisms by which thoughts and feelings and other "mental" stuff can affect bodily health.
For many years, it was believed that the main causal link between stress and disease was the immune suppression that occurs when the body redirects its energy toward the fight-or-flight response. But recent research has revealed a far more nuanced picture.
Stress is known to actually enhance one important immune response, inflammation, and increasingly this is being seen as the go-between in various stress-related diseases.
Ordinarily, inflammation is how the healthy body deals with damaged tissue: Cells at the site of infections or injuries produce signaling chemicals called cytokines, which in turn attract other immune cells to the site to help repair it. Cytokines also travel to the brain and are responsible for initiating sickness behavior. Overactive cytokine production has been found to put individuals at greater risk for a variety of aging-related illnesses.
Cytokines may be an important mediator in the relationship between stress and heart disease. When the arteries feeding the heart are damaged, cytokines induce more blood flow, and thus more white blood cells, to the site. White blood cells accumulate in vessel walls and, over time, become engorged with cholesterol, becoming plaques; these may later become destabilized and rupture, causing heart attacks.
Cytokine action also has been implicated in the link between stress and depression. People suffering from clinical depression have shown 40-50 percent higher concentrations of certain inflammatory cytokines. And about 50 percent of cancer patients whose immune responses are artificially boosted through the administration of cytokines show depressive symptoms.
The close connection between inflammation and both depression and heart disease has led some researchers to theorize that inflammation may be what mediates the two-way street between these two conditions: Depression can lead to heart disease, but heart disease also often leads to depression.
Sleep may be part of this puzzle too, as disturbed sleep, which often goes with anxiety and depression, increases levels of proinflammatory cytokines in the body.
Not everyone responds the same way to stress. Personality traits like negativity, pessimism, and neuroticism are known to be risk factors for stress-related disease, as are anger and hostility.
In the late 1950s, Friedman and Rosenman identified a major link between stress and health with their research on the "Type A" personality: a person who is highly competitive, aggressive, and impatient. This personality was found to be a strong predictor of heart disease, and later research clarified the picture: The salient factors in the relationship between the Type A personality and health are mainly anger, hostility, and a socially dominant personality style (for example, tending to interrupt other people while they are talking).
When negative emotions like anger are chronic, it is as if the body is in a constant state of fight or flight.
There is now evidence that another trait associated with success-striving in the modern world - persistence - may also lead to health problems in some circumstances. When goals are not readily attainable, the inability to detach from them may produce frustration, exhaustion, rumination on failures, and lack of sleep. These in turn activate harmful inflammatory responses that can lead to illness and lowered immunity.
Studies also have shown that optimistic people have lower incidence of heart disease, better prognosis after heart surgery, and longer life.
The effects of a positive attitude on immunity were shown in a study by Sheldon Cohen, Carnegie Mellon University, and his colleagues, in which individuals were exposed to a cold virus in a laboratory setting and watched over six days. Those with a positive emotional style were less likely to develop colds than were individuals with low levels of positive affect. Positive affect was also found to be correlated with reduced symptom severity and reduced pain.
Personality and environmental factors are not the whole story when it comes to stress.
The next frontier of stress research is the rapidly growing field of behavioral genetics. Modeling the interaction of genetic and environmental influences is no longer a matter of weighing the relative input of nature and nurture. The two intertwine in subtle and complicated ways, with environments affecting gene expression, and vice versa, throughout life. Thus, the current watchword is "stress-diathesis" models, in which environmental stressors have varying impact on individuals due to preexisting inherited vulnerabilities.
One major advance in this area was the discovery by Avshalom Caspi, University of Wisconsin, and his colleagues of a link between stress sensitivity and a particular gene called 5HTTLPR. Findings suggest certain genetic makeup seems to increase the risk for a serious illness through the mechanism of increased sensitivity to stressful occurrences.
Nathan Fox, University of Maryland, and his colleagues subsequently reported that children with two short alleles of the 5HTTLPR gene, whose mothers also reported receiving low social support, were more likely to show behavioral inhibition (fearfulness and a tendency to withdraw) at age 7. Those receiving high support did not show the tendency, and those with the long alleles but receiving low support also appeared "protected" by their genetic makeup.
Genetic predisposition to stress sensitivity may in some cases become a self-fulfilling cycle. Fox and colleagues found that some very behaviorally inhibited children were regarded by their mothers as hard to soothe and received less care and sensitivity as a result; this in turn tuned up the child's sensitivity to stress. In the model Fox and colleagues propose, genetically influenced temperament in early childhood influences the quality of caregiving children receive, which in turn shapes a child's attention bias to threat.
But look on the bright side: The newly refined science of stress could lead to new drug therapies that can control stress or inhibit its effects on health. Also, depression and anxiety are not only results of stress, but also causes, and existing therapeutic and medical treatments for these conditions can help change how people perceive threats, put their life challenges in context, and cut stressors down to manageable size. The cycle doesn't have to be vicious, in other words.
What's more, the confirmation that the mind directly affects the body can work as much in our favor as it does to our detriment, as the personality-and-stress research above indicates.
As Carol Dweck, Stanford University, has argued, personality is mutable. In theory, if our outlooks and beliefs about ourselves can be changed, so can our vulnerability to life's slings and arrows. Relaxation techniques such as meditation and yoga, for example, have been confirmed to quell stress demons.
Even if you are a determined workaholic glued to your cell phone or a fearful and angry urban neurotic, stress-reduction methods are readily available to cope with stress in the short term and even alter perceptions of stressors in the long term. The bottom line: Stress is not inevitable.
Current Research on Stress:
At the University of Chicago, APS President John Cacioppo and Louise Hawkley have studied the health effects of social isolation, an increasingly common malady in the modern world. Among their findings are that lonely older adults show more arterial stiffening and higher blood pressure than their nonlonely counterparts and that the association between loneliness and blood pressure increases with age.
In middle-aged and older adults (but not young adults), loneliness is associated with higher levels of epinephrine in the blood, and lonely people of all ages show elevated levels of cortisol. By desensitizing the mechanism whereby cortisol turns off more cortisol production, the social isolation frequently experienced by older adults may hasten physical decline. Lonely individuals of all ages also have poorer sleep than nonlonely people and therefore get less of sleep's essential restorative benefits.
Humans and other social animals particularly seek the company of others when facing threats - both for safety and for social support. The general affiliative response - what Shelley Taylor, UCLA, has called "tending and befriending." Oxytocin rises during times of separation or disrupted social relations. Just as the familiar "adrenaline rush" of epinephrine induces the familiar fight-or-flight reaction, it is oxytocin that causes us to desire company and social togetherness.
It may be especially important in females, reflecting their different reproductive and survival priorities from those of males - i.e., caregiving (tending offspring) and lessening social tensions through friendly overtures (befriending).
Author Contact: Eric Wargo
The full article appears in the December 2007 issue of the Observer, the monthly magazine of the Association for Psychological Science.
Source: Katie Kline
Association for Psychological Science
A study now reveals that stress causes deterioration in everything from your gums to your heart and can make you more susceptible to everything from the common cold to cancer. Thanks to new research crossing the disciplines of psychology, medicine, neuroscience, and genetics, the mechanisms underlying the connection are rapidly becoming understood.
The first clues to the link between stress and health were provided in the 1930s by Hans Selye, the first scientist to apply the word "stress"- then simply an engineering term - to the strains experienced by living organisms in their struggles to adapt and cope with changing environments.
One of Selye's major discoveries was that the stress hormone cortisol had a long-term effect on the health of rats.
Cortisol has been considered one of the main culprits in the stress-illness connection, although it plays a necessary role in helping us cope with threats. When an animal perceives danger, a system kicks into gear: A chain reaction of signals releases various hormones - most notably epinephrine ("adrenaline"), norepinephrine, and cortisol - from the adrenal glands above each kidney.
These hormones boost heart rate, increase respiration, and increase the availability of glucose (cellular fuel) in the blood, thereby enabling the famous "fight or flight" reaction.
Because these responses take a lot of energy, cortisol simultaneously tells other costly physical processes - including digestion, reproduction, physical growth, and some aspects of the immune system - to shut or slow down.
When occasions to fight or flee are infrequent and threats pass quickly, the body's stress thermostat adjusts accordingly: Cortisol levels return to baseline (it takes 40-60 minutes), the intestines resume digesting food, the sex organs kick back into gear, and the immune system resumes fighting infections.
But problems occur when stresses don't let up - or when, for various reasons, the brain continually perceives stress even if it isn't really there.
Stress begins with the perception of danger by the brain, and it appears that continued stress can actually bias the brain to perceive more danger by altering brain structures such as those which govern the perception of and response to threat. Prolonged exposure to cortisol inhibits the growth of new neurons, and can cause increased growth of the amygdala, the portion of the brain that controls fear and other emotional responses.
The end result is heightened expectation of and attention to threats in the environment. Stress hormones also inhibit neuron growth in parts of the hippocampus, a brain area essential in forming new memories. In this way, stress results in memory impairments and impairs the brain's ability to put emotional memories in context.
Think of it this way: Too much stress and you forget not to be stressed out.
These brain changes are thought by some researchers to be at the heart of the link between stress and depression - one of stress's most devastating health consequences - as well as posttraumatic stress disorder (PTSD).
Although when we think of stressors we might think of big things like abuse, illness, divorce, grieving, or getting fired, it is now known that the little things - traffic, workplace politics, noisy neighbors, a long line at the bank - can add up and have a similar impact on our well-being and our health.
People who report more minor irritants in their lives also have more mental and physical health problems than those who encounter fewer hassles. And recent research shows that PTSD may be the result of stressors adding up like building blocks, remodeling the plastic brain in a cumulative rather than a once-and-for-all fashion.
But the best known of stress's health impacts are on the heart.
The idea that stress directly causes coronary heart disease has been around since the 1950s; although once controversial, the direct stress-cardiac link is now well-documented by many studies. For instance, men who faced chronic stresses at work or at home ran a 30 percent higher likelihood of dying over the course of a nine-year study; in another study, individuals reporting neglect, abuse, or other stressors in childhood were over three times as likely as nonstressed individuals to develop heart disease in adulthood.
Adding insult to injury, stress may even have a selfperpetuating effect. Depression and heart disease, for example, are not only the results of stress, but also causes of (more) stress. Consequently, the chronically stressed body can appear less like a thermostat than like a wailing speaker placed too close to a microphone - a feedback loop in which the stress response goes out of control, hastening physical decline with age.
Growing evidence shows that our sensitivity to stress as adults is already "tuned," so to speak, in infancy. Specifically, the amount of stress encountered in early life sensitizes an organism to a certain level of adversity; high levels of early life stress may result in hypersensitivity to stress later, as well as to adult depression.
A history of various stressors such as abuse and neglect in early life are a common feature of those with chronic depression in adulthood, for example.
At McGill University in Montreal, Michael J. Meaney and his colleagues have studied mother and infant rats, using rat maternal behavior as a model of early life stress and its later ramifications in humans. The key variable in the world of rat nurturance is licking and grooming. Offspring of rat mothers who naturally lick and groom their pups a lot are less easily startled as adults and show less fear of novel or threatening situations - in other words, less sensitivity to stress - than offspring of less nurturant mothers.
The same thing is true of offspring of naturally less nurturant mothers who are raised (or "cross-fostered") by more nurturant ones. By the same token, low-licking-and-grooming rat mothers are themselves more fearful than the more nurturant rat moms; but again, female offspring of those non-nurturant mothers foster-parented by nurturant mothers show less fear and are themselves more nurturant when they have pups of their own.
This indicates that the connection between maternal nurturance and stress responsiveness is not simply genetic, but that fearfulness and nurturance are transmitted from generation to generation through maternal behavior.
The vicious cycle of stress hormones biasing us to perceive more threat and react with an increased stress response might seem like some kind perverse joke played by nature - or at least a serious design flaw in the brain. But it makes better sense if we take the brain out of its modern, urban, "civilized" context.
The stress response is a necessary response to danger.
For animals, including most likely our hominid ancestors, behavioral transmission of individual differences in stress reactivity from parents to offspring makes sense as an adaptation to fluctuating levels of danger in the environment.
Animals raised in chronically adverse conditions (e.g., high conflict, material deprivation) may expect more of the same in the near future; so in effect, the maternal treatment of offspring attunes them to the level of stress they may expect to encounter in their lives. As such, a response that seems baffling and counterproductive in a modern, civilized context may make more sense in the context of our distant evolutionary past.
Even depression has been theorized as playing an adaptive role in certain contexts.
The inactivity, lack of motivation, loss of interest in pleasurable activities like sex, and withdrawal from social relationships experienced by depressed people closely resemble "sickness behavior" - the energy-saving lethargy activated by the immune system in response to infection.
In a natural setting, the hopeless attitude of depression may be the most adaptive for an organism infected with a pathogen: The best strategy for survival is not to expend energy fruitlessly and become exposed to predators, but to hunker down, hide from threats, and direct energy to immune processes where it's needed.
And it turns out that baboons suffer from depression and other stress-related disorders, just like people do. According to Stanford neuroendocrinologist Robert Sapolsky, who has studied stress in baboon troops, it is the relative safety from predators and high amounts of leisure time enjoyed by some primates - including humans - that has transformed these useful biological coping mechanisms into a source of pointless suffering and illness.
Besides heart disease, PTSD, and depression, chronic stress has been linked to ailments as diverse as intestinal problems, gum disease, erectile dysfunction, adult-onset diabetes, growth problems, and even cancer. Chronic rises in stress hormones have been shown to accelerate the growth of precancerous cells and tumors; they also lower the body's resistance to HIV and cancer-causing viruses like human papilloma virus (the precursor to cervical cancer in women).
The great challenge in stress psychology - and the necessary precursor to developing interventions against stress's harmful effects - has been understanding the mechanisms by which thoughts and feelings and other "mental" stuff can affect bodily health.
For many years, it was believed that the main causal link between stress and disease was the immune suppression that occurs when the body redirects its energy toward the fight-or-flight response. But recent research has revealed a far more nuanced picture.
Stress is known to actually enhance one important immune response, inflammation, and increasingly this is being seen as the go-between in various stress-related diseases.
Ordinarily, inflammation is how the healthy body deals with damaged tissue: Cells at the site of infections or injuries produce signaling chemicals called cytokines, which in turn attract other immune cells to the site to help repair it. Cytokines also travel to the brain and are responsible for initiating sickness behavior. Overactive cytokine production has been found to put individuals at greater risk for a variety of aging-related illnesses.
Cytokines may be an important mediator in the relationship between stress and heart disease. When the arteries feeding the heart are damaged, cytokines induce more blood flow, and thus more white blood cells, to the site. White blood cells accumulate in vessel walls and, over time, become engorged with cholesterol, becoming plaques; these may later become destabilized and rupture, causing heart attacks.
Cytokine action also has been implicated in the link between stress and depression. People suffering from clinical depression have shown 40-50 percent higher concentrations of certain inflammatory cytokines. And about 50 percent of cancer patients whose immune responses are artificially boosted through the administration of cytokines show depressive symptoms.
The close connection between inflammation and both depression and heart disease has led some researchers to theorize that inflammation may be what mediates the two-way street between these two conditions: Depression can lead to heart disease, but heart disease also often leads to depression.
Sleep may be part of this puzzle too, as disturbed sleep, which often goes with anxiety and depression, increases levels of proinflammatory cytokines in the body.
Not everyone responds the same way to stress. Personality traits like negativity, pessimism, and neuroticism are known to be risk factors for stress-related disease, as are anger and hostility.
In the late 1950s, Friedman and Rosenman identified a major link between stress and health with their research on the "Type A" personality: a person who is highly competitive, aggressive, and impatient. This personality was found to be a strong predictor of heart disease, and later research clarified the picture: The salient factors in the relationship between the Type A personality and health are mainly anger, hostility, and a socially dominant personality style (for example, tending to interrupt other people while they are talking).
When negative emotions like anger are chronic, it is as if the body is in a constant state of fight or flight.
There is now evidence that another trait associated with success-striving in the modern world - persistence - may also lead to health problems in some circumstances. When goals are not readily attainable, the inability to detach from them may produce frustration, exhaustion, rumination on failures, and lack of sleep. These in turn activate harmful inflammatory responses that can lead to illness and lowered immunity.
Studies also have shown that optimistic people have lower incidence of heart disease, better prognosis after heart surgery, and longer life.
The effects of a positive attitude on immunity were shown in a study by Sheldon Cohen, Carnegie Mellon University, and his colleagues, in which individuals were exposed to a cold virus in a laboratory setting and watched over six days. Those with a positive emotional style were less likely to develop colds than were individuals with low levels of positive affect. Positive affect was also found to be correlated with reduced symptom severity and reduced pain.
Personality and environmental factors are not the whole story when it comes to stress.
The next frontier of stress research is the rapidly growing field of behavioral genetics. Modeling the interaction of genetic and environmental influences is no longer a matter of weighing the relative input of nature and nurture. The two intertwine in subtle and complicated ways, with environments affecting gene expression, and vice versa, throughout life. Thus, the current watchword is "stress-diathesis" models, in which environmental stressors have varying impact on individuals due to preexisting inherited vulnerabilities.
One major advance in this area was the discovery by Avshalom Caspi, University of Wisconsin, and his colleagues of a link between stress sensitivity and a particular gene called 5HTTLPR. Findings suggest certain genetic makeup seems to increase the risk for a serious illness through the mechanism of increased sensitivity to stressful occurrences.
Nathan Fox, University of Maryland, and his colleagues subsequently reported that children with two short alleles of the 5HTTLPR gene, whose mothers also reported receiving low social support, were more likely to show behavioral inhibition (fearfulness and a tendency to withdraw) at age 7. Those receiving high support did not show the tendency, and those with the long alleles but receiving low support also appeared "protected" by their genetic makeup.
Genetic predisposition to stress sensitivity may in some cases become a self-fulfilling cycle. Fox and colleagues found that some very behaviorally inhibited children were regarded by their mothers as hard to soothe and received less care and sensitivity as a result; this in turn tuned up the child's sensitivity to stress. In the model Fox and colleagues propose, genetically influenced temperament in early childhood influences the quality of caregiving children receive, which in turn shapes a child's attention bias to threat.
But look on the bright side: The newly refined science of stress could lead to new drug therapies that can control stress or inhibit its effects on health. Also, depression and anxiety are not only results of stress, but also causes, and existing therapeutic and medical treatments for these conditions can help change how people perceive threats, put their life challenges in context, and cut stressors down to manageable size. The cycle doesn't have to be vicious, in other words.
What's more, the confirmation that the mind directly affects the body can work as much in our favor as it does to our detriment, as the personality-and-stress research above indicates.
As Carol Dweck, Stanford University, has argued, personality is mutable. In theory, if our outlooks and beliefs about ourselves can be changed, so can our vulnerability to life's slings and arrows. Relaxation techniques such as meditation and yoga, for example, have been confirmed to quell stress demons.
Even if you are a determined workaholic glued to your cell phone or a fearful and angry urban neurotic, stress-reduction methods are readily available to cope with stress in the short term and even alter perceptions of stressors in the long term. The bottom line: Stress is not inevitable.
Current Research on Stress:
At the University of Chicago, APS President John Cacioppo and Louise Hawkley have studied the health effects of social isolation, an increasingly common malady in the modern world. Among their findings are that lonely older adults show more arterial stiffening and higher blood pressure than their nonlonely counterparts and that the association between loneliness and blood pressure increases with age.
In middle-aged and older adults (but not young adults), loneliness is associated with higher levels of epinephrine in the blood, and lonely people of all ages show elevated levels of cortisol. By desensitizing the mechanism whereby cortisol turns off more cortisol production, the social isolation frequently experienced by older adults may hasten physical decline. Lonely individuals of all ages also have poorer sleep than nonlonely people and therefore get less of sleep's essential restorative benefits.
Humans and other social animals particularly seek the company of others when facing threats - both for safety and for social support. The general affiliative response - what Shelley Taylor, UCLA, has called "tending and befriending." Oxytocin rises during times of separation or disrupted social relations. Just as the familiar "adrenaline rush" of epinephrine induces the familiar fight-or-flight reaction, it is oxytocin that causes us to desire company and social togetherness.
It may be especially important in females, reflecting their different reproductive and survival priorities from those of males - i.e., caregiving (tending offspring) and lessening social tensions through friendly overtures (befriending).
Author Contact: Eric Wargo
The full article appears in the December 2007 issue of the Observer, the monthly magazine of the Association for Psychological Science.
Source: Katie Kline
Association for Psychological Science
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