ScienceDaily (Dec. 28, 2011) — A UT Southwestern Medical Center study using a sophisticated "glass mouse" research model has found that multidrug-resistant tuberculosis (TB) is more likely caused in patients by speedy drug metabolism rather than inconsistent doses, as is widely believed.
If the study published in The Journal of Infectious Diseases is borne out in future investigations, it may lead to better ways to treat one of the world's major infectious diseases. Health workers worldwide currently are required to witness each administration of the combination of drugs during months of therapy.
"Tuberculosis is a common ailment, accounting for up to 3 percent of all deaths in many countries. Although effective therapy exists, there are still cases of treatment failure and drug resistance remains a threat," said Dr. Tawanda Gumbo, associate professor of internal medicine and senior author of the study.
The results seem to challenge the current approach endorsed by the World Health Organization.
Under that method, directly observed therapy-short-course strategy (DOTS), TB that responds to medication is treated with a cocktail of drugs under the supervision of health care workers, who in many countries must travel to isolated villages -- a costly and time-consuming process.
"Every TB patient is supposed to be watched as they swallow their pills in order to increase adherence and decrease emergence of drug resistance. This is the most expensive part of the program, but has been felt to be cost-effective since it improves compliance," said Dr. Gumbo, administrative director of research programs for the Office of Global Health at UT Southwestern.
In this study, UT Southwestern researchers created a sophisticated system of high-tech test tubes, which they called a "glass mouse," that mimicked standard therapy being given daily for 28 to 56 days, with dosing adherence varying between 0 percent and 100 percent. The threshold for defined non-adherence (failure to take a required dose of medication) was reached at 60 percent of the time or more.
"The first main finding in our laboratory model was that in fact non-adherence did not lead to multidrug resistance or emergence of any drug resistance in repeated studies, even when therapy failed. In fact, even when we started with a bacterial population that had been spiked with drug-resistant bacteria, non-adherence still did not lead to drug resistance," he said.
In fact, using computer simulations based on 10,000 TB patients in Cape Town, South Africa, the researchers discovered that approximately 1 percent of all TB patients with perfect adherence still developed drug resistance because they cleared the drugs from their bodies more quickly.
The body sees drugs as foreign chemicals and tries to rid itself of them, Dr. Gumbo said. A population of individuals with a genetic trait that speeds the process has been found in one area of South Africa that has a high rate of multidrug-resistant TB. In that population, patients who receive standard doses of drugs end up with concentrations in their bodies that are too low to kill the TB bacillus and drug resistance develops, he said.
A Journal of Infectious Diseases editorial that accompanies the study suggests that monitoring the levels of TB drugs in a patient's blood could be as important as monitoring compliance with therapy -- in contrast to current WHO guidelines.
"These data, based on our preclinical model, show that non-adherence alone is insufficient for the emergence of multidrug-resistant TB," Dr. Gumbo said. "It might be more cost-effective to measure patients' drug concentrations during treatment and intervene with dosage increases in those who quickly clear the drugs from their systems."
http://www.sciencedaily.com/releases/2011/12/111228111724.htm?utm_source=feedburner&utm_medium=email&utm_campaign=Feed%3A+sciencedaily+%28ScienceDaily%3A+Latest+Science+News%29
Saturday, December 31, 2011
Sunday, December 25, 2011
multiple sclerosis is not a disease of the immune system
An article to be published Friday (Dec. 23) in the December 2011 issue of The Quarterly Review of Biology argues that multiple sclerosis, long viewed as primarily an autoimmune disease, is not actually a disease of the immune system. Dr. Angelique Corthals, a forensic anthropologist and professor at the John Jay College of Criminal Justice in New York, suggests instead that MS is caused by faulty lipid metabolism, in many ways more similar to coronary atherosclerosis (hardening of the arteries) than to other autoimmune diseases.
Framing MS as a metabolic disorder helps to explain many puzzling aspects of the disease, particularly why it strikes women more than men and why cases are on the rise worldwide, Corthals says. She believes this new framework could help guide researchers toward new treatments and ultimately a cure for the disease.
Multiple sclerosis affects at least 1.3 million people worldwide. Its main characteristic is inflammation followed by scarring of tissue called myelin, which insulates nerve tissue in the brain and spinal cord. Over time, this scarring can lead to profound neurological damage. Medical researchers have theorized that a runaway immune system is at fault, but no one has been able to fully explain what triggers the onset of the disease. Genes, diet, pathogens, and vitamin D deficiency have all been linked to MS, but evidence for these risk factors is inconsistent and even contradictory, frustrating researchers in their search for effective treatment.
"Each time a genetic risk factor has shown a significant increase in MS risk in one population, it has been found to be unimportant in another," Corthals said. "Pathogens like Epstein-Barr virus have been implicated, but there's no explanation for why genetically similar populations with similar pathogen loads have drastically different rates of disease. The search for MS triggers in the context of autoimmunity simply hasn't led to any unifying conclusions about the etiology of the disease."
However, understanding MS as metabolic rather than an autoimmune begins to bring the disease and its causes into focus.
THE LIPID HYPOTHESIS
Corthals believes that the primary cause of MS can be traced to transcription factors in cell nuclei that control the uptake, breakdown, and release of lipids (fats and similar compounds) throughout the body. Disruption of these proteins, known as peroxisome proliferator-activated receptors (PPARs), causes a toxic byproduct of "bad" cholesterol called oxidized LDL to form plaques on the affected tissue. The accumulation of plaque in turn triggers an immune response, which ultimately leads to scarring. This is essentially the same mechanism involved in atherosclerosis, in which PPAR failure causes plaque accumulation, immune response, and scarring in coronary arteries.
"When lipid metabolism fails in the arteries, you get atherosclerosis," Corthals explains. "When it happens in the central nervous system, you get MS. But the underlying etiology is the same."
A major risk factor for disruption of lipid homeostasis is having high LDL cholesterol. So if PPARs are at the root of MS, it would explain why cases of the disease have been on the rise in recent decades. "In general people around the world are increasing their intake of sugars and animal fats, which often leads to high LDL cholesterol," Corthals said. "So we would expect to see higher rates of disease related to lipid metabolism—like heart disease and, in this case, MS." This also explains why statin drugs, which are used to treat high cholesterol, have shown promise as an MS treatment.
The lipid hypothesis also sheds light on the link between MS and vitamin D deficiency. Vitamin D helps to lower LDL cholesterol, so it makes sense that a lack of vitamin D increases the likelihood of the disease—especially in the context of a diet high in fats and carbohydrates.
Corthals's framework also explains why MS is more prevalent in women.
"Men and women metabolize fats differently," Corthals said. "In men, PPAR problems are more likely to occur in vascular tissue, which is why atherosclerosis is more prevalent in men. But women metabolize fat differently in relation to their reproductive role. Disruption of lipid metabolism in women is more likely to affect the production of myelin and the central nervous system. In this way, MS is to women what atherosclerosis is to men, while excluding neither sex from developing the other disease."
In addition to high cholesterol, there are several other risk factors for reduced PPAR function, including pathogens like Epstein-Barr virus, trauma that requires massive cell repair, and certain genetic profiles. In many cases, Corthals says, having just one of these risk factors isn't enough to trigger a collapse of lipid metabolism. But more than one risk factor could cause problems. For example, a genetically weakened PPAR system on its own might not cause disease, but combining that with a pathogen or with a poor diet can cause disease. This helps to explain why different MS triggers seem to be important for some people and populations but not others.
"In the context of autoimmunity, the various risk factors for MS are frustratingly incoherent," Corthals said. "But in the context of lipid metabolism, they make perfect sense."
Much more research is necessary to fully understand the role of PPARs in MS, but Corthals hopes that this new understanding of the disease could eventually lead to new treatments and prevention measures.
"This new framework makes a cure for MS closer than ever," Corthals said.
http://www.eurekalert.org/pub_releases/2011-12/uocp-rcm122211.php
Framing MS as a metabolic disorder helps to explain many puzzling aspects of the disease, particularly why it strikes women more than men and why cases are on the rise worldwide, Corthals says. She believes this new framework could help guide researchers toward new treatments and ultimately a cure for the disease.
Multiple sclerosis affects at least 1.3 million people worldwide. Its main characteristic is inflammation followed by scarring of tissue called myelin, which insulates nerve tissue in the brain and spinal cord. Over time, this scarring can lead to profound neurological damage. Medical researchers have theorized that a runaway immune system is at fault, but no one has been able to fully explain what triggers the onset of the disease. Genes, diet, pathogens, and vitamin D deficiency have all been linked to MS, but evidence for these risk factors is inconsistent and even contradictory, frustrating researchers in their search for effective treatment.
"Each time a genetic risk factor has shown a significant increase in MS risk in one population, it has been found to be unimportant in another," Corthals said. "Pathogens like Epstein-Barr virus have been implicated, but there's no explanation for why genetically similar populations with similar pathogen loads have drastically different rates of disease. The search for MS triggers in the context of autoimmunity simply hasn't led to any unifying conclusions about the etiology of the disease."
However, understanding MS as metabolic rather than an autoimmune begins to bring the disease and its causes into focus.
THE LIPID HYPOTHESIS
Corthals believes that the primary cause of MS can be traced to transcription factors in cell nuclei that control the uptake, breakdown, and release of lipids (fats and similar compounds) throughout the body. Disruption of these proteins, known as peroxisome proliferator-activated receptors (PPARs), causes a toxic byproduct of "bad" cholesterol called oxidized LDL to form plaques on the affected tissue. The accumulation of plaque in turn triggers an immune response, which ultimately leads to scarring. This is essentially the same mechanism involved in atherosclerosis, in which PPAR failure causes plaque accumulation, immune response, and scarring in coronary arteries.
"When lipid metabolism fails in the arteries, you get atherosclerosis," Corthals explains. "When it happens in the central nervous system, you get MS. But the underlying etiology is the same."
A major risk factor for disruption of lipid homeostasis is having high LDL cholesterol. So if PPARs are at the root of MS, it would explain why cases of the disease have been on the rise in recent decades. "In general people around the world are increasing their intake of sugars and animal fats, which often leads to high LDL cholesterol," Corthals said. "So we would expect to see higher rates of disease related to lipid metabolism—like heart disease and, in this case, MS." This also explains why statin drugs, which are used to treat high cholesterol, have shown promise as an MS treatment.
The lipid hypothesis also sheds light on the link between MS and vitamin D deficiency. Vitamin D helps to lower LDL cholesterol, so it makes sense that a lack of vitamin D increases the likelihood of the disease—especially in the context of a diet high in fats and carbohydrates.
Corthals's framework also explains why MS is more prevalent in women.
"Men and women metabolize fats differently," Corthals said. "In men, PPAR problems are more likely to occur in vascular tissue, which is why atherosclerosis is more prevalent in men. But women metabolize fat differently in relation to their reproductive role. Disruption of lipid metabolism in women is more likely to affect the production of myelin and the central nervous system. In this way, MS is to women what atherosclerosis is to men, while excluding neither sex from developing the other disease."
In addition to high cholesterol, there are several other risk factors for reduced PPAR function, including pathogens like Epstein-Barr virus, trauma that requires massive cell repair, and certain genetic profiles. In many cases, Corthals says, having just one of these risk factors isn't enough to trigger a collapse of lipid metabolism. But more than one risk factor could cause problems. For example, a genetically weakened PPAR system on its own might not cause disease, but combining that with a pathogen or with a poor diet can cause disease. This helps to explain why different MS triggers seem to be important for some people and populations but not others.
"In the context of autoimmunity, the various risk factors for MS are frustratingly incoherent," Corthals said. "But in the context of lipid metabolism, they make perfect sense."
Much more research is necessary to fully understand the role of PPARs in MS, but Corthals hopes that this new understanding of the disease could eventually lead to new treatments and prevention measures.
"This new framework makes a cure for MS closer than ever," Corthals said.
http://www.eurekalert.org/pub_releases/2011-12/uocp-rcm122211.php
Friday, December 23, 2011
Septin proteins take bacterial prisoners
Cellular proteins called septins might play an important part in the human body’s ability to fight off bacterial infections, according to a study.
Septins are found in many organisms, and are best known for building scaffolding to provide structural support during cell division and to rope off parts of the cell. However, most studies of septins, or guanosine-5′-triphosphate (GTP) binding proteins, have been confined to yeast cells. The latest research in human cells suggests that septins build 'cages' around bacterial pathogens, immobilizing the harmful microbes and preventing them from invading other healthy cells.
Septin proteins build cages (red) to trap bacteria (blue) that invade human cells.
S. Mostowy
This cellular defence system could help researchers to create therapies for dysentery and other illnesses, the researchers say. “This is a new way for cells to control an infection,” says Pascale Cossart, a cell biologist at the Pasteur Institute in Paris, who presented the findings in a poster session on Sunday at the annual meeting of the American Society for Cell Biology in Denver, Colorado.
The researchers discovered the caging behaviour with Shigella, a bacterium that causes sometimes lethal diarrhoea in humans and other primates. To propagate from cell to cell, Shigella bacteria develop actin-polymer 'tails', which propel the microbes around and allow them to force their way into neighbouring host cells. To counterattack, human cells produce a cell-signalling protein called TNF-α. The researchers found that when TNF-α is present, thick bundles of septin filaments encircle the microbes. This, in turn, interferes with tail formation and stops Shigella in its tracks1, 2.
Microbes that become trapped in septin cages are broken down in a stage of the cell's life cycle called autophagy. “Autophagy is more efficient because of the septin cage, and the septin cage does not occur if you do not have the autophagy,” says Cossart.
Joining the dots
The work “implies that septins are more dynamic than originally thought”, says Alexis Gautreau, a cell biologist at the French National Research Agency in Gif-sur-Yvette. Until now, he says, the function of septins in helping yeast cells to divide was well known, “but no one could relate that to mammalian cell physiology”.
“Septin’s role is pretty mysterious,” agrees Harry Higgs, a biochemist at Dartmouth Medical School in Hanover, New Hampshire. “The cool thing to me is that pathogenic bacteria have been so instrumental in figuring out how actin works, and this is the first sign that they will help to figure out how septins work.”
The researchers are now working to better understand the link between septins and autophagy, and to determine how important septins are in humans in vivo.
Previous studies have suggested that disruptions in septins and mutations in the genes that code for them could be involved in causing leukaemia, colon cancer and neurodegenerative conditions such as Parkinson’s disease and Alzheimer’s disease. Potential therapies for these, as well as for bacterial conditions such as dysentery caused by Shigella, might bolster the body’s immune system with drugs that mimic the behaviour of TNF-α and allow the septin cages to proliferate, says Cossart. “If you have a way to increase the number of cages, you have a new way to fight against infection,” she adds.
http://www.nature.com/news/septin-proteins-take-bacterial-prisoners-1.9540?WT.ec_id=NEWS-20111206
Septins are found in many organisms, and are best known for building scaffolding to provide structural support during cell division and to rope off parts of the cell. However, most studies of septins, or guanosine-5′-triphosphate (GTP) binding proteins, have been confined to yeast cells. The latest research in human cells suggests that septins build 'cages' around bacterial pathogens, immobilizing the harmful microbes and preventing them from invading other healthy cells.
Septin proteins build cages (red) to trap bacteria (blue) that invade human cells.
S. Mostowy
This cellular defence system could help researchers to create therapies for dysentery and other illnesses, the researchers say. “This is a new way for cells to control an infection,” says Pascale Cossart, a cell biologist at the Pasteur Institute in Paris, who presented the findings in a poster session on Sunday at the annual meeting of the American Society for Cell Biology in Denver, Colorado.
The researchers discovered the caging behaviour with Shigella, a bacterium that causes sometimes lethal diarrhoea in humans and other primates. To propagate from cell to cell, Shigella bacteria develop actin-polymer 'tails', which propel the microbes around and allow them to force their way into neighbouring host cells. To counterattack, human cells produce a cell-signalling protein called TNF-α. The researchers found that when TNF-α is present, thick bundles of septin filaments encircle the microbes. This, in turn, interferes with tail formation and stops Shigella in its tracks1, 2.
Microbes that become trapped in septin cages are broken down in a stage of the cell's life cycle called autophagy. “Autophagy is more efficient because of the septin cage, and the septin cage does not occur if you do not have the autophagy,” says Cossart.
Joining the dots
The work “implies that septins are more dynamic than originally thought”, says Alexis Gautreau, a cell biologist at the French National Research Agency in Gif-sur-Yvette. Until now, he says, the function of septins in helping yeast cells to divide was well known, “but no one could relate that to mammalian cell physiology”.
“Septin’s role is pretty mysterious,” agrees Harry Higgs, a biochemist at Dartmouth Medical School in Hanover, New Hampshire. “The cool thing to me is that pathogenic bacteria have been so instrumental in figuring out how actin works, and this is the first sign that they will help to figure out how septins work.”
The researchers are now working to better understand the link between septins and autophagy, and to determine how important septins are in humans in vivo.
Previous studies have suggested that disruptions in septins and mutations in the genes that code for them could be involved in causing leukaemia, colon cancer and neurodegenerative conditions such as Parkinson’s disease and Alzheimer’s disease. Potential therapies for these, as well as for bacterial conditions such as dysentery caused by Shigella, might bolster the body’s immune system with drugs that mimic the behaviour of TNF-α and allow the septin cages to proliferate, says Cossart. “If you have a way to increase the number of cages, you have a new way to fight against infection,” she adds.
http://www.nature.com/news/septin-proteins-take-bacterial-prisoners-1.9540?WT.ec_id=NEWS-20111206
Saturday, December 17, 2011
Why Tuberculosis Is So Hard to Cure
When microbes divide, you usually get more of the same: A cell splits up and creates two identical copies of itself. But a new study shows that's not true for mycobacteria, which cause tuberculosis (TB) in humans—and that may explain why the disease is so difficult to treat. Mycobacteria divide asymmetrically, generating a population of cells that grow at different rates, have different sizes, and differ in how susceptible they are to antibiotics, increasing the chances that at least some will survive. Researchers hope the findings will help them develop drugs against those cells that are especially hard to kill.
"It is incredible that we are finding such basic things out only now," says immunologist Sarah Fortune of at the Harvard School of Public Health in Boston, the paper's lead author. "But it reflects the fact that mycobacteria are relatively understudied."
More than a third of the world's population is estimated to be infected with Mycobacterium tuberculosis. Most people's immune system can keep the bacteria in check, but there is a lifetime chance of 1 in 10 that the dormant infection will progress to TB; the disease still kills 4000 people every day. Tuberculosis treatment is a combination of antibiotics taken for half a year or more—a major drawback, because patients often quit therapy prematurely, increasing the risk of drug-resistant strains emerging. Scientists have assumed that mycobacteria are so hard to kill because dormant cells exist even in patients with active disease and these cells are far less susceptible to antibiotics than metabolically active bacteria.
But Fortune and her colleagues found a second, more surprising mechanism. They cultured M. smegmatis, which is closely related to M. tuberculosis but faster growing, in a tiny chamber with a constant flow of nutrients, allowing them to watch single live cells growing and replicating. Unlike other rod-shaped bacteria, such as E. coli, mycobacterial cells divided asymmetrically, creating a tapestry of cell types with widely different sizes and growth rates, the team reports online today in Science.
By labeling the cell wall of the mycobacteria with a fluorescent dye and observing the new, unstained cell wall growing at the poles, the researchers found that daughter cells mainly grow at their "old" pole. As the new end, created by the cell division, grows older, it matures and the cell elongates faster. And as the cells go through numerous divisions, cells with poles of many different "ages" emerge, leading to the wide variety in growth rates.
Importantly, the cells also differed in their susceptibility to antibiotics: While "older," fast-growing cells were more susceptible to the drugs isoniazid and cycloserine; younger, slower-growing cells were more susceptible to rifampicin. "When I started working on mycobacteria, the assumption was that all the bacteria are indistinguishable. This is the first mechanistic insight into why the cells are phenotypically different," says Fortune. The asymmetry is a way for mycobacteria to keep their population diverse, she says, just like viruses create diversity by mutating frenetically.
"This is an important study, because it shows that our way of thinking that populations are the sum of equal organisms is incorrect," says immunologist Stefan Kaufmann of the Max Planck Institute for Infection Biology in Berlin. "As we look at individual microbes, we find diversity." Kaufmann cautions, however, that most of the experiments were done with M. smegmatis and need to be verified with M. tuberculosis. "But this could explain, at least in part, why tuberculosis is so hard to treat," he says. "And it could pave the way for a rational search for new combination therapies composed of drugs that attack the different types of bacteria."
http://news.sciencemag.org/sciencenow/2011/12/why-tuberculosis-is-so-hard-to.html?ref=em&elq=d661ccc382b64524836cc194d7243fc5
"It is incredible that we are finding such basic things out only now," says immunologist Sarah Fortune of at the Harvard School of Public Health in Boston, the paper's lead author. "But it reflects the fact that mycobacteria are relatively understudied."
More than a third of the world's population is estimated to be infected with Mycobacterium tuberculosis. Most people's immune system can keep the bacteria in check, but there is a lifetime chance of 1 in 10 that the dormant infection will progress to TB; the disease still kills 4000 people every day. Tuberculosis treatment is a combination of antibiotics taken for half a year or more—a major drawback, because patients often quit therapy prematurely, increasing the risk of drug-resistant strains emerging. Scientists have assumed that mycobacteria are so hard to kill because dormant cells exist even in patients with active disease and these cells are far less susceptible to antibiotics than metabolically active bacteria.
But Fortune and her colleagues found a second, more surprising mechanism. They cultured M. smegmatis, which is closely related to M. tuberculosis but faster growing, in a tiny chamber with a constant flow of nutrients, allowing them to watch single live cells growing and replicating. Unlike other rod-shaped bacteria, such as E. coli, mycobacterial cells divided asymmetrically, creating a tapestry of cell types with widely different sizes and growth rates, the team reports online today in Science.
By labeling the cell wall of the mycobacteria with a fluorescent dye and observing the new, unstained cell wall growing at the poles, the researchers found that daughter cells mainly grow at their "old" pole. As the new end, created by the cell division, grows older, it matures and the cell elongates faster. And as the cells go through numerous divisions, cells with poles of many different "ages" emerge, leading to the wide variety in growth rates.
Importantly, the cells also differed in their susceptibility to antibiotics: While "older," fast-growing cells were more susceptible to the drugs isoniazid and cycloserine; younger, slower-growing cells were more susceptible to rifampicin. "When I started working on mycobacteria, the assumption was that all the bacteria are indistinguishable. This is the first mechanistic insight into why the cells are phenotypically different," says Fortune. The asymmetry is a way for mycobacteria to keep their population diverse, she says, just like viruses create diversity by mutating frenetically.
"This is an important study, because it shows that our way of thinking that populations are the sum of equal organisms is incorrect," says immunologist Stefan Kaufmann of the Max Planck Institute for Infection Biology in Berlin. "As we look at individual microbes, we find diversity." Kaufmann cautions, however, that most of the experiments were done with M. smegmatis and need to be verified with M. tuberculosis. "But this could explain, at least in part, why tuberculosis is so hard to treat," he says. "And it could pave the way for a rational search for new combination therapies composed of drugs that attack the different types of bacteria."
http://news.sciencemag.org/sciencenow/2011/12/why-tuberculosis-is-so-hard-to.html?ref=em&elq=d661ccc382b64524836cc194d7243fc5
Friday, December 16, 2011
Red-type Rubiscos
Structural analyses of the first identified activase for red-type Rubiscos reveal key insights into Rubisco activation.
The authors propose that Cbbx (left) releases RuBP from Rubisco (right) through transient interactions with the C-terminal tail of the Rubisco large subunit (red wire). Figure courtesy of Andreas Bracher.
Red-type Rubiscos, present in photosynthetic bacteria, red algae, and phytoplankton, are responsible for most of the oceanic carbon uptake. Understanding the catalytic cycle of red-type Rubiscos could therefore aid in improving the CO2 uptake and biomass productions of photosynthetic organisms.
Rubiscos catalyze the carboxylation of Ribulose-1,5-bisphosphate (RuBP) by CO2 in the first step of carbon fixation in photosynthesis. Binding of Rubisco to RuBP in the absence of active site carbamylation creates an inactive complex that must be reactivated by Rubisco activase (Rca), which catalyzes the release of RuBP from Rubisco in an ATP-dependent manner. While Rca has been identified in green algae and plants, no Rca homolog has been identified in organisms containing red-type Rubiscos.
Mueller-Cajar and colleagues have now identified and characterized the Rubisco activase CbbX from the proteobacterium Rhodobacter sphaeroides. Like Rca, CbbX is an AAA+ protein with ATPase activity and is able to activate inhibited Rubisco in the presence of ATP. Unlike Rca, CbbX has no inherent ATPase activity in the absence of RuBP. Therefore, RuBP acts as an allosteric regulator of CbbX and ensures that the enzyme is only active during photosynthesis, when levels of RuBP are high.
Analysis of CbbX by negative stain electron microscopy revealed that CbbX forms ring-like structures similar to other AAA+ proteins in the presence of ATP and RuBP. The crystal structure of CbbX reveals a typical AAA+ fold with an N-terminal α/β domain and a C-terminal α-helical domain. The α/β domain contains the canonical Walker A and B motifs, which are important for binding ATP, and a conserved pore loop. The position of two bound sulfate ions in the α-helical domain reveals the likely binding site for RuBP.
Based on structural analyses, the authors proposed a model for Rubisco activation in which the C-terminal extension present in red-type Rubiscos, but not green-type Rubiscos, is pulled into the core of CbbX by the conserved pore loop. This pulling force opens up the active site of Rubisco and enables the inhibitory RuBP molecule to leave.
Jennifer Cable
References:
O. Mueller-Cajar et al. Structure and function of the AAA+ protein CbbX, a red-type Rubisco activase.
Nature. 479, 194-199 (2011). doi:10.1038/nature10568
The authors propose that Cbbx (left) releases RuBP from Rubisco (right) through transient interactions with the C-terminal tail of the Rubisco large subunit (red wire). Figure courtesy of Andreas Bracher.
Red-type Rubiscos, present in photosynthetic bacteria, red algae, and phytoplankton, are responsible for most of the oceanic carbon uptake. Understanding the catalytic cycle of red-type Rubiscos could therefore aid in improving the CO2 uptake and biomass productions of photosynthetic organisms.
Rubiscos catalyze the carboxylation of Ribulose-1,5-bisphosphate (RuBP) by CO2 in the first step of carbon fixation in photosynthesis. Binding of Rubisco to RuBP in the absence of active site carbamylation creates an inactive complex that must be reactivated by Rubisco activase (Rca), which catalyzes the release of RuBP from Rubisco in an ATP-dependent manner. While Rca has been identified in green algae and plants, no Rca homolog has been identified in organisms containing red-type Rubiscos.
Mueller-Cajar and colleagues have now identified and characterized the Rubisco activase CbbX from the proteobacterium Rhodobacter sphaeroides. Like Rca, CbbX is an AAA+ protein with ATPase activity and is able to activate inhibited Rubisco in the presence of ATP. Unlike Rca, CbbX has no inherent ATPase activity in the absence of RuBP. Therefore, RuBP acts as an allosteric regulator of CbbX and ensures that the enzyme is only active during photosynthesis, when levels of RuBP are high.
Analysis of CbbX by negative stain electron microscopy revealed that CbbX forms ring-like structures similar to other AAA+ proteins in the presence of ATP and RuBP. The crystal structure of CbbX reveals a typical AAA+ fold with an N-terminal α/β domain and a C-terminal α-helical domain. The α/β domain contains the canonical Walker A and B motifs, which are important for binding ATP, and a conserved pore loop. The position of two bound sulfate ions in the α-helical domain reveals the likely binding site for RuBP.
Based on structural analyses, the authors proposed a model for Rubisco activation in which the C-terminal extension present in red-type Rubiscos, but not green-type Rubiscos, is pulled into the core of CbbX by the conserved pore loop. This pulling force opens up the active site of Rubisco and enables the inhibitory RuBP molecule to leave.
Jennifer Cable
References:
O. Mueller-Cajar et al. Structure and function of the AAA+ protein CbbX, a red-type Rubisco activase.
Nature. 479, 194-199 (2011). doi:10.1038/nature10568
Saturday, December 10, 2011
Children with HIV in Asia Suffer Resistance to AIDS Drugs
Researchers with the HIV/AIDS network TREAT Asia are calling for improved access to advanced pediatric HIV drugs. The collaboration of clinics, hospitals, and research institutions has released a new long-term study of 4,000 patients under age 23 in six Asian countries: It finds growing evidence of drug resistance and loss of bone density among the youths.
“In our cohort, about 14 percent of the children have failed first-line drugs ... . Some of the children who are already on second-line [drugs] are under the age of five,” said TREAT Asia Director Annette Sohn, a pediatric HIV/AIDS specialist.
Drug resistance can be caused by poor adherence to AIDS drug regimens, though in Asia it also is due to a lack of formulations for children. “We all made some mistakes on how we managed patients with HIV in the beginning of the epidemic,” said Sohn. “We used adult tablets, we had no pediatric formulations in our countries.”
“Unless we develop access to third-line drugs, we are going to find ourselves in a clinic room with a patient that there is nothing left and we have no other drug to give them,” Sohn said.
The study - carried out in Cambodia, India, Indonesia, Malaysia, Thailand, and Vietnam - found a high percentage of teenage patients with low bone mineral density, a precursor to osteoporosis. “We did a special X-ray on these teenagers, who are about 16 years old, and found that 15 percent of them had low bone mass,” Sohn said. “This is not normal. Kids are not supposed to have low bone mass when they’re 16 years old and that’s because of the effect of HIV on their bodies ... brain, bone, immune system.”
Though she noted this may also be due to toxic effects that some AIDS drugs, such tenofovir, have on bone, Sohn added, “It is not so much about avoiding one drug or another but being aware of these side effects, studying what drug doses will suppress the virus while not being toxic, having the resources to monitor side effects, and having access to alternative drugs if they do arise.”
Reuters (12.01.11):: Tan Ee Lyn
“In our cohort, about 14 percent of the children have failed first-line drugs ... . Some of the children who are already on second-line [drugs] are under the age of five,” said TREAT Asia Director Annette Sohn, a pediatric HIV/AIDS specialist.
Drug resistance can be caused by poor adherence to AIDS drug regimens, though in Asia it also is due to a lack of formulations for children. “We all made some mistakes on how we managed patients with HIV in the beginning of the epidemic,” said Sohn. “We used adult tablets, we had no pediatric formulations in our countries.”
“Unless we develop access to third-line drugs, we are going to find ourselves in a clinic room with a patient that there is nothing left and we have no other drug to give them,” Sohn said.
The study - carried out in Cambodia, India, Indonesia, Malaysia, Thailand, and Vietnam - found a high percentage of teenage patients with low bone mineral density, a precursor to osteoporosis. “We did a special X-ray on these teenagers, who are about 16 years old, and found that 15 percent of them had low bone mass,” Sohn said. “This is not normal. Kids are not supposed to have low bone mass when they’re 16 years old and that’s because of the effect of HIV on their bodies ... brain, bone, immune system.”
Though she noted this may also be due to toxic effects that some AIDS drugs, such tenofovir, have on bone, Sohn added, “It is not so much about avoiding one drug or another but being aware of these side effects, studying what drug doses will suppress the virus while not being toxic, having the resources to monitor side effects, and having access to alternative drugs if they do arise.”
Reuters (12.01.11):: Tan Ee Lyn
Saturday, December 3, 2011
Simple blood test diagnoses Parkinson's disease long before symptoms appear
New research in the FASEB Journal suggests that phosphorylated alpha-synuclein, a substance found in the blood of Parkinson's patients, could lead to definitive diagnostic tool
Bethesda, MD—A new research report appearing in the December issue of the FASEB Journal (http://www.fasebj.org) shows how scientists from the United Kingdom have developed a simple blood test to detect Parkinson's disease even at the earliest stages. The test is possible because scientists found a substance in the blood, called "phosphorylated alpha-synuclein," which is common in people with Parkinson's disease, and then developed a way to identify its presence in our blood.
"A blood test for Parkinson's disease would mean you could find out if a person was in danger of getting the disease, before the symptoms started," said David Allsop, Ph.D., a researcher involved in the work from the Division of Biomedical and Life Sciences and the School of Health and Medicine at the University of Lancaster, in Lancaster, UK. "This would help the development of medicines that could protect the brain, which would be better for the quality of life and future health of older people."
To develop the blood test for Parkinson's disease, Allsop and colleagues studied a group of people diagnosed with the disease and a second group of healthy people of a similar age. Blood samples from each group were analyzed to determine the levels of phosphorylated alpha-synuclein present. They found those with Parkinson's disease had increased levels of the substance. Based upon these findings, researchers developed a blood test that detects the presence of phosphorylated alpha-synuclein, which could allow for diagnosis of the disease well before symptoms appear but when brain damage has already begun to occur.
"When most people think of Parkinson's disease, they think of the outward symptoms, such as involuntary movements," said Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal, "but many people with Parkinson's also develop neurological problems that may be more difficult to detect right away. Having a blood test not only helps doctors rule out other possible causes of the outward symptoms, but it also allows for early detection which can help patients and their caregivers prepare for the possibility of the mental, emotional, and behavioral problems that the disease can cause."
http://www.eurekalert.org/pub_releases/2011-11/foas-sbt113011.php
Bethesda, MD—A new research report appearing in the December issue of the FASEB Journal (http://www.fasebj.org) shows how scientists from the United Kingdom have developed a simple blood test to detect Parkinson's disease even at the earliest stages. The test is possible because scientists found a substance in the blood, called "phosphorylated alpha-synuclein," which is common in people with Parkinson's disease, and then developed a way to identify its presence in our blood.
"A blood test for Parkinson's disease would mean you could find out if a person was in danger of getting the disease, before the symptoms started," said David Allsop, Ph.D., a researcher involved in the work from the Division of Biomedical and Life Sciences and the School of Health and Medicine at the University of Lancaster, in Lancaster, UK. "This would help the development of medicines that could protect the brain, which would be better for the quality of life and future health of older people."
To develop the blood test for Parkinson's disease, Allsop and colleagues studied a group of people diagnosed with the disease and a second group of healthy people of a similar age. Blood samples from each group were analyzed to determine the levels of phosphorylated alpha-synuclein present. They found those with Parkinson's disease had increased levels of the substance. Based upon these findings, researchers developed a blood test that detects the presence of phosphorylated alpha-synuclein, which could allow for diagnosis of the disease well before symptoms appear but when brain damage has already begun to occur.
"When most people think of Parkinson's disease, they think of the outward symptoms, such as involuntary movements," said Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal, "but many people with Parkinson's also develop neurological problems that may be more difficult to detect right away. Having a blood test not only helps doctors rule out other possible causes of the outward symptoms, but it also allows for early detection which can help patients and their caregivers prepare for the possibility of the mental, emotional, and behavioral problems that the disease can cause."
http://www.eurekalert.org/pub_releases/2011-11/foas-sbt113011.php
Medical researchers in Canada and the US discover hidden side of prion diseases
Medical researchers in Canada and the United States recently published their joint findings that fatal prion diseases, which include BSE or "mad cow disease," have a hidden signature.
Findings published this month in the peer-reviewed journal, Public Library of Science (PLoS) Pathogens, demonstrate that up to seven months before an animal shows physical signs of having a prion infection, a particular prion protein in the brain was being eradicated. This member of the prion family is known as shadoo protein.
"What we discovered is that as the early prion disease process unfolds in an infected brain, that the shadoo protein is simultaneously disappearing," said lead author and co-principal investigator, David Westaway, a researcher in the Faculty of Medicine & Dentistry at the University of Alberta.
"This is telling us there is a process within the disease that we were previously unaware of, a process that is happening before the infected animals are getting sick. It's telling us that the brain cells are more active in defending themselves than what we thought they were. The brain cells are in fact trying to get rid of the prion protein and as a consequence, this bystander shadoo protein is being destroyed unintentionally.
"This finding suggests that prion diseases are dynamic and not necessarily unstoppable, that there could be a cellular process trying to destroy the infectious prions as they appear. And if we could help that process a little bit more, that might be an avenue to attenuate the disease."
Westaway, who works in both the Division of Neurology of the Faculty of Medicine & Dentistry, and the Centre for Prions and Protein Folding Diseases at the U of A, collaborated with a team of researchers from Ontario, the University of California, the Institute for Systems Biology in Washington, the McLaughlin Research Institute in Montana and a researcher in Germany, on this discovery.
The same day this paper was published, very similar findings were published by a team of researchers from the University of California, which demonstrates "these new chemical changes are a concrete and reproducible hallmark of prion disease," says Westaway.
Co-principal investigator George Carlson, from the McLaughlin Research Institute, added: "Given that shadoo may be destroyed by a process that actually targets infectious prions, it was surprising that when we increased the amount of shadoo in laboratory models that the course of disease was not changed. We need to understand why."
The next step for Westaway's research team is to determine why this shadoo protein is disappearing.
The finding opens up a new window of research opportunities.
"We need to better understand this. We want to solve this mystery," he says.
http://www.eurekalert.org/pub_releases/2011-11/uoaf-mri112811.php
Findings published this month in the peer-reviewed journal, Public Library of Science (PLoS) Pathogens, demonstrate that up to seven months before an animal shows physical signs of having a prion infection, a particular prion protein in the brain was being eradicated. This member of the prion family is known as shadoo protein.
"What we discovered is that as the early prion disease process unfolds in an infected brain, that the shadoo protein is simultaneously disappearing," said lead author and co-principal investigator, David Westaway, a researcher in the Faculty of Medicine & Dentistry at the University of Alberta.
"This is telling us there is a process within the disease that we were previously unaware of, a process that is happening before the infected animals are getting sick. It's telling us that the brain cells are more active in defending themselves than what we thought they were. The brain cells are in fact trying to get rid of the prion protein and as a consequence, this bystander shadoo protein is being destroyed unintentionally.
"This finding suggests that prion diseases are dynamic and not necessarily unstoppable, that there could be a cellular process trying to destroy the infectious prions as they appear. And if we could help that process a little bit more, that might be an avenue to attenuate the disease."
Westaway, who works in both the Division of Neurology of the Faculty of Medicine & Dentistry, and the Centre for Prions and Protein Folding Diseases at the U of A, collaborated with a team of researchers from Ontario, the University of California, the Institute for Systems Biology in Washington, the McLaughlin Research Institute in Montana and a researcher in Germany, on this discovery.
The same day this paper was published, very similar findings were published by a team of researchers from the University of California, which demonstrates "these new chemical changes are a concrete and reproducible hallmark of prion disease," says Westaway.
Co-principal investigator George Carlson, from the McLaughlin Research Institute, added: "Given that shadoo may be destroyed by a process that actually targets infectious prions, it was surprising that when we increased the amount of shadoo in laboratory models that the course of disease was not changed. We need to understand why."
The next step for Westaway's research team is to determine why this shadoo protein is disappearing.
The finding opens up a new window of research opportunities.
"We need to better understand this. We want to solve this mystery," he says.
http://www.eurekalert.org/pub_releases/2011-11/uoaf-mri112811.php
Friday, November 18, 2011
lack of tenure creates a dynamic lab environment
Sean Eddy has his dream job: he is a group leader in computational genomics at the Janelia Farm Research Campus of the Howard Hughes Medical Institute (HHMI), in Ashburn, Virginia. Yet, as he approaches his first cyclical review next year, he faces the prospect of being asked to leave if his work is not deemed worthy of the institute's mission.
Eddy was one of ten scientists who, aiming to energize their research and forge multidisciplinary ties, decided in 2006 to join a newly opened research institute with unconventional operating and funding models. Although he was once a tenured researcher at the Washington University School of Medicine in St Louis, Missouri, Eddy is unruffled by the lack of tenure at Janelia. In July 2012, Eddy will undergo a review, required for all Janelia group leaders — there are now 26 — after their initial six years. If an external review panel finds his work deserving, he will be offered the chance to renew for five years. If his work doesn't measure up, he has to be out by July 2014. But the uncertainty of his future never keeps him up at night.
OCEAN/CORBIS
Eddy is “wonderfully stressed” about the review. “I like knowing they can kick me out to the street,” he says. But he isn't revealing a masochistic streak. Remove the security blanket of tenure, says Eddy, and he is driven to work harder, and to assess his research programme more frequently to make sure that it is still on the right track. Furthermore, he says, tenure, which is especially coveted in the United States, brings its own job-related anxieties. “If I'm tenured at Washington University or anywhere, they can't fire me, but they can put me in a closet and take away my space,” he says. “I prefer it this way — I think it's appropriate to have a little fire under you.”
Top model?
As Janelia reaches its fifth anniversary, its research and culture continue to draw notice, and the question of whether its approach is effective remains unanswered (see page 284). Its operating model was a head-turner in 2000, when the HHMI announced plans to create the research campus; and when Janelia opened in 2006, it sparked articles in the academic, scientific and mainstream press that noted its 'radical' departure from the conventional US academic approach (see Nature 443, 128–129; 2006).
But executive director Gerry Rubin, a former academic, emphasizes that Janelia's cyclical-review model is not new. It is based in large part on similar models at established institutes that offer fixed-term contracts with reviews and opportunities to renew, such as the Medical Research Council Laboratory of Molecular Biology (LMB) in Cambridge, UK, and the former basic-research model at Bell Laboratories in Murray Hill, New Jersey, which is now the research arm of French telecommunications company Alcatel-Lucent. Similar models at Cold Spring Harbor Laboratory, a biological sciences institute in New York, and the Carnegie Institution for Science, based in Washington DC, also helped to inspire Janelia. The European Molecular Biology Laboratory, which has five sites across Europe, offers rotating contracts too (see Nature 478, 547–548; 2011).
Scientists at Janelia and similar institutions don't baulk at giving up the comfort and protection of a longer-term job — and in many cases, tenure. On the contrary, they're eager to abandon the academic prototype in favour of a workplace culture in which research is the focus and high-risk, inventive projects are the norm. They are also generally less worried about grants, teaching, committee service and other off-the-bench activities. Indeed, despite the job security and intellectual freedom that tenure confers, it is hardly universally relevant or obligatory, argue administrators and some bench scientists. Limited-term, research-focused contracts, they say, sharpen research programmes by ensuring that scientists are actively involved in day-to-day experiments.
Still, only researchers with an appetite for high-risk work and a willingness to change institutions and lab environments should embrace such a model. Young scientists should also keep in mind that labs at these institutions tend to be far smaller than those in academia, which could create logistical problems if people leave. Researchers who enjoy teaching or the university setting are also more likely to find career satisfaction elsewhere.
Tenure time-out
From the start, Rubin felt sure that Janelia held promise. “We looked at the LMB and Bell and Cold Spring and Carnegie and we saw that you did not have to offer tenure to get the highest quality of scientists,” he says.
Tenure can be antithetical to good science, says Eric Betzig, a group leader in physics at Janelia, who spent six years at Bell. “The chase for tenure enforces a certain conservatism — you learn not to stick your neck out,” says Betzig. “Then, once you have it, it's possible to get stale. And it's small enough around here that we can't afford to have a bunch of stale people.”
Limited-contract institutions typically provide generous funding packages, with a salary for four to five years and enough money to buy equipment and supplies, and hire a postdoc and lab technician. The publish-or-perish imperative of academia is greatly reduced, because such institutions focus more on the researcher's overall scientific programme than on his or her publication rate.
M. STALEY/JANELIA FARM
At Janelia Farm Research Campus, scientists forgo tenure for short-term contracts and cutting-edge labs.
And, because few of these institutions, at least in the United States, offer classes for students, scientists working at them typically don't have to teach; instead, researchers spend a lot of time in the lab. At some facilities, such as Janelia and Bell, scientists have virtually no obligations outside their research; Janelia, in fact, requires its scientists to spend 75% of their time at the bench. Other organizations require a nominal level of non-research commitment, such as service on a committee. “The postdocs here are ticked off because the principal investigators are having so much fun,” says Eddy. “At Janelia, we're all saying, 'Yeah, I guess I should let the postdoc do an experiment'.” Harald Hess, a group leader doing high-resolution microscopy at Janelia, who also spent 11 years at Bell, says that there are few time-sinks to keep scientists away from the bench at either institution. Rubin agrees. “If you want to work in the lab with your own hands, you have to come here,” he says. “That's not going to happen at most academic institutions.”
In return for the right to concentrate so closely on their research, scientists tend to be reviewed on how innovative their programmes are, and on the likelihood of field-changing discoveries, rather than on more conventional metrics. “You may not succeed, and you may not have anything to show for your five or seven years,” says Karel Svoboda, a neurobiologist and biophysicist at Janelia who has worked at both Bell and Cold Spring Harbor. “But in this environment, you may still be viewed as successful, even if you don't have the big paper.”
Judgement day
Review committees at non-tenure institutions examine investigators' work at set intervals, usually every four or five years; researchers who don't make the cut generally have between six months and two years to find a new position. Panels can be internal, external or a combination of both. For example, when the first reviews start happening at Janelia, the committee will consist of about 20 scientists, half from the group that reviews HHMI-funded investigators at other institutions, and half from the field of the person being reviewed. The reviewees will give 45-minute presentations on their work to the full panel.
Review criteria vary, but institutions strive to ensure that their researchers' science is original and creative, and will have an impact. “We don't just count papers or citations, we make a judgement about whether people are doing something that's worth doing,” says Hugh Pelham, director of the LMB. Carnegie asks whether the reviewees are taking advantage of the opportunities provided by the institution, notes president Richard Meserve — in particular, that they are effectively using the time freed up by not having to teach or chase grants. Institutions may consider how much collaboration principal investigators have been involved in and how active they have been on committees; Rubin says he will also provide input on reviewees' performance as lab colleagues and mentors to junior scientists. At the LMB, Pelham and others who regularly interact with reviewees can step in and disagree with the panel's comments; Pelham can even override a recommendation to dismiss, if he thinks the reviewee is on the cusp of a big breakthrough.
At Janelia, investigators aren't allowed to seek external funding, so grant success is irrelevant in reviews. But this is not true everywhere: for example, Cold Spring Harbor does take grant success, and indeed publication rate, into account. Its internal review panel uses both to gauge whether investigators have developed independent research programmes and have the potential to become leaders in their fields. Ideally, the lab would like investigators who are renewed in their fourth-year reviews to earn enough external funding to support 80% of their work by their fifth year.
Meserve declines to reveal Carnegie's staff-retention rates, but says that “very few” of the scientists hired as permanent staff members have left in the past two cycles. Rubin expects about 80% retention at Janelia.
Risky business
E. GRINNELL/HARVARD UNIV.
Cherry Murray: "It was an incredibly highly competitive atmosphere."
A limited-contract system is not for the faint of heart. “There are risks,” says Sydney Brenner, a Nobel-prizewinning molecular biologist and senior resident fellow at Janelia, who was once a senior researcher at the LMB. He notes that doses of uncertainty are par for the course. “But if you're passionate enough about doing science, and you have confidence in yourself, you'll be willing to take them,” he adds.
The pressures of such models are clear. Working at Bell “was an incredibly highly competitive atmosphere”, says Cherry Murray, a physicist who spent 26 years at the lab in research and management positions, including research vice-president, and is now dean of the Harvard School of Engineering and Applied Sciences in Cambridge, Massachusetts. “You were given some leeway, say for a few years after your arrival, to build up your research programme,” she says. But those who consistently stayed in the bottom 10% after that — who weren't exploring imaginative, original ideas as assessed by their managers, and whose research never led to an invention or the possibility of one — were politely asked to leave. Evelyn Hu, an electrical engineer at Harvard who spent nine years as a Bell researcher, recalls a chilling prophecy from company management early on. “I remember attending an orientation for new hires and being told, 'Look to your right, look to your left — in five years, only one of you will be here',” she says.
Those willing to embrace the pressure may face other constraints. The small size of labs in limited-contract institutes can be inhibiting, says Chris Field, director of global ecology at Carnegie and a biologist and environmental Earth systems scientist at Stanford University in California, where he conducts his research but gets no financial or other benefits. “There are some people for whom Carnegie becomes a stage that's not the right size,” he says. “Some people find that as they move through their programme, they're more interested in building a bigger lab group.”
Those running small labs can risk losing a critical mass of personnel, says Douglas Koshland, a geneticist who spent a long time at Carnegie but accepted a tenured position at the University of California, Berkeley, last year. “If you have four people and two leave, then you've got two left, and that can be painful,” he says. But Koshland is still a proponent of small labs, pointing out that the same reduced lab size also enables principal investigators to actually do research, rather than just supervise a dozen or more junior researchers.
Jim Broach is a molecular biologist at Princeton University in New Jersey, but he began his career at Cold Spring Harbor. It was lack of teaching, not of tenure, that drove him into academia. “Postdocs aren't as eager to explore new ideas as graduate students,” he says, noting that Cold Spring Harbor does now have an on-campus graduate programme, the Watson School of Biological Sciences, founded in 1999. “Teaching benefits your research — you learn to formulate your questions more precisely and you learn how to organize and present your ideas in a very powerful way,” he says.
Soft landing
Being asked to leave a place such as Janelia does not usually spell disaster. Murray notes that any researcher who, voluntarily or otherwise, left Bell while she was there had no problem finding an industrial or tenured academic research position elsewhere. For some, that is a fair exchange. Joanna Aizenberg, a materials scientist at Harvard, spent nine years at Bell, where she loved her work. But when the company began to move away from a basic-research focus to concentrate more on applied, product-driven research, she decided to resign. Shortly after Aizenberg left the company in 2007, she accepted an offer at Harvard. “It's obviously wonderful to have tenure,” says Aizenberg, “and to think that whatever happens, I have it.”
At Janelia, group leaders who don't receive a renewal offer for a second term will get transitional funding of up to US$1 million a year for two years, a bonus that significantly boosts their recruitment value. Those who get a renewal offer but decide to leave anyway can take their HHMI investigator status, and they get the same transitional funding. “You show up with a really big cheque in your pocket — that's really valuable in academia,” says Tim Harris, director of the applied physics and instrumentation group at Janelia. At the LMB, those who are asked to leave are given a month's pay for each year they've worked at the Medical Research Council, up to a maximum of 21 months, and get about a year's notice before they actually have to leave. At Cold Spring Harbor, researchers are reviewed four years into their five-year contracts, so if they are asked to leave, they still have a year to find a job, and may have some money left over from their start-up packages. At Carnegie, departures are often based on mutual agreement. Scientists who go elsewhere receive a lump sum representing their unused annual leave.
Supporters of the short-term model note that tenured academic positions are tough to find — and, in any case, few jobs have long-term guarantees. “Having any job in research, especially now, is such a gift,” says Hess. He says researchers should focus on their innovations, rather than on how long their jobs will last. “For me, the reward has always been on the positive side — what's exciting, what's new, and to not be fear-driven about when my job might end,” he says. “It's really a blessing to have this kind of opportunity — where people pay you to do what you love doing.”
http://www.nature.com/naturejobs/science/articles/10.1038%2Fnj7373-433a?WT.ec_id=NATUREjobs-20111103
Eddy was one of ten scientists who, aiming to energize their research and forge multidisciplinary ties, decided in 2006 to join a newly opened research institute with unconventional operating and funding models. Although he was once a tenured researcher at the Washington University School of Medicine in St Louis, Missouri, Eddy is unruffled by the lack of tenure at Janelia. In July 2012, Eddy will undergo a review, required for all Janelia group leaders — there are now 26 — after their initial six years. If an external review panel finds his work deserving, he will be offered the chance to renew for five years. If his work doesn't measure up, he has to be out by July 2014. But the uncertainty of his future never keeps him up at night.
OCEAN/CORBIS
Eddy is “wonderfully stressed” about the review. “I like knowing they can kick me out to the street,” he says. But he isn't revealing a masochistic streak. Remove the security blanket of tenure, says Eddy, and he is driven to work harder, and to assess his research programme more frequently to make sure that it is still on the right track. Furthermore, he says, tenure, which is especially coveted in the United States, brings its own job-related anxieties. “If I'm tenured at Washington University or anywhere, they can't fire me, but they can put me in a closet and take away my space,” he says. “I prefer it this way — I think it's appropriate to have a little fire under you.”
Top model?
As Janelia reaches its fifth anniversary, its research and culture continue to draw notice, and the question of whether its approach is effective remains unanswered (see page 284). Its operating model was a head-turner in 2000, when the HHMI announced plans to create the research campus; and when Janelia opened in 2006, it sparked articles in the academic, scientific and mainstream press that noted its 'radical' departure from the conventional US academic approach (see Nature 443, 128–129; 2006).
But executive director Gerry Rubin, a former academic, emphasizes that Janelia's cyclical-review model is not new. It is based in large part on similar models at established institutes that offer fixed-term contracts with reviews and opportunities to renew, such as the Medical Research Council Laboratory of Molecular Biology (LMB) in Cambridge, UK, and the former basic-research model at Bell Laboratories in Murray Hill, New Jersey, which is now the research arm of French telecommunications company Alcatel-Lucent. Similar models at Cold Spring Harbor Laboratory, a biological sciences institute in New York, and the Carnegie Institution for Science, based in Washington DC, also helped to inspire Janelia. The European Molecular Biology Laboratory, which has five sites across Europe, offers rotating contracts too (see Nature 478, 547–548; 2011).
Scientists at Janelia and similar institutions don't baulk at giving up the comfort and protection of a longer-term job — and in many cases, tenure. On the contrary, they're eager to abandon the academic prototype in favour of a workplace culture in which research is the focus and high-risk, inventive projects are the norm. They are also generally less worried about grants, teaching, committee service and other off-the-bench activities. Indeed, despite the job security and intellectual freedom that tenure confers, it is hardly universally relevant or obligatory, argue administrators and some bench scientists. Limited-term, research-focused contracts, they say, sharpen research programmes by ensuring that scientists are actively involved in day-to-day experiments.
Still, only researchers with an appetite for high-risk work and a willingness to change institutions and lab environments should embrace such a model. Young scientists should also keep in mind that labs at these institutions tend to be far smaller than those in academia, which could create logistical problems if people leave. Researchers who enjoy teaching or the university setting are also more likely to find career satisfaction elsewhere.
Tenure time-out
From the start, Rubin felt sure that Janelia held promise. “We looked at the LMB and Bell and Cold Spring and Carnegie and we saw that you did not have to offer tenure to get the highest quality of scientists,” he says.
Tenure can be antithetical to good science, says Eric Betzig, a group leader in physics at Janelia, who spent six years at Bell. “The chase for tenure enforces a certain conservatism — you learn not to stick your neck out,” says Betzig. “Then, once you have it, it's possible to get stale. And it's small enough around here that we can't afford to have a bunch of stale people.”
Limited-contract institutions typically provide generous funding packages, with a salary for four to five years and enough money to buy equipment and supplies, and hire a postdoc and lab technician. The publish-or-perish imperative of academia is greatly reduced, because such institutions focus more on the researcher's overall scientific programme than on his or her publication rate.
M. STALEY/JANELIA FARM
At Janelia Farm Research Campus, scientists forgo tenure for short-term contracts and cutting-edge labs.
And, because few of these institutions, at least in the United States, offer classes for students, scientists working at them typically don't have to teach; instead, researchers spend a lot of time in the lab. At some facilities, such as Janelia and Bell, scientists have virtually no obligations outside their research; Janelia, in fact, requires its scientists to spend 75% of their time at the bench. Other organizations require a nominal level of non-research commitment, such as service on a committee. “The postdocs here are ticked off because the principal investigators are having so much fun,” says Eddy. “At Janelia, we're all saying, 'Yeah, I guess I should let the postdoc do an experiment'.” Harald Hess, a group leader doing high-resolution microscopy at Janelia, who also spent 11 years at Bell, says that there are few time-sinks to keep scientists away from the bench at either institution. Rubin agrees. “If you want to work in the lab with your own hands, you have to come here,” he says. “That's not going to happen at most academic institutions.”
In return for the right to concentrate so closely on their research, scientists tend to be reviewed on how innovative their programmes are, and on the likelihood of field-changing discoveries, rather than on more conventional metrics. “You may not succeed, and you may not have anything to show for your five or seven years,” says Karel Svoboda, a neurobiologist and biophysicist at Janelia who has worked at both Bell and Cold Spring Harbor. “But in this environment, you may still be viewed as successful, even if you don't have the big paper.”
Judgement day
Review committees at non-tenure institutions examine investigators' work at set intervals, usually every four or five years; researchers who don't make the cut generally have between six months and two years to find a new position. Panels can be internal, external or a combination of both. For example, when the first reviews start happening at Janelia, the committee will consist of about 20 scientists, half from the group that reviews HHMI-funded investigators at other institutions, and half from the field of the person being reviewed. The reviewees will give 45-minute presentations on their work to the full panel.
Review criteria vary, but institutions strive to ensure that their researchers' science is original and creative, and will have an impact. “We don't just count papers or citations, we make a judgement about whether people are doing something that's worth doing,” says Hugh Pelham, director of the LMB. Carnegie asks whether the reviewees are taking advantage of the opportunities provided by the institution, notes president Richard Meserve — in particular, that they are effectively using the time freed up by not having to teach or chase grants. Institutions may consider how much collaboration principal investigators have been involved in and how active they have been on committees; Rubin says he will also provide input on reviewees' performance as lab colleagues and mentors to junior scientists. At the LMB, Pelham and others who regularly interact with reviewees can step in and disagree with the panel's comments; Pelham can even override a recommendation to dismiss, if he thinks the reviewee is on the cusp of a big breakthrough.
At Janelia, investigators aren't allowed to seek external funding, so grant success is irrelevant in reviews. But this is not true everywhere: for example, Cold Spring Harbor does take grant success, and indeed publication rate, into account. Its internal review panel uses both to gauge whether investigators have developed independent research programmes and have the potential to become leaders in their fields. Ideally, the lab would like investigators who are renewed in their fourth-year reviews to earn enough external funding to support 80% of their work by their fifth year.
Meserve declines to reveal Carnegie's staff-retention rates, but says that “very few” of the scientists hired as permanent staff members have left in the past two cycles. Rubin expects about 80% retention at Janelia.
Risky business
E. GRINNELL/HARVARD UNIV.
Cherry Murray: "It was an incredibly highly competitive atmosphere."
A limited-contract system is not for the faint of heart. “There are risks,” says Sydney Brenner, a Nobel-prizewinning molecular biologist and senior resident fellow at Janelia, who was once a senior researcher at the LMB. He notes that doses of uncertainty are par for the course. “But if you're passionate enough about doing science, and you have confidence in yourself, you'll be willing to take them,” he adds.
The pressures of such models are clear. Working at Bell “was an incredibly highly competitive atmosphere”, says Cherry Murray, a physicist who spent 26 years at the lab in research and management positions, including research vice-president, and is now dean of the Harvard School of Engineering and Applied Sciences in Cambridge, Massachusetts. “You were given some leeway, say for a few years after your arrival, to build up your research programme,” she says. But those who consistently stayed in the bottom 10% after that — who weren't exploring imaginative, original ideas as assessed by their managers, and whose research never led to an invention or the possibility of one — were politely asked to leave. Evelyn Hu, an electrical engineer at Harvard who spent nine years as a Bell researcher, recalls a chilling prophecy from company management early on. “I remember attending an orientation for new hires and being told, 'Look to your right, look to your left — in five years, only one of you will be here',” she says.
Those willing to embrace the pressure may face other constraints. The small size of labs in limited-contract institutes can be inhibiting, says Chris Field, director of global ecology at Carnegie and a biologist and environmental Earth systems scientist at Stanford University in California, where he conducts his research but gets no financial or other benefits. “There are some people for whom Carnegie becomes a stage that's not the right size,” he says. “Some people find that as they move through their programme, they're more interested in building a bigger lab group.”
Those running small labs can risk losing a critical mass of personnel, says Douglas Koshland, a geneticist who spent a long time at Carnegie but accepted a tenured position at the University of California, Berkeley, last year. “If you have four people and two leave, then you've got two left, and that can be painful,” he says. But Koshland is still a proponent of small labs, pointing out that the same reduced lab size also enables principal investigators to actually do research, rather than just supervise a dozen or more junior researchers.
Jim Broach is a molecular biologist at Princeton University in New Jersey, but he began his career at Cold Spring Harbor. It was lack of teaching, not of tenure, that drove him into academia. “Postdocs aren't as eager to explore new ideas as graduate students,” he says, noting that Cold Spring Harbor does now have an on-campus graduate programme, the Watson School of Biological Sciences, founded in 1999. “Teaching benefits your research — you learn to formulate your questions more precisely and you learn how to organize and present your ideas in a very powerful way,” he says.
Soft landing
Being asked to leave a place such as Janelia does not usually spell disaster. Murray notes that any researcher who, voluntarily or otherwise, left Bell while she was there had no problem finding an industrial or tenured academic research position elsewhere. For some, that is a fair exchange. Joanna Aizenberg, a materials scientist at Harvard, spent nine years at Bell, where she loved her work. But when the company began to move away from a basic-research focus to concentrate more on applied, product-driven research, she decided to resign. Shortly after Aizenberg left the company in 2007, she accepted an offer at Harvard. “It's obviously wonderful to have tenure,” says Aizenberg, “and to think that whatever happens, I have it.”
At Janelia, group leaders who don't receive a renewal offer for a second term will get transitional funding of up to US$1 million a year for two years, a bonus that significantly boosts their recruitment value. Those who get a renewal offer but decide to leave anyway can take their HHMI investigator status, and they get the same transitional funding. “You show up with a really big cheque in your pocket — that's really valuable in academia,” says Tim Harris, director of the applied physics and instrumentation group at Janelia. At the LMB, those who are asked to leave are given a month's pay for each year they've worked at the Medical Research Council, up to a maximum of 21 months, and get about a year's notice before they actually have to leave. At Cold Spring Harbor, researchers are reviewed four years into their five-year contracts, so if they are asked to leave, they still have a year to find a job, and may have some money left over from their start-up packages. At Carnegie, departures are often based on mutual agreement. Scientists who go elsewhere receive a lump sum representing their unused annual leave.
Supporters of the short-term model note that tenured academic positions are tough to find — and, in any case, few jobs have long-term guarantees. “Having any job in research, especially now, is such a gift,” says Hess. He says researchers should focus on their innovations, rather than on how long their jobs will last. “For me, the reward has always been on the positive side — what's exciting, what's new, and to not be fear-driven about when my job might end,” he says. “It's really a blessing to have this kind of opportunity — where people pay you to do what you love doing.”
http://www.nature.com/naturejobs/science/articles/10.1038%2Fnj7373-433a?WT.ec_id=NATUREjobs-20111103
Monday, November 14, 2011
Mitochondria Can’t Be Cleared out When Damaged
ScienceDaily (Nov. 10, 2011) — Current thinking about Parkinson's disease is that it's a disorder of mitochondria, the energy-producing organelles inside cells, causing neurons in the brain's substantia nigra to die or become impaired. A study from Children's Hospital Boston now shows that genetic mutations causing a hereditary form of Parkinson's disease cause mitochondria to run amok inside the cell, leaving the cell without a brake to stop them.
Findings appear in the Nov. 11 issue of Cell.
Mitochondrial movement is often a good thing, especially in neurons, which need to get mitochondria to cells' periphery in order to fuel the axons and dendrites that send and receive signals. However, arresting this movement is equally important, says senior investigator Thomas Schwarz, PhD, of Children's F.M. Kirby Neurobiology Center, since it allows mitochondria to be quarantined and destroyed when they go bad.
"Mitochondria, when damaged, produce reactive oxygen species that are highly destructive, and can fuse with healthy mitochondria and contaminate them, too," Schwarz says. "It's the equivalent of an environmental disaster in the cell."
Studying neurons from fruit flies, rats and mice, as well as cultured human cells, Schwarz and colleagues provide the most detailed understanding to date of the effects of the gene mutations, which encode the proteins Parkin and PINK1. They demonstrate how these proteins interact with proteins responsible for mitochondrial movement -- in particular Miro, which literally hitches a molecular motor onto the organelle.
Normally, when mitochondria go bad, PINK1 tags Miro to be destroyed by Parkin and enzymes in the cell, the researchers showed. When Miro is destroyed, the motor detaches from the mitochondrion. The organelle, unable to move, can then be disposed of: The cell literally digests it.
But when either PINK1 or Parkin is mutated, this containment system fails, leaving the damaged mitochondria free to move about the cell, spewing toxic compounds and fusing to otherwise healthy mitochondria and introducing damaged components.
The study's findings are consistent with observed changes in mitochondrial distribution, transport and dynamics in other neurodegenerative diseases such as Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), and Charcot-Marie-Tooth disease, the researchers note.
Although the team studied a rare hereditary form of Parkinson's, the findings may shed light on what's going on in the more common sporadic form of the disease, Schwarz says.
"Whether it's clearing out damaged mitochondria, or preventing mitochondrial damage, the common thread is that there's too much damage in mitochondria in a particular brain region," he says.
While Schwarz sees potential in gene therapy to restore normal PINK1 or Parkin to neurons, he is more interested in the possibility of helping neurons flush out bad mitochondria or make enough new, healthy mitochondria to keep them viable. "We may need to do both," he says.
The study was funded by the Ellison Medical Foundation, the Hartman Foundation for Parkinson's Research, the National Institutes of Health and a LSRF Novartis Fellowship. Xinnan Wang, PhD, of the F.M. Kirby Neurobiology Center at Children's, was first author.
Findings appear in the Nov. 11 issue of Cell.
Mitochondrial movement is often a good thing, especially in neurons, which need to get mitochondria to cells' periphery in order to fuel the axons and dendrites that send and receive signals. However, arresting this movement is equally important, says senior investigator Thomas Schwarz, PhD, of Children's F.M. Kirby Neurobiology Center, since it allows mitochondria to be quarantined and destroyed when they go bad.
"Mitochondria, when damaged, produce reactive oxygen species that are highly destructive, and can fuse with healthy mitochondria and contaminate them, too," Schwarz says. "It's the equivalent of an environmental disaster in the cell."
Studying neurons from fruit flies, rats and mice, as well as cultured human cells, Schwarz and colleagues provide the most detailed understanding to date of the effects of the gene mutations, which encode the proteins Parkin and PINK1. They demonstrate how these proteins interact with proteins responsible for mitochondrial movement -- in particular Miro, which literally hitches a molecular motor onto the organelle.
Normally, when mitochondria go bad, PINK1 tags Miro to be destroyed by Parkin and enzymes in the cell, the researchers showed. When Miro is destroyed, the motor detaches from the mitochondrion. The organelle, unable to move, can then be disposed of: The cell literally digests it.
But when either PINK1 or Parkin is mutated, this containment system fails, leaving the damaged mitochondria free to move about the cell, spewing toxic compounds and fusing to otherwise healthy mitochondria and introducing damaged components.
The study's findings are consistent with observed changes in mitochondrial distribution, transport and dynamics in other neurodegenerative diseases such as Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), and Charcot-Marie-Tooth disease, the researchers note.
Although the team studied a rare hereditary form of Parkinson's, the findings may shed light on what's going on in the more common sporadic form of the disease, Schwarz says.
"Whether it's clearing out damaged mitochondria, or preventing mitochondrial damage, the common thread is that there's too much damage in mitochondria in a particular brain region," he says.
While Schwarz sees potential in gene therapy to restore normal PINK1 or Parkin to neurons, he is more interested in the possibility of helping neurons flush out bad mitochondria or make enough new, healthy mitochondria to keep them viable. "We may need to do both," he says.
The study was funded by the Ellison Medical Foundation, the Hartman Foundation for Parkinson's Research, the National Institutes of Health and a LSRF Novartis Fellowship. Xinnan Wang, PhD, of the F.M. Kirby Neurobiology Center at Children's, was first author.
Weird Cases Point Up Allergists' Weird World
BOSTON -- If there's a limit to the range of ways in which the human body can fail, medical science has yet to find it, and allergists may be more aware of that fact than clinicians in other specialties.
Poster presentations at the American College of Allergy, Asthma, and Immunology's annual meeting here highlighted the bizarre and every-expanding number of substances that the immune system can regard as noxious, ranging from Mom's breast milk to a man's own semen.
Some of these case reports were the first ever to describe such allergies, according to the physicians presenting them. That raises the question of their importance to the allergist community -- what is the value of knowing about a possible allergy that most clinicians will never encounter in their entire careers?
John Oppenheimer, MD, who headed the ACAAI's abstract selection committee for the meeting, had a ready answer. "It may be one in a million, but if it's you [with the allergy], it's 100%," he told MedPage Today.
He also noted that allergies now recognized as common were initially noticed in a single patient, with latex allergy being an example.
"When latex was first reported as an allergy, it was an abstract and it was forgotten for years. All of a sudden it became a signal when HIV came and this was a big issue. Having had that as a prior report allowed us to move forward," Oppenheimer said.
"What might be wacky today might be an epidemic tomorrow," he added.
With that in mind, here's a sample of some of the more unusual reports presented at this year's meeting.
Semen Allergy Explains Flu-Like Symptoms
Againdra Bewtra, MBBS, of Creighton University in Omaha, Neb., and colleagues described the case of a man who complained of head and body aches, accompanied by what he called "brain fog," within a day after ejaculation irrespective of the circumstances.
Bewtra's group had previously identified semen allergy in a series of female patients and, since there was no ready explanation of the man's symptoms, they tested him with a sample of his semen.
Skin prick testing with the sample yielded "mildly positive" results and a follow-up with intradermal testing showed a large reaction, the researchers reported.
They recommended that the man try prednisone and/or high doses of antihistamines before having sexual activity, but they did not indicate whether or not it worked.
Peanut Allergy in an Exclusively Breastfed Infant
Researchers at the University of Michigan in Ann Arbor reported what they believed to be the first case of enterocolitis triggered by peanut allergy in an infant whose only exposure appeared to be breast milk from his mother.
The case involved a 7-month-old who would vomit copiously after breastfeeding, but only when his mother had recently eaten peanut products. As far as could be determined, the baby boy was exclusively breastfed and had never eaten any peanut products directly.
Patch testing indicated peanut sensitivity, although skin prick and serum IgE results were negative for peanut. Oral challenge testing was not performed.
When peanut products were eliminated from the mother's diet, the baby's symptoms disappeared, according to David Robertson, MD, MPH, and Matthew Greenhawt, MD.
Although development of peanut allergy in this way appeared unprecedented, the researchers noted that previous studies had shown that breast milk can contain peanut protein and that other types of food allergies have been induced in exclusively breastfed infants.
Another Way Alcohol Can Be Bad for You
Alcohol not only ruins the liver and causes accidents, it also can be an allergen, according to researchers at Walter Reed National Military Medical Center in Bethesda, Md.
They described a case involving a 25-year-old woman who would develop hives on her back whenever she had alcoholic beverages, including wine, beer, and distilled spirits.
An oral challenge test at Walter Reed reproduced the syndrome, reported Wayne Wolverton, DO, and colleagues, and no recurrence was reported after they recommended strict avoidance.
The researchers said this was only the second reported case of systemic dermatitis attributed to ethanol allergy.
Anaphylaxis in an Allergy Clinic Worker
Needlesticks are hazardous even in the absence of contamination with infectious pathogens, according to another group of military doctors, who reported a case of anaphylaxis in a careless allergy clinic worker.
The worker was preparing syringes to be used for routine immunotherapy injections. She accidentally pricked herself with one containing Timothy grass allergens.
She was known to be mildly allergic to Timothy grass and had previously taken loratadine for it, but severe hypersensitivity had not been suspected.
Within five minutes of the needlestick, she developed a systemic reaction. It took five doses of epinephrine to bring her hypotension, tachycardia, and breathing difficulties under control, according to Capt. Michelle Bandino, MD, and Michael Tankersley, MD, of Lackland Air Force Base in San Antonio.
Post hoc review disclosed that the worker was also taking a beta-blocker, which is known to increase the risk of severe allergic reactions in sensitive individuals.
The Lackland physicians suggested that healthcare workers be screened for such risk factors before being assigned to duties that could expose them to potential anaphylaxis triggers.
Pork-Cat Syndrome: No Longer the French Disease
An odd co-allergy to pork meat and to cats previously reported only in France has now been detected in the U.S., according to a report from researchers at the University of Virginia.
In a platform presentation at the ACAAI meeting, Jonathon Posthumus, MD, said his clinic had confirmed "pork-cat" syndrome in six patients.
The condition appears to involve cross-reactive sensitivity to serum albumin from pigs and cats. In the case of cats, the protein is contained in skin and saliva, so the exposure is similar to that responsible for the more common cat allergy related to the Fel d1 protein.
Objective testing in the six patients showed that they were sensitive to cat and pork serum albumins.
Posthumus said a complicating factor in diagnosing the condition was that patients reported that reactions were inconsistent following pork ingestion. However, albumin proteins can be broken down by heating, so that different cooking methods could explain the variability.
About That Runny Nose ...
Two case reports here described patients whose rhinitis turned out not to be allergic, but something potentially far more serious.
Both patients complained of runny noses that did not appear correlated with any known allergen, either temporally or in objective testing.
Finally, physicians examined the nasal discharge itself and found that it was not the normal type, but in fact was cerebrospinal fluid. Follow-up imaging exams revealed fistulas through which CSF was leaking into the nasosinus cavity.
The two reports offered different tips on how to distinguish the condition from allergic rhinitis.
Richard Harris, MD, in private practice in Beverly Hills, Calif., noted that CSF contains glucose whereas normal nasal secretions do not. He suggested that urinary glucose test strips meant for monitoring diabetic patients can be used to determine that a nasal discharge is likely to be CSF.
The other group, led by Rohit Divekar, MD, PhD, of the University of Texas Medical Branch in Galveston, said that cranial CT findings were reliably diagnostic.
"An empty sella is a robust radiographic marker and is almost universally present in this group of patients, but not in patients with nonspontaneous leaks," they indicated.
http://www.medpagetoday.com/MeetingCoverage/ACAAI/29563?utm_source=WC&utm_medium=email&utm_campaign=Meeting_Roundup_ACAAI
Poster presentations at the American College of Allergy, Asthma, and Immunology's annual meeting here highlighted the bizarre and every-expanding number of substances that the immune system can regard as noxious, ranging from Mom's breast milk to a man's own semen.
Some of these case reports were the first ever to describe such allergies, according to the physicians presenting them. That raises the question of their importance to the allergist community -- what is the value of knowing about a possible allergy that most clinicians will never encounter in their entire careers?
John Oppenheimer, MD, who headed the ACAAI's abstract selection committee for the meeting, had a ready answer. "It may be one in a million, but if it's you [with the allergy], it's 100%," he told MedPage Today.
He also noted that allergies now recognized as common were initially noticed in a single patient, with latex allergy being an example.
"When latex was first reported as an allergy, it was an abstract and it was forgotten for years. All of a sudden it became a signal when HIV came and this was a big issue. Having had that as a prior report allowed us to move forward," Oppenheimer said.
"What might be wacky today might be an epidemic tomorrow," he added.
With that in mind, here's a sample of some of the more unusual reports presented at this year's meeting.
Semen Allergy Explains Flu-Like Symptoms
Againdra Bewtra, MBBS, of Creighton University in Omaha, Neb., and colleagues described the case of a man who complained of head and body aches, accompanied by what he called "brain fog," within a day after ejaculation irrespective of the circumstances.
Bewtra's group had previously identified semen allergy in a series of female patients and, since there was no ready explanation of the man's symptoms, they tested him with a sample of his semen.
Skin prick testing with the sample yielded "mildly positive" results and a follow-up with intradermal testing showed a large reaction, the researchers reported.
They recommended that the man try prednisone and/or high doses of antihistamines before having sexual activity, but they did not indicate whether or not it worked.
Peanut Allergy in an Exclusively Breastfed Infant
Researchers at the University of Michigan in Ann Arbor reported what they believed to be the first case of enterocolitis triggered by peanut allergy in an infant whose only exposure appeared to be breast milk from his mother.
The case involved a 7-month-old who would vomit copiously after breastfeeding, but only when his mother had recently eaten peanut products. As far as could be determined, the baby boy was exclusively breastfed and had never eaten any peanut products directly.
Patch testing indicated peanut sensitivity, although skin prick and serum IgE results were negative for peanut. Oral challenge testing was not performed.
When peanut products were eliminated from the mother's diet, the baby's symptoms disappeared, according to David Robertson, MD, MPH, and Matthew Greenhawt, MD.
Although development of peanut allergy in this way appeared unprecedented, the researchers noted that previous studies had shown that breast milk can contain peanut protein and that other types of food allergies have been induced in exclusively breastfed infants.
Another Way Alcohol Can Be Bad for You
Alcohol not only ruins the liver and causes accidents, it also can be an allergen, according to researchers at Walter Reed National Military Medical Center in Bethesda, Md.
They described a case involving a 25-year-old woman who would develop hives on her back whenever she had alcoholic beverages, including wine, beer, and distilled spirits.
An oral challenge test at Walter Reed reproduced the syndrome, reported Wayne Wolverton, DO, and colleagues, and no recurrence was reported after they recommended strict avoidance.
The researchers said this was only the second reported case of systemic dermatitis attributed to ethanol allergy.
Anaphylaxis in an Allergy Clinic Worker
Needlesticks are hazardous even in the absence of contamination with infectious pathogens, according to another group of military doctors, who reported a case of anaphylaxis in a careless allergy clinic worker.
The worker was preparing syringes to be used for routine immunotherapy injections. She accidentally pricked herself with one containing Timothy grass allergens.
She was known to be mildly allergic to Timothy grass and had previously taken loratadine for it, but severe hypersensitivity had not been suspected.
Within five minutes of the needlestick, she developed a systemic reaction. It took five doses of epinephrine to bring her hypotension, tachycardia, and breathing difficulties under control, according to Capt. Michelle Bandino, MD, and Michael Tankersley, MD, of Lackland Air Force Base in San Antonio.
Post hoc review disclosed that the worker was also taking a beta-blocker, which is known to increase the risk of severe allergic reactions in sensitive individuals.
The Lackland physicians suggested that healthcare workers be screened for such risk factors before being assigned to duties that could expose them to potential anaphylaxis triggers.
Pork-Cat Syndrome: No Longer the French Disease
An odd co-allergy to pork meat and to cats previously reported only in France has now been detected in the U.S., according to a report from researchers at the University of Virginia.
In a platform presentation at the ACAAI meeting, Jonathon Posthumus, MD, said his clinic had confirmed "pork-cat" syndrome in six patients.
The condition appears to involve cross-reactive sensitivity to serum albumin from pigs and cats. In the case of cats, the protein is contained in skin and saliva, so the exposure is similar to that responsible for the more common cat allergy related to the Fel d1 protein.
Objective testing in the six patients showed that they were sensitive to cat and pork serum albumins.
Posthumus said a complicating factor in diagnosing the condition was that patients reported that reactions were inconsistent following pork ingestion. However, albumin proteins can be broken down by heating, so that different cooking methods could explain the variability.
About That Runny Nose ...
Two case reports here described patients whose rhinitis turned out not to be allergic, but something potentially far more serious.
Both patients complained of runny noses that did not appear correlated with any known allergen, either temporally or in objective testing.
Finally, physicians examined the nasal discharge itself and found that it was not the normal type, but in fact was cerebrospinal fluid. Follow-up imaging exams revealed fistulas through which CSF was leaking into the nasosinus cavity.
The two reports offered different tips on how to distinguish the condition from allergic rhinitis.
Richard Harris, MD, in private practice in Beverly Hills, Calif., noted that CSF contains glucose whereas normal nasal secretions do not. He suggested that urinary glucose test strips meant for monitoring diabetic patients can be used to determine that a nasal discharge is likely to be CSF.
The other group, led by Rohit Divekar, MD, PhD, of the University of Texas Medical Branch in Galveston, said that cranial CT findings were reliably diagnostic.
"An empty sella is a robust radiographic marker and is almost universally present in this group of patients, but not in patients with nonspontaneous leaks," they indicated.
http://www.medpagetoday.com/MeetingCoverage/ACAAI/29563?utm_source=WC&utm_medium=email&utm_campaign=Meeting_Roundup_ACAAI
Friday, November 11, 2011
Food Sheath
Consciousness: What You Don't Know Might Kill You
Ever ask yourself, "Where does consciousness come from?" Or, "Can consciousness come from an absence of consciousness?" Albeit, not the subject of your everyday discourse, these are still interesting and relevant questions. When inquiring about consciousness a valid qualifying question might be, "What type of consciousness are we talking about?" For example, dreaming consciousness comes from the REM cycle. A medical coma consciousness comes from pharmaceutical drugs. Enlightenment consciousness comes from meditation or some other practiced ability to observe and focus attention. However, when it comes to your physical consciousness, such as how emotional and mentally astute you are and how healthy you are on a cellular level, the answer might surprise you.
The Eastern sciences, such as Indian or Tibetan Ayurveda and Chinese medicine, have a very clear-cut and direct answer to this last aspect of consciousness. These ancient sources of wisdom say that the food you eat is the foundation upon which your emotional, mental and physical well-being is based upon. Ayurveda has a very succinct term for the physical body. It is referred to as the "Food Sheath." They call the physical body that because it requires a myriad of different types of food. It requires oxygen food, light food, physical "tactile" food, hydrating water food and solid alimentary food, all as sources of nourishment. The "Food Sheath" term eliminates all the "judgment" issues from the physical -- no charges about the butt being too big or small, no painful comparisons or emphasis on beauty of any kind. The body is simply the "Food Sheath."
The physical body or "Food Sheath" receives its quality of intelligence from the food you eat. We're not talking brain science or rocket surgery here. If you start your morning by drinking nothing but coffee and eating a donut, then you run around all day, some time in the afternoon you are going to start tanking. You will find it increasingly difficult to focus and concentrate. You will find yourself becoming more and more agitated and impatient when life's daily dose of obstacles smacks you right on your... food sheath. You may experience shaking of the extremities or a headache. You may find your mind easily distracted and unable to remember simple details: Where are my glasses, keys or cell phone?
As stated in age-old philosophy and co-opted by the high-tech world, "garbage in; garbage out." That's because a calorie is not a calorie. The quality of your energy comes directly from the quality of the food/fuel you take in. Now Ayurveda goes deeper with this understanding than may initially seem self-evident. For example, if you eat a lot of foods that have been grown to produce no seeds, such as some types of oranges or watermelon, over time, that could compromise your body's fertility. After all what are seeds? They are highly concentrated forms of fertility consciousness/energy. Bear in mind these types of food would have to be pervasive in your diet and you would have to be exposed to these fertility-sterilized forms of foods consistently for prolonged periods of time. It is unlikely anyone is going to eat that much seedless fruits with no diversity. But what if all crop seeds were sterile? Would that change the dynamics?
With that in mind, let's now look at a pervasive form of food that we have all been exposed to for a prolonged period of time: GMOs. Genetically modified food organisms. Even though GMOs are foods that have been genetically injected with extremely poisonous material, the FDA in its infinite wisdom has declared that these foods do not require any testing whatsoever. In fact, the FDA has never done any testing on them! Monsanto has been legally, genetically poisoning our food supply for decades. It's no surprise that wildlife such as migrating birds will not touch a single kernel of GMO corn when growing side by side a crop of non-GMO corn. In fact no animal, other than humans, when given a choice, will consume a GMO food.
These animals intuitively know what Ayurveda and Chinese Medicine teach: Food is your first wave of either medicine or poison. When you eat foods that are packed with Chi, life force energy, your mind, body and emotions are energized. When you eat foods that are packed with antioxidants, your immune system becomes stronger and empowered to destroy free radicals, because that is where the consciousness that directs the body comes from. Conversely, when you eat foods that have been genetically altered to contain chemicals that are designed to kill and destroy life, how can that have a positive affect on your energy?
In addition to the GMO nightmare, Monsanto has produced "terminator seeds." These are seeds especially designed to die after one crop. They carry a sterilized energy that does not allow another generation of plants to grow. Why? Money. The farmer has to go back to Monsanto each and every growing season for more seeds, so Monsanto's profits have increased accordingly. It is pure and simple greed, even though the planet destroying consequences of this greed are neither pure nor simple.
How can Monsanto get away with poisoning our food supply? You may find it interesting to know that many high level FDA people are former Monsanto employees. And, that's right; you guessed it. Incestuously many of the upper level Monsanto employees are former FDA staff. Well, maybe it isn't interesting. Pathetic may be closer to the truth. We have the best politicians money can buy.
Most people are unaware of these healing sciences that have survived scrutiny for thousand of years. What they have to say about the quality of consciousness that feeds your health or disease is still relevant in today's world. You need to look no further than cancers, both common and exotic, which are on the rise, or that the rate of obesity and insulin resistant disorders like diabetes have been increasing exponentially. Attention deficit disorders and autism cases seem omnipresent. Isn't it interesting that the expansion of all of these diseases happens to magically correspond to the ever-increasing presence of GMO's in the American diet.
If you are thinking, "Oh, but I'm not eating GMOs," think again. You probably are; you just don't know it. Since the FDA has declared that foods containing GMOs do not have to be labeled as such, you are not informed that the food you are consuming is toxic. If you are not eating organic foods exclusively, if you are eating or drinking anything with high fructose corn syrup (sodas, ketchup, fruit juices), corn, soybeans, cottonseed, sugar beets, canola oil, most fast food meals or pre-packaged processed foods from large food corporations, you are most likely eating GMOs. For more information please visit: http://www.nongmoshoppingguide.com/tips-for-avoiding-gmos.html.
What you may have become painfully aware of is that you are fatigued all the time. You may have noticed that you having a harder time concentrating or remembering things. You may have observed an increase in health issues or poor sleep. You may have sensed that the consciousness of the body is off in some way but have not yet connected all the dots. All of these are profound reasons to examine what you are consuming that is feeding the quality of consciousness that governs your human experience.
Socrates once commented, "The unexamined life is not worth living." If he were alive today, his consciousness cry might be, "The unexamined diet is not worth eating."
http://www.huffingtonpost.com/vaishali/gmo-seeds-food_b_1031515.html
Ever ask yourself, "Where does consciousness come from?" Or, "Can consciousness come from an absence of consciousness?" Albeit, not the subject of your everyday discourse, these are still interesting and relevant questions. When inquiring about consciousness a valid qualifying question might be, "What type of consciousness are we talking about?" For example, dreaming consciousness comes from the REM cycle. A medical coma consciousness comes from pharmaceutical drugs. Enlightenment consciousness comes from meditation or some other practiced ability to observe and focus attention. However, when it comes to your physical consciousness, such as how emotional and mentally astute you are and how healthy you are on a cellular level, the answer might surprise you.
The Eastern sciences, such as Indian or Tibetan Ayurveda and Chinese medicine, have a very clear-cut and direct answer to this last aspect of consciousness. These ancient sources of wisdom say that the food you eat is the foundation upon which your emotional, mental and physical well-being is based upon. Ayurveda has a very succinct term for the physical body. It is referred to as the "Food Sheath." They call the physical body that because it requires a myriad of different types of food. It requires oxygen food, light food, physical "tactile" food, hydrating water food and solid alimentary food, all as sources of nourishment. The "Food Sheath" term eliminates all the "judgment" issues from the physical -- no charges about the butt being too big or small, no painful comparisons or emphasis on beauty of any kind. The body is simply the "Food Sheath."
The physical body or "Food Sheath" receives its quality of intelligence from the food you eat. We're not talking brain science or rocket surgery here. If you start your morning by drinking nothing but coffee and eating a donut, then you run around all day, some time in the afternoon you are going to start tanking. You will find it increasingly difficult to focus and concentrate. You will find yourself becoming more and more agitated and impatient when life's daily dose of obstacles smacks you right on your... food sheath. You may experience shaking of the extremities or a headache. You may find your mind easily distracted and unable to remember simple details: Where are my glasses, keys or cell phone?
As stated in age-old philosophy and co-opted by the high-tech world, "garbage in; garbage out." That's because a calorie is not a calorie. The quality of your energy comes directly from the quality of the food/fuel you take in. Now Ayurveda goes deeper with this understanding than may initially seem self-evident. For example, if you eat a lot of foods that have been grown to produce no seeds, such as some types of oranges or watermelon, over time, that could compromise your body's fertility. After all what are seeds? They are highly concentrated forms of fertility consciousness/energy. Bear in mind these types of food would have to be pervasive in your diet and you would have to be exposed to these fertility-sterilized forms of foods consistently for prolonged periods of time. It is unlikely anyone is going to eat that much seedless fruits with no diversity. But what if all crop seeds were sterile? Would that change the dynamics?
With that in mind, let's now look at a pervasive form of food that we have all been exposed to for a prolonged period of time: GMOs. Genetically modified food organisms. Even though GMOs are foods that have been genetically injected with extremely poisonous material, the FDA in its infinite wisdom has declared that these foods do not require any testing whatsoever. In fact, the FDA has never done any testing on them! Monsanto has been legally, genetically poisoning our food supply for decades. It's no surprise that wildlife such as migrating birds will not touch a single kernel of GMO corn when growing side by side a crop of non-GMO corn. In fact no animal, other than humans, when given a choice, will consume a GMO food.
These animals intuitively know what Ayurveda and Chinese Medicine teach: Food is your first wave of either medicine or poison. When you eat foods that are packed with Chi, life force energy, your mind, body and emotions are energized. When you eat foods that are packed with antioxidants, your immune system becomes stronger and empowered to destroy free radicals, because that is where the consciousness that directs the body comes from. Conversely, when you eat foods that have been genetically altered to contain chemicals that are designed to kill and destroy life, how can that have a positive affect on your energy?
In addition to the GMO nightmare, Monsanto has produced "terminator seeds." These are seeds especially designed to die after one crop. They carry a sterilized energy that does not allow another generation of plants to grow. Why? Money. The farmer has to go back to Monsanto each and every growing season for more seeds, so Monsanto's profits have increased accordingly. It is pure and simple greed, even though the planet destroying consequences of this greed are neither pure nor simple.
How can Monsanto get away with poisoning our food supply? You may find it interesting to know that many high level FDA people are former Monsanto employees. And, that's right; you guessed it. Incestuously many of the upper level Monsanto employees are former FDA staff. Well, maybe it isn't interesting. Pathetic may be closer to the truth. We have the best politicians money can buy.
Most people are unaware of these healing sciences that have survived scrutiny for thousand of years. What they have to say about the quality of consciousness that feeds your health or disease is still relevant in today's world. You need to look no further than cancers, both common and exotic, which are on the rise, or that the rate of obesity and insulin resistant disorders like diabetes have been increasing exponentially. Attention deficit disorders and autism cases seem omnipresent. Isn't it interesting that the expansion of all of these diseases happens to magically correspond to the ever-increasing presence of GMO's in the American diet.
If you are thinking, "Oh, but I'm not eating GMOs," think again. You probably are; you just don't know it. Since the FDA has declared that foods containing GMOs do not have to be labeled as such, you are not informed that the food you are consuming is toxic. If you are not eating organic foods exclusively, if you are eating or drinking anything with high fructose corn syrup (sodas, ketchup, fruit juices), corn, soybeans, cottonseed, sugar beets, canola oil, most fast food meals or pre-packaged processed foods from large food corporations, you are most likely eating GMOs. For more information please visit: http://www.nongmoshoppingguide.com/tips-for-avoiding-gmos.html.
What you may have become painfully aware of is that you are fatigued all the time. You may have noticed that you having a harder time concentrating or remembering things. You may have observed an increase in health issues or poor sleep. You may have sensed that the consciousness of the body is off in some way but have not yet connected all the dots. All of these are profound reasons to examine what you are consuming that is feeding the quality of consciousness that governs your human experience.
Socrates once commented, "The unexamined life is not worth living." If he were alive today, his consciousness cry might be, "The unexamined diet is not worth eating."
http://www.huffingtonpost.com/vaishali/gmo-seeds-food_b_1031515.html
AIDS-free generation
Hillary Clinton Says U.S. Aims to Wipe Out AIDS
WASHINGTON -- The United States will, for the first time, make it a policy goal to have an "AIDS-free generation" in the near future, Secretary of State Hillary Clinton announced.
The administration's new AIDS-free generation goal will focus on "combination prevention strategy," combining three interventions that have been proven to slow the spread of the disease: ending mother-to-child transmissions; expanding voluntary male circumcision; and making greater use of antiretroviral medications.
Scientist now have a better understanding of the virus that has infected 60 million people and killed nearly 30 million since the first case of HIV was reported in 1981. And that better understanding of a once-mysterious virus makes it an achievable goal to eradicate AIDS, Clinton said during an event at National Institutes of Health (NIH) on Tuesday.
"HIV may be with us well into the future, but the disease that it causes need not be," Clinton said.
She outlined the three main areas of focus for the government's AIDS-free generation plan.
Prevention of mother-to-child transmissions, which are responsible for one in seven new infections worldwide -- it's already a global goal of the President's Emergency Plan For AIDS Relief (PEPFAR) to eliminate new infections in babies by 2015
Increase rates of voluntary male circumcision -- the procedure has been shown to reduce the risk of female-to-male transmission by more than 60%
Use treatment to prevent new infections -- recent studies show that treating HIV-positive patients with anti-retroviral drugs helps reduce transmission of the virus to a non-infected partner by 96%
Clinton said the U.S. government would commit an additional $60 million beyond the $50 million it's already spent to explore which prevention tactics work best in sub-Saharan Africa, where AIDS is the leading cause of death.
In 2003, when President George W. Bush signed the PEPFAR legislation, only 50,000 people in sub-Saharan Africa were receiving anti-retroviral drugs. Today, more than five million sub-Saharan Africans receive the drugs, along with another one million people in other regions of the world. Most of those drugs are paid for by the U.S., either through PEPFAR or through the Global Fund to Fight AIDS, Tuberculosis, and Malaria.
Speaking with MedPage Today after Clinton's speech, Anthony Fauci, MD, director of the NIH's National Institute of Allergy and Infectious Diseases, said he thought an AIDS-free generation was an achievable goal, especially in light of the relatively recent findings from the HPTN 052 trial that, in heterosexual discordant couples, if the HIV-positive partner is treated with antiretrovirals it "remarkably diminishes" the likelihood of infecting the HIV-negative partner.
"Within a reasonable amount of time, we could have an AIDS-free generation," he said.
Another physician in the audience, Thomas Quinn, MD, director of the Johns Hopkins Center for Global Health, said that science achieved a "home run" with the HPTN 052 trial, but the challenge is convincing policymakers to fund scientifically-proven interventions. But Clinton's message convinced him that at least one policymaker is sure that ramping up the nation's effort to combat HIV is something that needs to be done.
"Science here has led to a policy change," he said.
By Emily P. Walker, Washington Correspondent, MedPage Today
Published: November 09, 2011
WASHINGTON -- The United States will, for the first time, make it a policy goal to have an "AIDS-free generation" in the near future, Secretary of State Hillary Clinton announced.
The administration's new AIDS-free generation goal will focus on "combination prevention strategy," combining three interventions that have been proven to slow the spread of the disease: ending mother-to-child transmissions; expanding voluntary male circumcision; and making greater use of antiretroviral medications.
Scientist now have a better understanding of the virus that has infected 60 million people and killed nearly 30 million since the first case of HIV was reported in 1981. And that better understanding of a once-mysterious virus makes it an achievable goal to eradicate AIDS, Clinton said during an event at National Institutes of Health (NIH) on Tuesday.
"HIV may be with us well into the future, but the disease that it causes need not be," Clinton said.
She outlined the three main areas of focus for the government's AIDS-free generation plan.
Prevention of mother-to-child transmissions, which are responsible for one in seven new infections worldwide -- it's already a global goal of the President's Emergency Plan For AIDS Relief (PEPFAR) to eliminate new infections in babies by 2015
Increase rates of voluntary male circumcision -- the procedure has been shown to reduce the risk of female-to-male transmission by more than 60%
Use treatment to prevent new infections -- recent studies show that treating HIV-positive patients with anti-retroviral drugs helps reduce transmission of the virus to a non-infected partner by 96%
Clinton said the U.S. government would commit an additional $60 million beyond the $50 million it's already spent to explore which prevention tactics work best in sub-Saharan Africa, where AIDS is the leading cause of death.
In 2003, when President George W. Bush signed the PEPFAR legislation, only 50,000 people in sub-Saharan Africa were receiving anti-retroviral drugs. Today, more than five million sub-Saharan Africans receive the drugs, along with another one million people in other regions of the world. Most of those drugs are paid for by the U.S., either through PEPFAR or through the Global Fund to Fight AIDS, Tuberculosis, and Malaria.
Speaking with MedPage Today after Clinton's speech, Anthony Fauci, MD, director of the NIH's National Institute of Allergy and Infectious Diseases, said he thought an AIDS-free generation was an achievable goal, especially in light of the relatively recent findings from the HPTN 052 trial that, in heterosexual discordant couples, if the HIV-positive partner is treated with antiretrovirals it "remarkably diminishes" the likelihood of infecting the HIV-negative partner.
"Within a reasonable amount of time, we could have an AIDS-free generation," he said.
Another physician in the audience, Thomas Quinn, MD, director of the Johns Hopkins Center for Global Health, said that science achieved a "home run" with the HPTN 052 trial, but the challenge is convincing policymakers to fund scientifically-proven interventions. But Clinton's message convinced him that at least one policymaker is sure that ramping up the nation's effort to combat HIV is something that needs to be done.
"Science here has led to a policy change," he said.
By Emily P. Walker, Washington Correspondent, MedPage Today
Published: November 09, 2011
Sunday, November 6, 2011
Ten tips on getting recruited abroad
At the recent Naturejobs Career Expo in London, Michael Schneider from Imperial College London spoke about how to maximise your chances of getting recruited overseas. Schneider, currently director of Imperial's British Heart Foundation Centre of Research Excellence, studied at Harvard, the University of Pennsylvania, and Duke, followed by research training at the US National Institutes of Health (NIH). In our final follow-up to the Expo we present a summary of his advice - if you have any tips to share, please add them below.
If you're at an early stage of your science career, be aware that a strong academic record is not enough to secure a position abroad. "Posts go to those with something more [than excellent qualifications]," says Schneider.
Early research experience is the key discriminator - and it should be sustained or unusually intensive.
If you're still studying, find high-impact summer and winter research opportunities - examples that Schneider highlighted include the Erasmus student exchange programme in Europe and the Cold Spring Harbor Undergraduate Research Program (URP) in the United States.
You'll need to make personal contacts with overseas scientists - and email is generally the best way to make initial speculative enquiries with overseas labs.
Don't focus exclusively on the usual suspects - in the United States for example, Schneider says there are at least a dozen universities where mentors are as good as at prestigious institutes such as Harvard, MIT, University of California and Stanford - but there is less competition because they are less well-known.
Try to have complete research 'stories' - and be aware that for this reason completing a three-year PhD can put you at a disadvantage against those whose PhDs typically last longer, such as in the United States.
Fund yourself if possible.
Carefully check the eligibility criteria of funding opportunities - for example the US NIH only offers postdoc fellowships to US citizens, with one exception, says Schneider - the Pathway to Independence Award (K99-R00) is open to overseas applicants.
When considering a career move, vertical promotion - where you move up within the same institution - can be counter-productive, says Schneider: "Research funders typically prefer to see relocation as proof of independence."
When considering who to apply to, make sure you check where your potential superior publishes, and also where their trainees have gone afterwards.
http://blogs.nature.com/naturejobs/2011/11/02/ten-tips-on-getting-recruited-abroad?WT.ec_id=NATUREjobs-20111103
Monday, October 31, 2011
An antibiotic effect minus resistance
After 70 years, antibiotics are still the primary treatment for halting the spread of bacterial infections. But the prevalence of antibiotic resistance is now outpacing the rate of new drug discovery and approval.
A microbiologist at the University of Wisconsin-Milwaukee (UWM) has discovered a different approach: Instead of killing the bacteria, why not disarm them, quashing disease without the worry of antibiotic resistance?
Ching-Hong Yang, associate professor of biological sciences, has developed a compound that shuts off the "valve" in a pathogen's DNA that allows it to invade and infect.
The research is so promising that two private companies are testing it with an eye toward commercialization.
"We analyzed the genomic defense pathways in plants to identify all the precursors to infection," says Yang. "Then we used the information to discover a group of novel small molecules that interrupt one channel in the intricate pathway system."
Yang and collaborator Xin Chen, a professor of chemistry at Changzhou University in China, have tested the compound on two virulent bacteria that affect plants and one that attacks humans. They found it effective against all three and believe the compound can be applied to treatments for plants, animals and people.
The work was published online this month in the journal Antimicrobial Agents and Chemotherapy.
Urgent concerns about antibiotics
The economic costs and health threats of antibiotic resistance have become so serious that the World Health Organization (WHO) this year dedicated World Health Day to call global attention to the issue.
Antibiotics are routinely sprayed on crops and widely used in factory farming of animals, which causes resistance to develop quickly. That antibiotic resistance is then transferred to humans who eat the food containing antibiotic-resistant bacteria.
Among the bacteria tested by the researchers is Pseudomonas aeruginosa, which is resistant to a broad range of antibiotics. It causes infections in people with compromised immune systems, such as HIV and cancer patients. It's also responsible for lung infections in patients with cystic fibrosis, and hospital-related infections such as urinary tract infections, pneumonia and infections from burns.
The fatality rate from these is about 50 percent. Hospital-acquired urinary tract infections by P. aeruginosa alone cost more than $3.5 billion a year in the U.S.
Road to the market
The research has attracted interest from two companies. Creative Antibiotics, a Swedish pharmaceutical company, is testing the compound and derivatives for human therapeutic uses and Wilbur-Ellis Agribusiness Division, based in Washington and California, is examining them for agricultural uses.
Despite the constant threat of disease in agriculture, says John Frieden, a biologist and R&D manager with Wilbur-Ellis, the industry has not had access to any new antibiotics in many years. U.S. regulatory agencies do not allow agribusiness to use antibiotics that are also used for human health – even if they would be effective.
"The thing that caught my attention," Frieden says, "was that this was not an antibiotic, but it accomplishes the same thing as an antibiotic."
Although he says it is too soon to tell if a product could spring from the research, the approach is "incredibly unique. I've never seen anything that is even close to a commercial application like this. It could be very big."
The researchers have filed two patents on the work through the UWM Research Foundation (UWMRF), and Yang is partially funded through two UWMRF Bradley Catalyst Grants and a UWM Research Growth Initiative (RGI) grant.
Virulence factors
The compounds Yang and Chen have developed are unique because they take aim at one component of a cluster that makes pathogenic bacteria harmful.
One of those components, the type III secretion system (T3SS), gives pathogens their ability to invade a cell, letting in a host of proteins that enhance the bacterium's ability to cause disease.
"These bacteria are very smart," says Yang. "They grow a narrow appendage that acts as a 'needle,' injecting the virulence factors, such as toxins, into the host cell. The host cell cannot recognize the pathogen's 'needle,' so its defense mechanism is not triggered."
Yang and Chen's compounds block the production of T3SS. Although they have tested the compounds on only three pathogens, they have reason to believe the compounds will be effective against far more.
"T3SS exists in many different kinds of disease-causing bacteria," says Yang, "so the compounds can target multiple pathogens. That's the beauty of it."
http://www.eurekalert.org/pub_releases/2011-10/uow--aae102811.php
A microbiologist at the University of Wisconsin-Milwaukee (UWM) has discovered a different approach: Instead of killing the bacteria, why not disarm them, quashing disease without the worry of antibiotic resistance?
Ching-Hong Yang, associate professor of biological sciences, has developed a compound that shuts off the "valve" in a pathogen's DNA that allows it to invade and infect.
The research is so promising that two private companies are testing it with an eye toward commercialization.
"We analyzed the genomic defense pathways in plants to identify all the precursors to infection," says Yang. "Then we used the information to discover a group of novel small molecules that interrupt one channel in the intricate pathway system."
Yang and collaborator Xin Chen, a professor of chemistry at Changzhou University in China, have tested the compound on two virulent bacteria that affect plants and one that attacks humans. They found it effective against all three and believe the compound can be applied to treatments for plants, animals and people.
The work was published online this month in the journal Antimicrobial Agents and Chemotherapy.
Urgent concerns about antibiotics
The economic costs and health threats of antibiotic resistance have become so serious that the World Health Organization (WHO) this year dedicated World Health Day to call global attention to the issue.
Antibiotics are routinely sprayed on crops and widely used in factory farming of animals, which causes resistance to develop quickly. That antibiotic resistance is then transferred to humans who eat the food containing antibiotic-resistant bacteria.
Among the bacteria tested by the researchers is Pseudomonas aeruginosa, which is resistant to a broad range of antibiotics. It causes infections in people with compromised immune systems, such as HIV and cancer patients. It's also responsible for lung infections in patients with cystic fibrosis, and hospital-related infections such as urinary tract infections, pneumonia and infections from burns.
The fatality rate from these is about 50 percent. Hospital-acquired urinary tract infections by P. aeruginosa alone cost more than $3.5 billion a year in the U.S.
Road to the market
The research has attracted interest from two companies. Creative Antibiotics, a Swedish pharmaceutical company, is testing the compound and derivatives for human therapeutic uses and Wilbur-Ellis Agribusiness Division, based in Washington and California, is examining them for agricultural uses.
Despite the constant threat of disease in agriculture, says John Frieden, a biologist and R&D manager with Wilbur-Ellis, the industry has not had access to any new antibiotics in many years. U.S. regulatory agencies do not allow agribusiness to use antibiotics that are also used for human health – even if they would be effective.
"The thing that caught my attention," Frieden says, "was that this was not an antibiotic, but it accomplishes the same thing as an antibiotic."
Although he says it is too soon to tell if a product could spring from the research, the approach is "incredibly unique. I've never seen anything that is even close to a commercial application like this. It could be very big."
The researchers have filed two patents on the work through the UWM Research Foundation (UWMRF), and Yang is partially funded through two UWMRF Bradley Catalyst Grants and a UWM Research Growth Initiative (RGI) grant.
Virulence factors
The compounds Yang and Chen have developed are unique because they take aim at one component of a cluster that makes pathogenic bacteria harmful.
One of those components, the type III secretion system (T3SS), gives pathogens their ability to invade a cell, letting in a host of proteins that enhance the bacterium's ability to cause disease.
"These bacteria are very smart," says Yang. "They grow a narrow appendage that acts as a 'needle,' injecting the virulence factors, such as toxins, into the host cell. The host cell cannot recognize the pathogen's 'needle,' so its defense mechanism is not triggered."
Yang and Chen's compounds block the production of T3SS. Although they have tested the compounds on only three pathogens, they have reason to believe the compounds will be effective against far more.
"T3SS exists in many different kinds of disease-causing bacteria," says Yang, "so the compounds can target multiple pathogens. That's the beauty of it."
http://www.eurekalert.org/pub_releases/2011-10/uow--aae102811.php
fatty acid binding protein (FABP4)
A large pad of fat cells that extends from the stomach and covers the intestines provides nutrients that promote the spread and growth of ovarian cancer, reports a research team based at the University of Chicago in the journal Nature Medicine, published online October 30th, 2011.
Ovarian cancer, the fifth leading cause of cancer deaths in women, tends to spread within the abdominal cavity as opposed to distant organs. In 80 percent of women, by the time ovarian cancer is diagnosed, it has spread to the pad of fat cells, called the omentum. Often, cancer growth in the omentum exceeds the growth of the original ovarian cancer.
"This fatty tissue, which is extraordinarily rich in energy-dense lipids, acts as a launching pad and energy source for the likely lethal spread of ovarian cancer," said study author Ernst Lengyel, MD, PhD, professor of obstetrics and gynecology at the University of Chicago. "The cells that make up the omentum contain the biological equivalent of jet fuel. They feed the cancer cells, enabling them to multiply rapidly. Gaining a better understanding of this process could help us learn how to disrupt it."
The researchers performed a series of experiments to identify the role of these fat cells as major mediators of ovarian cancer metastasis. The first step was to understand the biological signals that attract ovarian cancer cells to the omentum and use it for rapid growth.
The spread of ovarian cancer cells to the omentum can happen quickly. Ovarian cancer cells injected into the abdomen of healthy mice find their way to the omentum within 20 minutes. The researchers found that protein signals emitted by the omentum can attract the tumor cells. Inhibitors which disturbed these signals reduced this attraction by at least 50 percent.
Once ovarian cancer cells reach the omentum, they quickly develop the tools to devour the sustenance provided by this fatty tissue, reprogramming their metabolism to thrive on lipids acquired from fat cells. Ovarian cancer can rapidly convert the entire omentum, a soft fat pad, into a solid mass of cancer cells.
"This mechanism may not be limited to ovarian cancer cells," the authors note. Fat metabolism may also contribute to cancer development in other environments where fat cells are abundant, such as breast cancer.
A protein known as fatty acid binding protein (FABP4), a fat carrier, may be crucial to this process and could be a target for treatment.
When the researchers compared primary ovarian cancer tissue with ovarian cancer tissue which had spread to the omentum, they found that tumor cells next to omental fat cells produced high levels of FABP4. Cancer cells distant from the fat cells did not produce FABP4.
When they inhibited FABP4, the transfer of nutrients from fat cells to cancer cells was drastically reduced. Inhibition of FABP4 also reduced tumor growth and the ability of tumors to generate new blood vessels.
"Therefore," the authors wrote, "FABP4 emerges as an excellent target in the treatment of intra-abdominally disseminating tumors, which preferentially metastasize to adipose tissue such as ovarian, gastric, and colon cancers."
http://www.eurekalert.org/pub_releases/2011-10/uocm-fci102611.php
Ovarian cancer, the fifth leading cause of cancer deaths in women, tends to spread within the abdominal cavity as opposed to distant organs. In 80 percent of women, by the time ovarian cancer is diagnosed, it has spread to the pad of fat cells, called the omentum. Often, cancer growth in the omentum exceeds the growth of the original ovarian cancer.
"This fatty tissue, which is extraordinarily rich in energy-dense lipids, acts as a launching pad and energy source for the likely lethal spread of ovarian cancer," said study author Ernst Lengyel, MD, PhD, professor of obstetrics and gynecology at the University of Chicago. "The cells that make up the omentum contain the biological equivalent of jet fuel. They feed the cancer cells, enabling them to multiply rapidly. Gaining a better understanding of this process could help us learn how to disrupt it."
The researchers performed a series of experiments to identify the role of these fat cells as major mediators of ovarian cancer metastasis. The first step was to understand the biological signals that attract ovarian cancer cells to the omentum and use it for rapid growth.
The spread of ovarian cancer cells to the omentum can happen quickly. Ovarian cancer cells injected into the abdomen of healthy mice find their way to the omentum within 20 minutes. The researchers found that protein signals emitted by the omentum can attract the tumor cells. Inhibitors which disturbed these signals reduced this attraction by at least 50 percent.
Once ovarian cancer cells reach the omentum, they quickly develop the tools to devour the sustenance provided by this fatty tissue, reprogramming their metabolism to thrive on lipids acquired from fat cells. Ovarian cancer can rapidly convert the entire omentum, a soft fat pad, into a solid mass of cancer cells.
"This mechanism may not be limited to ovarian cancer cells," the authors note. Fat metabolism may also contribute to cancer development in other environments where fat cells are abundant, such as breast cancer.
A protein known as fatty acid binding protein (FABP4), a fat carrier, may be crucial to this process and could be a target for treatment.
When the researchers compared primary ovarian cancer tissue with ovarian cancer tissue which had spread to the omentum, they found that tumor cells next to omental fat cells produced high levels of FABP4. Cancer cells distant from the fat cells did not produce FABP4.
When they inhibited FABP4, the transfer of nutrients from fat cells to cancer cells was drastically reduced. Inhibition of FABP4 also reduced tumor growth and the ability of tumors to generate new blood vessels.
"Therefore," the authors wrote, "FABP4 emerges as an excellent target in the treatment of intra-abdominally disseminating tumors, which preferentially metastasize to adipose tissue such as ovarian, gastric, and colon cancers."
http://www.eurekalert.org/pub_releases/2011-10/uocm-fci102611.php
new DNA letter in brain suggest distinct function
In 2009, the DNA alphabet expanded. Scientists discovered that an extra letter or "sixth nucleotide" was surprisingly abundant in DNA from stem cells and brain cells.
Now, researchers at Emory University School of Medicine have mapped the patterns formed by that letter in the brains of mice, observing how its pattern of distribution in the genome changes during development and aging.
Those patterns, stable or dynamic depending on the gene, suggest that 5-hydroxymethylcytosine (5-hmC) has its own distinct functions, which still need to be fully brought to light.
"Our data tells us that 5-hmC is not just an intermediate state," says senior author Peng Jin, PhD, associate professor of human genetics at Emory University School of Medicine. "It looks like it has specific functions in stem cells and brain. 5-hmC may poise a gene to be turned on after being repressed."
The results were published online Sunday by the journal Nature Neuroscience. The paper is the first report on how the patterns of 5-hmC's distribution change in mouse brain during development, and also contains data on 5-hmC in DNA samples from human brain.
Postdoctoral fellow Keith Szulwach and instructor Xuekun Li are co-first authors, and collaborators from the University of Chicago and the University of Wisconsin-Madison contributed to the paper.
5-hydroxymethylcytosine (5-hmC) is an epigenetic modification of cytosine, one of the four bases or "letters" making up DNA. Epigenetic modifications are changes in the way genes are turned on or off, but are not part of the underlying DNA sequence. 5-hmC resembles 5-methylcytosine (5-mC), another modified DNA base that scientists have been studying for decades. Until recently, chemical techniques did not allow scientists to tell the difference between them.
In contrast to 5-mC, 5-hmC appears to be enriched on active genes, especially in brain cells. 5-mC is generally found on genes that are turned off or on repetitive "junk" regions of the genome. When stem cells change into the cells that make up blood, muscle or brain, 5-mC helps shut off genes that aren't supposed to be turned on. Changes in 5-mC's distribution also underpin a healthy cell's transformation into a cancer cell.
It looks like 5-hmC can only appear on DNA where 5-mC already was present. This could be a clue that 5-hmC could be a transitory sign that the cell is going to remove a 5-mC mark. Jin says the patterns his team sees tell a different story, at least for some genes. On those genes, the level of 5-hmC is stably maintained and increases with age.
The Emory team used a method for chemically labeling 5-hmC they developed in cooperation with scientists at the University of Chicago. They find that 5-hmC is ten times more abundant in brain than in stem cells, and it is found more in the body of some genes, compared to stem cells.
In addition, the researchers found a relative lack of 5-hmC on X chromosomes in both males and females. That result is a surprise, Jin says, because it was already known that the X chromosome is subject to a special form of regulation in females only. Males have one X chromosome and females have two, and in female cells one of the X chromosomes is inactivated.
Jin's team is beginning to map how 5-hmC changes in neurological disorders, including Rett syndrome and autism, and refining techniques for detecting 5-hmC in DNA at high resolution.
http://www.eurekalert.org/pub_releases/2011-10/eu-pon102711.php
Now, researchers at Emory University School of Medicine have mapped the patterns formed by that letter in the brains of mice, observing how its pattern of distribution in the genome changes during development and aging.
Those patterns, stable or dynamic depending on the gene, suggest that 5-hydroxymethylcytosine (5-hmC) has its own distinct functions, which still need to be fully brought to light.
"Our data tells us that 5-hmC is not just an intermediate state," says senior author Peng Jin, PhD, associate professor of human genetics at Emory University School of Medicine. "It looks like it has specific functions in stem cells and brain. 5-hmC may poise a gene to be turned on after being repressed."
The results were published online Sunday by the journal Nature Neuroscience. The paper is the first report on how the patterns of 5-hmC's distribution change in mouse brain during development, and also contains data on 5-hmC in DNA samples from human brain.
Postdoctoral fellow Keith Szulwach and instructor Xuekun Li are co-first authors, and collaborators from the University of Chicago and the University of Wisconsin-Madison contributed to the paper.
5-hydroxymethylcytosine (5-hmC) is an epigenetic modification of cytosine, one of the four bases or "letters" making up DNA. Epigenetic modifications are changes in the way genes are turned on or off, but are not part of the underlying DNA sequence. 5-hmC resembles 5-methylcytosine (5-mC), another modified DNA base that scientists have been studying for decades. Until recently, chemical techniques did not allow scientists to tell the difference between them.
In contrast to 5-mC, 5-hmC appears to be enriched on active genes, especially in brain cells. 5-mC is generally found on genes that are turned off or on repetitive "junk" regions of the genome. When stem cells change into the cells that make up blood, muscle or brain, 5-mC helps shut off genes that aren't supposed to be turned on. Changes in 5-mC's distribution also underpin a healthy cell's transformation into a cancer cell.
It looks like 5-hmC can only appear on DNA where 5-mC already was present. This could be a clue that 5-hmC could be a transitory sign that the cell is going to remove a 5-mC mark. Jin says the patterns his team sees tell a different story, at least for some genes. On those genes, the level of 5-hmC is stably maintained and increases with age.
The Emory team used a method for chemically labeling 5-hmC they developed in cooperation with scientists at the University of Chicago. They find that 5-hmC is ten times more abundant in brain than in stem cells, and it is found more in the body of some genes, compared to stem cells.
In addition, the researchers found a relative lack of 5-hmC on X chromosomes in both males and females. That result is a surprise, Jin says, because it was already known that the X chromosome is subject to a special form of regulation in females only. Males have one X chromosome and females have two, and in female cells one of the X chromosomes is inactivated.
Jin's team is beginning to map how 5-hmC changes in neurological disorders, including Rett syndrome and autism, and refining techniques for detecting 5-hmC in DNA at high resolution.
http://www.eurekalert.org/pub_releases/2011-10/eu-pon102711.php
stem cell key to lung regeneration
Scientists at A*STAR'S Genome Institute of Singapore (GIS) and Institute of Molecular Biology (IMB), have made a breakthrough discovery in the understanding of lung regeneration. Their research showed for the first time that distal airway stem cells (DASCs), a specific type of stem cells in the lungs, are involved in forming new alveoli to replace and repair damaged lung tissue, providing a firm foundation for understanding lung regeneration.
Lung damage is caused by a wide range of lung diseases including influenza infections and chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD). Influenza infection induces acute respiratory distress syndrome (ARDS) which affects more than 150,000 patients a year in the US, with a death rate of up to 50 percent. COPD is the fifth biggest killer worldwide.
The team took a novel approach in tackling the question of lung regeneration. They cloned adult stem cells taken from three different parts of the lungs - nasal epithelial stem cells (NESCs), tracheal airway stem cells (TASCs) and distal airway stem cells (DASCs). Despite the three types of cells being nearly 99 percent genetically identical, the team made the surprising observation that only DASCs formed alveoli when cloned in vitro.
"We are the first researchers to demonstrate that adult stem cells are intrinsically committed and will only differentiate into the specific cell type they originated from. In this case, only DASCs formed alveoli because alveolar cells are found in the distal airways, not in the nasal epithelial or tracheal airway", said Dr Wa Xian, Principal Investigator at IMB. "This is a big advancement in the understanding of adult stem cells that will encourage further research into their potential for regenerative medicine."
Using a mouse model of influenza, the team showed that after infection, DASCs rapidly grow and migrate to influenza-damaged lung areas where they form "pods". These "pods" mature to new alveoli which replace the alveoli that were destroyed by the infection, leading to lung regeneration.
"We have harvested these "pods" to provide insight into genes and secreted factors that likely represent key components in tissue regeneration.
These secreted factors might be used as biological drugs (biologics) to enhance regeneration of the lung and airways," said Dr Frank McKeon, Senior Group Leader of the Stem Cell and Developmental Biology at GIS.
The research was jointly led by Dr Frank McKeon from GIS and Dr Wa Xian from IMB in collaboration with scientists at the National University of Singapore (NUS), and clinicians at the Harvard Medical School and the Brigham and Women's Hospital in Boston.
Prof Birgitte Lane, Executive Director of IMB, said, "This groundbreaking work is a fine example of collaborative research, which has brought us new insight into lung epithelial stem cells. This will have breakthrough consequences in many areas." Dr Edison Liu, Executive Director of GIS, added, "We will continue to seek impactful collaborations and build upon this research area where there is a need for novel therapies, which will offer hope for patients suffering from respiratory diseases."
http://www.eurekalert.org/pub_releases/2011-10/afst-asf102711.php
Lung damage is caused by a wide range of lung diseases including influenza infections and chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD). Influenza infection induces acute respiratory distress syndrome (ARDS) which affects more than 150,000 patients a year in the US, with a death rate of up to 50 percent. COPD is the fifth biggest killer worldwide.
The team took a novel approach in tackling the question of lung regeneration. They cloned adult stem cells taken from three different parts of the lungs - nasal epithelial stem cells (NESCs), tracheal airway stem cells (TASCs) and distal airway stem cells (DASCs). Despite the three types of cells being nearly 99 percent genetically identical, the team made the surprising observation that only DASCs formed alveoli when cloned in vitro.
"We are the first researchers to demonstrate that adult stem cells are intrinsically committed and will only differentiate into the specific cell type they originated from. In this case, only DASCs formed alveoli because alveolar cells are found in the distal airways, not in the nasal epithelial or tracheal airway", said Dr Wa Xian, Principal Investigator at IMB. "This is a big advancement in the understanding of adult stem cells that will encourage further research into their potential for regenerative medicine."
Using a mouse model of influenza, the team showed that after infection, DASCs rapidly grow and migrate to influenza-damaged lung areas where they form "pods". These "pods" mature to new alveoli which replace the alveoli that were destroyed by the infection, leading to lung regeneration.
"We have harvested these "pods" to provide insight into genes and secreted factors that likely represent key components in tissue regeneration.
These secreted factors might be used as biological drugs (biologics) to enhance regeneration of the lung and airways," said Dr Frank McKeon, Senior Group Leader of the Stem Cell and Developmental Biology at GIS.
The research was jointly led by Dr Frank McKeon from GIS and Dr Wa Xian from IMB in collaboration with scientists at the National University of Singapore (NUS), and clinicians at the Harvard Medical School and the Brigham and Women's Hospital in Boston.
Prof Birgitte Lane, Executive Director of IMB, said, "This groundbreaking work is a fine example of collaborative research, which has brought us new insight into lung epithelial stem cells. This will have breakthrough consequences in many areas." Dr Edison Liu, Executive Director of GIS, added, "We will continue to seek impactful collaborations and build upon this research area where there is a need for novel therapies, which will offer hope for patients suffering from respiratory diseases."
http://www.eurekalert.org/pub_releases/2011-10/afst-asf102711.php
Saturday, October 29, 2011
Toughest Exam Question: What Is the Best Way to Study?
Here's a pop quiz: What foods are best to eat before a high-stakes test? When is the best time to review the toughest material? A growing body of research on the best study techniques offers some answers.
Chiefly, testing yourself repeatedly before an exam teaches the brain to retrieve and apply knowledge from memory. The method is more effective than re-reading a textbook, says Jeffrey Karpicke, an assistant professor of psychological sciences at Purdue University. If you are facing a test on the digestive system, he says, practice explaining how it works from start to finish, rather than studying a list of its parts.
In his junior year of high school in Cary, N.C., Keenan Harrell bought test-prep books and subjected himself to a "relentless and repetitive" series of nearly 30 practice SAT college-entrance exams. "I just took it over and over again, until it became almost aggravating," he says.
Practice paid off. Mr. Harrell, now 19, was accepted at University of North Carolina-Chapel Hill, a college he's dreamed of attending since the third grade. He scored 1800 (out of 2400) on the SAT, up 50% from 1200 on the PSAT, a preliminary test during his sophomore year.
Taking pretests "felt like hard work," Mr. Harrell says, but seeing steady increases in his scores boosted his confidence. Practice tests also help with test-taking skills, such as pacing, says Paul Weeks, vice president of educational services for the ACT, which creates and administers college-entrance exams.
Getty Images
Repeated practice tests help master test format and pacing.
Sleep also plays a role in test performance, but in two unexpected ways. Review the toughest material right before going to bed the night before the test. That approach makes it easier to recall the material later, says Dan Taylor, director of a sleep-and-health-research lab at the University of North Texas in Denton. And don't wake up earlier than usual to study; this could interfere with the rapid-eye-movement sleep that aids memory, he says.
A common study habit—the all-nighter—is a bad idea. Although 60% of college students stay up all night at some point in school, the practice is linked to lower grades, says Pamela Thacher, an associate professor of psychology at St. Lawrence University in Canton, N.Y., based on a 2008 study of 120 students. It also impairs reasoning and memory for as long as four days.
Being Confident
Write down fears and anxieties before the test to free working memory and prevent distractions during the test.
To combat self-doubts (such as 'I'm bad in math'), remind yourself of proven personal traits and strengths that can propel you to success.
Practice in advance facing all the pressures you will face on exam day, such as driving to the testing center or visiting an unfamiliar testing room.
Test yourself by recalling broad concepts rather than trying to memorize facts or re-reading textbooks.
Before the test, envision yourself answering questions calmly and with confidence.
Everybody knows you should eat breakfast the day of a big test. High-carb, high-fiber, slow-digesting foods like oatmeal are best, research shows. But what you eat a week in advance matters, too. When 16 college students were tested on attention and thinking speed, then fed a five-day high-fat, low-carb diet heavy on meat, eggs, cheese and cream and tested again, their performance declined. The students who ate a balanced diet that included fruit and vegetables, however, held steady, says Cameron Holloway, a senior clinical researcher at the University of Oxford. The brain requires a constant supply of energy and "has only a limited backup battery," he says.
While many teens insist they study better while listening to music or texting their friends, research shows the opposite: Information reviewed amid distractions is less likely to be recalled later, says Nicole Dudukovic, assistant professor of psychology at Trinity College, Hartford, Conn.
In her research, college students categorized and made judgments about pictures of more than 100 items. Then, they were tested on a new mix of pictures and asked to recall which ones they had already seen and how they had categorized them; half the time, they were also asked to listen and respond to a set of rhythmic sounds. When the students were tested later, they were more likely to remember correctly what they had studied without distractions.
"Students do have this belief that they can do it all and they aren't really being distracted" by music or sounds from a noisy cafe, Dr. Dudukovic says. But while the sounds may "make them feel more relaxed," she says, they won't help them ace the midterm.
Bryan Almanza says he did poorly on the PSAT as a high-school sophomore because he didn't know how to prepare. He got too little sleep the night before and ate only a bowl of cereal for breakfast. On the test, some hard physics questions made him nervous and distracted, says Mr. Almanza, 18, a senior at Campbell High in Smyrna, Ga. "I'm going to fail," he remembers thinking at the time. A test-prep program at his school taught him to get plenty of sleep, eat a good breakfast and pace himself on the test. By staying calm, optimistic and focused, he raised his score significantly on the SAT.
Tips on Conquering Test-Day Jitters
Even when students are fully prepared, anxiety can be another burden on test day.
An estimated 35% of students are so nervous before high-stakes tests that it impairs their performance, says Richard Driscoll, a Knoxville, Tenn., clinical psychologist who has researched text anxiety.
To help ease fears, Julie Hartline, lead counselor at Campbell High School in Smyrna, Ga., helped start a three-week program last year to teach juniors anxiety-reduction techniques.
One calming tactic that has been shown to improve scores is to teach yourself in advance to think differently about the test, Dr. Driscoll says. Envision yourself in a situation you find challenging and invigorating; a soccer player might imagine scoring a goal, or a mountain climber might envision herself topping a ridge, he says. Then switch your mental image to the testing room and imagine yourself feeling the same way. With practice, you'll be able to summon up more confidence on test day.
Also, reducing "novelty and stress on the day of the exam" can prevent choking under pressure, says Sian Beilock, a researcher and author on cognitive performance. If you are taking the exam in an unfamiliar place, visit the room in advance.
If you are still feeling anxious, set aside 10 minutes beforehand to write down your worries, says Dr. Beilock, an associate professor of psychology at the University of Chicago. She and a fellow researcher tested 106 ninth-graders for anxiety before their first high-pressure exam, then asked half of them to spend 10 minutes writing down their thoughts right before the test. The anxious kids who did the writing exercise performed as well on the
test as the students who had been calm all along. But anxious students who didn't do the writing performed more poorly. Expressing one's worries in writing, Dr. Beilock says, unburdens the brain.
http://online.wsj.com/public/search?article-doc-type=%7BWork+%26+Family%7D&HEADER_TEXT=work+%26+family
Chiefly, testing yourself repeatedly before an exam teaches the brain to retrieve and apply knowledge from memory. The method is more effective than re-reading a textbook, says Jeffrey Karpicke, an assistant professor of psychological sciences at Purdue University. If you are facing a test on the digestive system, he says, practice explaining how it works from start to finish, rather than studying a list of its parts.
In his junior year of high school in Cary, N.C., Keenan Harrell bought test-prep books and subjected himself to a "relentless and repetitive" series of nearly 30 practice SAT college-entrance exams. "I just took it over and over again, until it became almost aggravating," he says.
Practice paid off. Mr. Harrell, now 19, was accepted at University of North Carolina-Chapel Hill, a college he's dreamed of attending since the third grade. He scored 1800 (out of 2400) on the SAT, up 50% from 1200 on the PSAT, a preliminary test during his sophomore year.
Taking pretests "felt like hard work," Mr. Harrell says, but seeing steady increases in his scores boosted his confidence. Practice tests also help with test-taking skills, such as pacing, says Paul Weeks, vice president of educational services for the ACT, which creates and administers college-entrance exams.
Getty Images
Repeated practice tests help master test format and pacing.
Sleep also plays a role in test performance, but in two unexpected ways. Review the toughest material right before going to bed the night before the test. That approach makes it easier to recall the material later, says Dan Taylor, director of a sleep-and-health-research lab at the University of North Texas in Denton. And don't wake up earlier than usual to study; this could interfere with the rapid-eye-movement sleep that aids memory, he says.
A common study habit—the all-nighter—is a bad idea. Although 60% of college students stay up all night at some point in school, the practice is linked to lower grades, says Pamela Thacher, an associate professor of psychology at St. Lawrence University in Canton, N.Y., based on a 2008 study of 120 students. It also impairs reasoning and memory for as long as four days.
Being Confident
Write down fears and anxieties before the test to free working memory and prevent distractions during the test.
To combat self-doubts (such as 'I'm bad in math'), remind yourself of proven personal traits and strengths that can propel you to success.
Practice in advance facing all the pressures you will face on exam day, such as driving to the testing center or visiting an unfamiliar testing room.
Test yourself by recalling broad concepts rather than trying to memorize facts or re-reading textbooks.
Before the test, envision yourself answering questions calmly and with confidence.
Everybody knows you should eat breakfast the day of a big test. High-carb, high-fiber, slow-digesting foods like oatmeal are best, research shows. But what you eat a week in advance matters, too. When 16 college students were tested on attention and thinking speed, then fed a five-day high-fat, low-carb diet heavy on meat, eggs, cheese and cream and tested again, their performance declined. The students who ate a balanced diet that included fruit and vegetables, however, held steady, says Cameron Holloway, a senior clinical researcher at the University of Oxford. The brain requires a constant supply of energy and "has only a limited backup battery," he says.
While many teens insist they study better while listening to music or texting their friends, research shows the opposite: Information reviewed amid distractions is less likely to be recalled later, says Nicole Dudukovic, assistant professor of psychology at Trinity College, Hartford, Conn.
In her research, college students categorized and made judgments about pictures of more than 100 items. Then, they were tested on a new mix of pictures and asked to recall which ones they had already seen and how they had categorized them; half the time, they were also asked to listen and respond to a set of rhythmic sounds. When the students were tested later, they were more likely to remember correctly what they had studied without distractions.
"Students do have this belief that they can do it all and they aren't really being distracted" by music or sounds from a noisy cafe, Dr. Dudukovic says. But while the sounds may "make them feel more relaxed," she says, they won't help them ace the midterm.
Bryan Almanza says he did poorly on the PSAT as a high-school sophomore because he didn't know how to prepare. He got too little sleep the night before and ate only a bowl of cereal for breakfast. On the test, some hard physics questions made him nervous and distracted, says Mr. Almanza, 18, a senior at Campbell High in Smyrna, Ga. "I'm going to fail," he remembers thinking at the time. A test-prep program at his school taught him to get plenty of sleep, eat a good breakfast and pace himself on the test. By staying calm, optimistic and focused, he raised his score significantly on the SAT.
Tips on Conquering Test-Day Jitters
Even when students are fully prepared, anxiety can be another burden on test day.
An estimated 35% of students are so nervous before high-stakes tests that it impairs their performance, says Richard Driscoll, a Knoxville, Tenn., clinical psychologist who has researched text anxiety.
To help ease fears, Julie Hartline, lead counselor at Campbell High School in Smyrna, Ga., helped start a three-week program last year to teach juniors anxiety-reduction techniques.
One calming tactic that has been shown to improve scores is to teach yourself in advance to think differently about the test, Dr. Driscoll says. Envision yourself in a situation you find challenging and invigorating; a soccer player might imagine scoring a goal, or a mountain climber might envision herself topping a ridge, he says. Then switch your mental image to the testing room and imagine yourself feeling the same way. With practice, you'll be able to summon up more confidence on test day.
Also, reducing "novelty and stress on the day of the exam" can prevent choking under pressure, says Sian Beilock, a researcher and author on cognitive performance. If you are taking the exam in an unfamiliar place, visit the room in advance.
If you are still feeling anxious, set aside 10 minutes beforehand to write down your worries, says Dr. Beilock, an associate professor of psychology at the University of Chicago. She and a fellow researcher tested 106 ninth-graders for anxiety before their first high-pressure exam, then asked half of them to spend 10 minutes writing down their thoughts right before the test. The anxious kids who did the writing exercise performed as well on the
test as the students who had been calm all along. But anxious students who didn't do the writing performed more poorly. Expressing one's worries in writing, Dr. Beilock says, unburdens the brain.
http://online.wsj.com/public/search?article-doc-type=%7BWork+%26+Family%7D&HEADER_TEXT=work+%26+family
Saturday, October 22, 2011
Structure of human mitochondrial RNA polymerase
Transcription of the mitochondrial genome is performed by a single-subunit RNA polymerase (mtRNAP) that is distantly related to the RNAP of bacteriophage T7, the pol I family of DNA polymerases, and single-subunit RNAPs from chloroplasts.
Whereas T7 RNAP can initiate transcription by itself, mtRNAP requires the factors TFAM and TFB2M for binding and melting promoter DNA5.
TFAM is an abundant protein that binds and bends promoter DNA 15–40 base pairs upstream of the transcription start site, and stimulates the recruitment of mtRNAP and TFB2M to the promoter.
TFB2M assists mtRNAP in promoter melting and reaches the active site of mtRNAP to interact with the first base pair of the RNA–DNA hybrid10.
The X-ray structure of human mtRNAP at 2.5 Å resolution, which reveals a T7-like catalytic carboxy-terminal domain, an amino-terminal domain that remotely resembles the T7 promoter-binding domain, a novel pentatricopeptide repeat domain, and a flexible N-terminal extension.
The pentatricopeptide repeat domain sequesters an AT-rich recognition loop, which binds promoter DNA in T7 RNAP, probably explaining the need for TFAM during promoter binding.
Consistent with this, substitution of a conserved arginine residue in the AT-rich recognition loop, or release of this loop by deletion of the N-terminal part of mtRNAP, had no effect on transcription.
The fingers domain and the intercalating hairpin, which melts DNA in phage RNAPs, are repositioned, explaining the need for TFB2M during promoter melting.
The results provide a new venue for the mechanistic analysis of mitochondrial transcription. They also indicate how an early phage-like mtRNAP lost functions in promoter binding and melting, which were provided by initiation factors in trans during evolution, to enable mitochondrial gene regulation and the adaptation of mitochondrial function to changes in the environment.
http://www.nature.com/nature/journal/v478/n7368/full/nature10435.html
Whereas T7 RNAP can initiate transcription by itself, mtRNAP requires the factors TFAM and TFB2M for binding and melting promoter DNA5.
TFAM is an abundant protein that binds and bends promoter DNA 15–40 base pairs upstream of the transcription start site, and stimulates the recruitment of mtRNAP and TFB2M to the promoter.
TFB2M assists mtRNAP in promoter melting and reaches the active site of mtRNAP to interact with the first base pair of the RNA–DNA hybrid10.
The X-ray structure of human mtRNAP at 2.5 Å resolution, which reveals a T7-like catalytic carboxy-terminal domain, an amino-terminal domain that remotely resembles the T7 promoter-binding domain, a novel pentatricopeptide repeat domain, and a flexible N-terminal extension.
The pentatricopeptide repeat domain sequesters an AT-rich recognition loop, which binds promoter DNA in T7 RNAP, probably explaining the need for TFAM during promoter binding.
Consistent with this, substitution of a conserved arginine residue in the AT-rich recognition loop, or release of this loop by deletion of the N-terminal part of mtRNAP, had no effect on transcription.
The fingers domain and the intercalating hairpin, which melts DNA in phage RNAPs, are repositioned, explaining the need for TFB2M during promoter melting.
The results provide a new venue for the mechanistic analysis of mitochondrial transcription. They also indicate how an early phage-like mtRNAP lost functions in promoter binding and melting, which were provided by initiation factors in trans during evolution, to enable mitochondrial gene regulation and the adaptation of mitochondrial function to changes in the environment.
http://www.nature.com/nature/journal/v478/n7368/full/nature10435.html
An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor
Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology. TDO-derived Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO–AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival. Because Kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, these results provide evidence for a previously unidentified pathophysiological function of the AHR with profound implications for cancer and immune biology.
http://www.nature.com/nature/journal/v478/n7368/full/nature10491.html
http://www.nature.com/nature/journal/v478/n7368/full/nature10491.html
Gene Mutation Link to Inflammation Identified
A loss-of-function mutation in a gene known as ADAM17 is likely to be the cause of neonatal inflammatory skin and bowel lesions in two children born to consanguineous parents, researchers reported.
This gene, located on chromosome 2, encodes a protein that cleaves membrane-bound tumor necrosis factor (TNF)-α, converting it to soluble TNF-α, according to David P. Kelsell, PhD, of the London School of Medicine and Dentistry, and colleagues.
The two out of three affected siblings, one boy and one girl, both developed severe erythema and pustular rashes within two days of birth, and later showed abnormalities of the hair and nails.
They also were susceptible to skin infections throughout childhood.
In addition, within a week of birth, both children developed bloody diarrhea suggestive of malabsorption, which in the girl was associated with failure to thrive.
She died at age 12 from myocarditis associated with parvovirus B19 infection.
Subsequent evaluation of her affected brother revealed the presence of mild left ventricular abnormalities.
To identify the genetic basis of this disorder, Kelsell and colleagues obtained biopsy specimens from the skin and intestines of the family members and age-matched controls.
Genetic analysis identified a deletion in exon 5 of ADAM17 in the two affected children that was not present in the unaffected sibling. Both affected children were homozygous for the mutation.
Histochemical analysis then revealed a lack of expression of ADAM17 in biopsy specimens and peripheral blood mononuclear cells in the affected children, which was not the case in unaffected family members or controls.
Because of the inflammatory nature of the disorder, the researchers also examined cytokine production in peripheral blood mononuclear cells.
Stimulation with lipopolysaccharide or anti-CD3 and anti-CD28 antibodies led to robust production of TNF-α in samples from controls and the mother, but only weak production in samples from the affected boy.
Other cytokines, including interleukin-1β, interleukin-6, and interferon-γ, were secreted in all samples, including those from the affected boy.
A knockout mouse model lacking ADAM17 exhibits a severe phenotype with a lack of development of epithelial cells in various organs including the intestine, and few mice carrying the mutation survive long after birth.
The mutant mice typically also have abnormalities of the skin and hair.
The researchers noted that there were phenotypic similarities between the knockout mice and the affected children, but there also were differences.
Although the children manifested skin and gut abnormalities soon after birth, intestinal biopsies done later in childhood found few abnormalities.
This, according to the researchers, suggests "the presence in humans of compensatory mechanisms" for epithelial repair even when ADAM17 is lacking.
"The cause of the gut problems in both children has never been satisfactorily resolved and requires more investigation," they noted.
A possible explanation for the attenuated phenotype in humans compared with the mice is that the expression of ADAM10 was retained, and there is some overlap in the activity of that enzyme and ADAM17, such as in targeting desmoglein 2 in the skin and hair follicles.
Desmoglein 2 is known to be expressed in myocytes in the heart, which may help explain the cardiac abnormalities in the affected children, they suggested.
Moreover, the lack of TNF-α, which has cardioprotective properties as well as immune-regulating activity, may have played a role in the affected girl's death at age 12.
The inadequate levels of TNF-α also may have contributed to the children's susceptibility to opportunistic skin infections. "Given the redundancy in the immune system, however, other pathways were probably operating in the patient's skin and gut to limit infection and inflammation," the researchers hypothesized.
ADAM17 has previously been considered a potential pharmacologic target in diseases characterized by chronic inflammation and overproduction of TNF-α, but the severe phenotype seen in the knockout mice suggested that blocking this target could be lethal in humans as well.
These researchers' findings suggest that such a concern may be unwarranted, and they noted that reconsideration of targeting ADAM17 might be useful for patients with conditions such as rheumatoid arthritis and psoriasis, although the possibility for adverse cardiac effects exists.
Source reference:
Blaydon D, et al "Inflammatory skin and bowel disease linked to ADAM17 deletion" N Engl J Med 2011; 365: 1502-1508.
This gene, located on chromosome 2, encodes a protein that cleaves membrane-bound tumor necrosis factor (TNF)-α, converting it to soluble TNF-α, according to David P. Kelsell, PhD, of the London School of Medicine and Dentistry, and colleagues.
The two out of three affected siblings, one boy and one girl, both developed severe erythema and pustular rashes within two days of birth, and later showed abnormalities of the hair and nails.
They also were susceptible to skin infections throughout childhood.
In addition, within a week of birth, both children developed bloody diarrhea suggestive of malabsorption, which in the girl was associated with failure to thrive.
She died at age 12 from myocarditis associated with parvovirus B19 infection.
Subsequent evaluation of her affected brother revealed the presence of mild left ventricular abnormalities.
To identify the genetic basis of this disorder, Kelsell and colleagues obtained biopsy specimens from the skin and intestines of the family members and age-matched controls.
Genetic analysis identified a deletion in exon 5 of ADAM17 in the two affected children that was not present in the unaffected sibling. Both affected children were homozygous for the mutation.
Histochemical analysis then revealed a lack of expression of ADAM17 in biopsy specimens and peripheral blood mononuclear cells in the affected children, which was not the case in unaffected family members or controls.
Because of the inflammatory nature of the disorder, the researchers also examined cytokine production in peripheral blood mononuclear cells.
Stimulation with lipopolysaccharide or anti-CD3 and anti-CD28 antibodies led to robust production of TNF-α in samples from controls and the mother, but only weak production in samples from the affected boy.
Other cytokines, including interleukin-1β, interleukin-6, and interferon-γ, were secreted in all samples, including those from the affected boy.
A knockout mouse model lacking ADAM17 exhibits a severe phenotype with a lack of development of epithelial cells in various organs including the intestine, and few mice carrying the mutation survive long after birth.
The mutant mice typically also have abnormalities of the skin and hair.
The researchers noted that there were phenotypic similarities between the knockout mice and the affected children, but there also were differences.
Although the children manifested skin and gut abnormalities soon after birth, intestinal biopsies done later in childhood found few abnormalities.
This, according to the researchers, suggests "the presence in humans of compensatory mechanisms" for epithelial repair even when ADAM17 is lacking.
"The cause of the gut problems in both children has never been satisfactorily resolved and requires more investigation," they noted.
A possible explanation for the attenuated phenotype in humans compared with the mice is that the expression of ADAM10 was retained, and there is some overlap in the activity of that enzyme and ADAM17, such as in targeting desmoglein 2 in the skin and hair follicles.
Desmoglein 2 is known to be expressed in myocytes in the heart, which may help explain the cardiac abnormalities in the affected children, they suggested.
Moreover, the lack of TNF-α, which has cardioprotective properties as well as immune-regulating activity, may have played a role in the affected girl's death at age 12.
The inadequate levels of TNF-α also may have contributed to the children's susceptibility to opportunistic skin infections. "Given the redundancy in the immune system, however, other pathways were probably operating in the patient's skin and gut to limit infection and inflammation," the researchers hypothesized.
ADAM17 has previously been considered a potential pharmacologic target in diseases characterized by chronic inflammation and overproduction of TNF-α, but the severe phenotype seen in the knockout mice suggested that blocking this target could be lethal in humans as well.
These researchers' findings suggest that such a concern may be unwarranted, and they noted that reconsideration of targeting ADAM17 might be useful for patients with conditions such as rheumatoid arthritis and psoriasis, although the possibility for adverse cardiac effects exists.
Source reference:
Blaydon D, et al "Inflammatory skin and bowel disease linked to ADAM17 deletion" N Engl J Med 2011; 365: 1502-1508.
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