Ещё - окислительный стресс и ДНК

Моей радости нет предела - ещё одна новость об оксидативном повреждении ДНК, на http://www.eurekalert.org/pub_releases/2009-03/eu-drm032609.php

Public release date: 26-Mar-2009

Contact: Holly Korschun
hkorsch@emory.edu
404-727-3990
Emory University

Like doctors making house calls, some DNA repair enzymes can relocate to the part of the cell that needs their help, a collaborative team of scientists at Emory University School of Medicine has found.

The signal that prompts relocation is oxidative stress, an imbalance of cellular metabolism connected with several human diseases.

The study integrated the expertise of three Emory groups and resulted in a new level of understanding of the cell's response to genetic damage. The finding could lead to new targets for anti-cancer drugs that interfere with DNA repair, says Paul Doetsch, PhD, professor of biochemistry, radiation oncology, and hematology and oncology at Emory University School of Medicine.

The results were published in the February 1 issue of Molecular and Cellular Biology. The journal's editors chose an image of yeast cells with fluorescent DNA repair enzymes for the cover.

"DNA damage and oxidative stress are very closely related," Doetsch says. "For example, the way radiation inflicts most of its damage on DNA is through oxidative stress. The more we know about how cells respond to oxidative stress, the more chances there could be to influence those responses for diagnostic or therapeutic purposes."

The DNA inside cells is continually under assault by heat, radiation and oxygen. Cells have an extensive set of repair enzymes that comb through DNA, continually excising and re-copying damaged segments. To complicate matters, mitochondria (cells' miniature power plants) have their own DNA.

Working with Doetsch, Emory graduate students Lyra Griffiths and Dan Swartzlander, and biochemists Anita Corbett and Keith Wilkinson, genetically modified strains of yeast so that two different DNA repair enzymes would be fluorescent. They were able to follow the enzymes around the cell when yeast was exposed to hydrogen peroxide, causing oxidative stress, or to other chemicals causing DNA damage.

One DNA repair enzyme they studied, Ntg1, moves to the nucleus or the mitochondria depending on where DNA damage is concentrated, the authors found. In contrast, a related enzyme, Ntg2, stays in the nucleus under all conditions.

Cells appear to direct Ntg1's relocation by briefly attaching a small protein called SUMO to what needs to be moved around, the authors found. SUMO is found in fungi, plants and animals and is already being investigated by several research groups as a possible target for anti-cancer drugs.

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The Robert W. Woodruff Health Sciences Center of Emory University is an academic health science and service center focused on missions of teaching, research, health care and public service. Its components include schools of medicine, nursing, and public health; the Yerkes National Primate Research Center; the Emory Winship Cancer Institute; and Emory Healthcare, the largest, most comprehensive health system in Georgia. The Woodruff Health Sciences Center has a $2.3 billion budget, 17,000 employees, 2,300 full-time and 1,900 affiliated faculty, 4,300 students and trainees, and a $4.9 billion economic impact on metro Atlanta.

И снова о депрессии

Об очень интересном исследовании мне довелось прочитать на http://www.scienceblog.com/cms/depressed-people-have-trouble-learning-good-things-life-19595.html, оказывается, восприятие позитивной и негативной информации отличается у людей в депрессии и нормальных...

COLUMBUS, Ohio - While depression is often linked to negative thoughts and emotions, a new study suggests the real problem may be a failure to appreciate positive experiences.

Researchers at Ohio State University found that depressed and non-depressed people were about equal in their ability to learn negative information that was presented to them.

But depressed people weren't nearly as successful at learning positive information as were their non-depressed counterparts.

"Since depression is characterized by negative thinking, it is easy to assume that depressed people learn the negative lessons of life better than non-depressed people - but that's not true," said Laren Conklin, co-author of the study and a graduate student in psychology at Ohio State.

The study appears in the March issue of the Journal of Behavior Therapy and Experimental Psychiatry.

Researchers tested 34 college students, 17 of whom met criteria for clinical depression and 17 of whom were not depressed.

This study is one of the first to be able to link clinical levels of depression to how people form attitudes when they encounter new events or information, said Daniel Strunk, co-author of the study and assistant professor of psychology at Ohio State.

Strunk said the key to conducting this study was the use of a computer game paradigm co-developed at Ohio State in 2004 by Russell Fazio, a professor of psychology and co-author of this new study. Fazio and his collaborators, Natalie Shook, a PhD graduate of Ohio State now at Virginia Commonwealth University and J. Richard Eiser of the University of Sheffield (England) have used the game in many studies examining differences in the development of positive and negative attitudes.

The developers affectionately call the game "BeanFest." It involves people encountering images of beans on the computer screen. The beans could be good or bad, depending on their shape and the number of speckles they had.

Good beans earned the players points, while bad beans took points away. The goal was to earn as many points as possible.

While the game may seem trivial to a naive audience, Strunk said it offers a unique and powerful way to measure how people learn new attitudes.

"Before, if researchers wanted to investigate how people formed new attitudes, it was very difficult to do," Strunk said. If researchers asked about real-life issues, the problem is that prior learning and attitudes may impact how people respond to new information. But in this game, participants don't have any prior knowledge or attitudes about the beans so researchers could learn how they formed their attitudes in a novel situation, without interference from past experiences.

In the game phase of this study, participants had to choose whether they would accept a bean when it appeared on the screen. If they accepted the bean, the points were added or deducted from their total. If they rejected the bean, they were still told how many points they would have earned or lost if they had accepted it.

Each of the 34 beans was shown three times during the game phase, giving the participants a good opportunity to learn which beans were good and which were bad.

Then, in the test phase, participants had to indicate whether beans they learned about in the game phase were "good" (choosing it would increase points) or "bad" (choosing it would decrease points). The researchers tallied how well participants did in correctly identifying positive and negative beans.

The non-depressed students correctly identified 61 percent of the negative beans, which was about the same as the depressed students, who correctly identified 66 percent of the "bad" beans.

But while the non-depressed students correctly identified 60 percent of the positive beans, depressed students correctly classified only 49 percent of these good beans. Non-depressed students identified the good beans better than the depressed students, who failed to identify good beans better than chance.

"The depressed people showed a bias against learning positive information although they had no trouble learning the negative," Strunk said.

One of measures researchers used in the study classified whether the depressed participants were currently undergoing a mild, moderate or severe episode of depression. In the study, those undergoing a severe depressive episode did more poorly on correctly choosing positive beans than those with mild depression, further strengthening the results.

While more research is needed, Conklin and Strunk said this study suggests possible ways to improve treatment of depressed people.

"Depressed people may have a tendency to remember the negative experiences in a situation, but not remember the good things that happened," Conklin said. "Therapists need to be aware of that."

For example, a depressed person who is trying out a new exercise program may mention how it makes him feel sore and tired - but not consider the weight he has lost as a result of the exercise.

"Therapists might focus more on helping their depressed clients recognize and remember the positive aspects of their new experiences," Strunk said.

Тромбоциты и сепсис

Тема тромбоцитов сейчас меня особо интересует, поэтому советую почитать статейку на http://www.eurekalert.org/pub_releases/2009-03/cnmc-cnr031009.php
Contact: Jennifer Leischerjleische@cnmc.org202-476-4500Children's National Medical Center
Children's National research links platelets to sepsis-related organ failure
Conventionally thought to be the bloodstream's 'innocent bystanders,' platelets may actually play a more sinister role in organ failure caused by severe sepsis
WASHINGTON, DC—Scientists at Children's National Medical Center have identified a previously unknown contributor to organ failure in patients suffering from sepsis: platelets.
The finding, published in the American Journal of Respiratory and Critical Care Medicine, is the first time doctors have looked at and linked platelets to poor outcomes from this often fatal infection.
"Despite many medical advances over the last few decades, mortality rates for sepsis have not really improved," said Robert Freishtat, MD, MPH, of the Center for Genetic Medicine Research at Children's National Medical Center, who led the study. "But now that we know that platelets, which we previously believed to be merely 'innocent bystanders,' can actually contribute to the development of fatal complications from sepsis, we can use this knowledge to better gauge someone's risk of dying and to design new interventions."
Sepsis is the tenth leading cause of death in the United States. More than 40 percent of sepsis cases are fatal, and in most, the resulting organ failure, not the underlying infection, is the primary cause of death. Through gene and protein analyses in both septic mice and humans, scientists found that cases of severe sepsis featured a unique attribute: the genes within platelets were triggered to produce a protein known as granzyme B, which has been shown in previous studies to contribute to cell death as part of the body's immune response to cancer and viruses. During sepsis, platelets collect within major organs including the spleen, an important infection-fighting organ. As they collect and come into contact with the organ's cells, the granzyme B, if present, will cause the organ's cells to die. Previous research has shown that that this factor may be a major contributor to organ failure. Granzyme B was only detected in humans and mice with the most severe sepsis.
"Detection of granzyme B in platelets could be a huge step forward in battling sepsis," said Dr. Freishtat. "First, as a prognostic indicator, the protein's presence could show more aggressive treatments are needed right off the bat. Eventually, perhaps this knowledge will help us find a way to prevent organ failure by targeting interventions directly at the platelets and granzyme B production."
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The study was funded by the National Institutes of Health and Children's National Medical Center.
The full manuscript, "Sepsis Alters the Megakaryocyte-Platelet Transcriptional Axis Resulting in Granzyme B-mediated Lymphotoxicity" is available on the journal's website.
About Children's National Medical Center
Children's National Medical Center, located in Washington, DC, is a proven leader in the development of innovative new treatments for childhood illness and injury. Children's has been serving the nation's children for more than 135 years. Children's National is proudly ranked among the best pediatric hospitals in America by US News & World Report and the Leapfrog Group. For more information, visit www.childrensnational.org. Children's Research Institute, the academic arm of Children's National Medical Center, encompasses the translational, clinical, and community research efforts of the institution. Learn more about our research programs at www.childrensnational.org/research.

Работа над ошибками (белки в клетке) :)

Отличная новость!!! http://www.biologynews.net/archives/2009/03/12/cells_get_two_chances_not_just_one_to_fix_their_mistakes.html

Оказывается, клетки имеют не один шанс исправить ошибки!!!

Cells have two chances to fix the same mistake in their protein-making process instead of just one – a so-called proofreading step – that had previously been identified, according to new research.
Proteins are essential to life and do most of the work in cells, so avoiding mistakes during their production is a critical way to prevent a variety of harmful conditions that result when mutations cause damage or when cells die.
Better knowledge of the mechanism behind these occasional mistakes could increase understanding of various disease processes, especially in neurodegenerative disorders, some of which scientists suspect are associated with mutated proteins, Ohio State University researchers say.
The discovery of this second step also gives drug-makers a new target to consider, especially in the development of antibiotics. Drugs designed to interfere with the enzymes that make, find and repair the mistakes during protein production could be powerful agents in stopping bacterial cell growth.
One key enzyme involved in cell quality control is called phenylalanyl-tRNA synthetase (PheRS). This enzyme's job within the cell is to correctly select one of the amino acids that will be strung together into a molecule to make a protein.
"We're describing a pretty simple process where the cell says, 'I think I'll have one more look at that,'" said Michael Ibba, senior author of the study and an associate professor of microbiology at Ohio State. "It looks at the building blocks and checks that they're right before it makes the protein."
The research is published in the March 13 issue of the journal Molecular Cell.
In past examinations of this mechanism in the cell, Ibba's lab had identified a single quality-control measure cells take as they produce proteins. The researchers initially thought that this proofreading step was the only check during the protein-making process.
"There was a step at which we thought, now it's done, and if a mistake gets through here, it's irreversible and is going to end up as a mistake. But it turns out there is yet another step at which the cell has another look. It's checking itself," Ibba said. "The bottom line is we must have been missing something."
Previous research has suggested that cells, on average, make one error during protein production for every 10,000 amino acids strung together.
"What we do is try to find out where that error rate number comes from," said Ibba, also an investigator in Ohio State's Biochemistry Program and its Center for RNA Biology. "Understanding where the mistakes come from means you can try to predict conditions that will either raise or lower the frequency of mistakes."
Within the cell, PheRS is one member of a family of enzymes responsible for selecting amino acids that will be attached to an adapter molecule that facilitates the protein-building process. The amino acids must be attached to the appropriate adapter to ensure the genetic code is deciphered properly.
Ibba's lab has been studying this enzyme's activities for years. After observing over time what appeared to be a second quality-control step, the scientists had to devise a method they could use to prove the second step occurred. So the researchers first generated the mistake synthetically, and then introduced other enzymes that would normally be present later in protein production to see if they could then observe the second quality check.
The researchers discovered that the same enzyme that makes the mistake, PheRS, also checks and cleans up after itself in a process that removes the incorrect amino acid and attaches the correct one in its place. And the enzyme can do this even after an initial check misses the mistake and allows the protein-building process to continue.
"The enzyme is two catalysts, one that can make the mistake and one that can correct the mistake. It can let the mistake go and grab it back. Nothing tells it to do this. It figures it out on its own," Ibba said.
These experiments were conducted using E. coli bacterial cells, which are a preferred model for many cell studies. But understanding this mechanism can be particularly useful in the design of antibiotics because many such drugs specifically target the protein-production process to halt the growth of bacteria.
"We're trying to understand the process which in the past has proven to be very fruitful as a target for antibiotics," Ibba said. "The hope is when you target protein synthesis in general, either you stop it completely or make the process too inaccurate so the cell can't grow."
This very same quality-control process, involving a different enzyme, is being targeted in the development of an antifungal agent that is currently being tested in humans to treat toenail fungus, Ibba noted.
Even with this second editing step identified, there is still plenty to learn. For example, these enzymes do not act alone. Their interactions with other enzymes in the cell affect their behavior. And exactly what happens when mutant proteins slip through the quality-control system remains poorly understood, as well.
"Sometimes mistakes do get in, and that's what we're still uncertain about. Even in some neurodegenerative disorders, we can see that there are almost certainly errors, but the frequency is impossible to know at present," Ibba said. "If we know more about the mechanism, then if we find mutations, we'll have a much better chance of finding what the consequences of those mutations are."
Source : Ohio State University

Соль - антидепрессант!

Прочитала новую статью на http://www.scienceblog.com/cms/study-suggests-salt-might-be-natures-antidepressant-19352.html и призадумалась...
Most people consume far too much salt, and a University of Iowa researcher has discovered one potential reason we crave it: it might put us in a better mood.

UI psychologist Kim Johnson and colleagues found in their research that when rats are deficient in sodium chloride, common table salt, they shy away from activities they normally enjoy, like drinking a sugary substance or pressing a bar that stimulates a pleasant sensation in their brains.

"Things that normally would be pleasurable for rats didn't elicit the same degree of relish, which leads us to believe that a salt deficit and the craving associated with it can induce one of the key symptoms associated with depression," Johnson said.

The UI researchers can't say it is full-blown depression because several criteria factor into such a diagnosis, but a loss of pleasure in normally pleasing activities is one of the most important features of psychological depression. And, the idea that salt is a natural mood-elevating substance could help explain why we're so tempted to over-ingest it, even though it's known to contribute to high blood pressure, heart disease and other health problems.

Past research has shown that the worldwide average for salt intake per individual is about 10 grams per day, which is greater than the U.S. Food and Drug Administration recommended intake by about 4 grams, and may exceed what the body actually needs by more than 8 grams.

Johnson, who holds appointments in psychology and integrative physiology in the College of Liberal Arts and Sciences and in pharmacology in the Carver College of Medicine, published a review of these findings in the July issue of the journal Physiology & Behavior with Michael J. Morris and Elisa S. Na, UI graduate students. In addition to reporting their own findings, the authors reviewed others' research on the reasons behind salt appetite.

High levels of salt are contained in everything from pancakes to pasta these days, but once upon a time, it was hard to come by. Salt consumption and its price skyrocketed around 2000 B.C. when it was discovered as a food preservative. Roman soldiers were paid in salt; the word salary is derived from the Latin for salt. Even when mechanical refrigeration lessened the need for salt in the 19th century, consumption continued in excess because people liked the taste and it had become fairly inexpensive. Today, 77 percent of our salt intake comes from processed and restaurant foods, like frozen dinners and fast food.

Evolution might have played an important part in the human hankering for salt. Humans evolved from creatures that lived in salty ocean water. Once on land, the body continued to need sodium and chloride because minerals play key roles in allowing fluids to pass in and out of cells, and in helping nerve cells transfer information throughout the brain and body. But as man evolved in the hot climate of Africa, perspiration robbed the body of sodium. Salt was scarce because our early ancestors ate a veggie-rich diet and lived far from the ocean.

"Most of our biological systems require sodium to function properly, but as a species that didn't have ready access to it, our kidneys evolved to become salt misers," Johnson said.

Behavior also came to play a key role in making sure we have enough salt on board. Animals like us come equipped with a taste system designed to detect salt and a brain that remembers the location of salt sources -- like salt licks in a pasture. A pleasure mechanism in the brain is activated when salt is consumed.

So the body needs salt and knows how to find it and how to conserve it. But today scientists are finding evidence that it's an abused, addictive substance -- almost like a drug.

One sign of addiction is using a substance even when it's known to be harmful. Many people are told to reduce sodium due to health concerns, but they have trouble doing so because they like the taste and find low-sodium foods bland.

Another strong aspect of addiction is the development of intense cravings when drugs are withheld. Experiments by Johnson and colleagues indicate similar changes in brain activity whether rats are exposed to drugs or salt deficiency.

"This suggests that salt need and cravings may be linked to the same brain pathways as those related to drug addiction and abuse," Johnson said.

О каинатных рецепторах

Интересные новости о стрессе и депрессии нашла я на http://www.scienceblog.com/cms/protein-found-linking-stress-and-depression-18947.html
Stress, the ever-present threat to health and happy living, is tough on the brain. If the strain goes on too long, it can lead to debilitating psychological problems.

Part of the reason, according to scientists at The Rockefeller University, may have to do with a little-known family of proteins called kainate receptors that has recently been implicated in major depression. New research in rats may help explain one mechanism by which stress reshapes the brain: namely, by ramping up production of a particular part of these proteins.

“We’ve recently seen large human studies that suggest kainate receptors are targets for response to certain antidepressants and are also involved in major depression and the susceptibility to suicidal thoughts,” says Richard Hunter, a postdoctoral fellow in Bruce S. McEwen’s Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology at Rockefeller. “We are trying to build up a molecular understanding of what is going on here.”

In experiments published recently in a special issue of PLoS ONE, Hunter and his colleagues homed in on one of five subunits of the kainate receptor called KA1. Performing a series of experiments exploring the impact of stress and steroids on rats, they found that stress, simulated by restraining the rats for six hours a day for three weeks, caused the genes to send instructions — messenger RNA — to increase production of KA1 subunits in particular parts of the hippocampus, a highly plastic brain structure involved in learning and memory.

The lab produced a similar result by injecting unstressed rats with hormones called corticosteroids, suggesting that an increase in these hormones is largely responsible for the stress response in rats. But the researchers also found that the dose is critical. While a moderate amount of corticosteroids increased KA1 messenger RNA, a high dose of the steroids did not. The relationship between the hormone and its impact is an inverted U response, a pattern familiar to biologists.

“The body seeks to maintain ideal levels, whether it is salts in the blood or any number of other things like KA1,” Hunter says. “Deviations to either side of these levels can cause pathologies or changes. The body adapts to changing circumstances to keep the levels healthy.”

Stress and depression are known to cause a reversible retraction of dendrites in certain brain cells, particularly in the hippocampus, that McEwen and colleagues refer to as “adaptive plasticity.” The new research suggests that an increase in KA1, caused by the corticosteroid response in rats, may trigger this retraction. The finding follows recent work by Rockefeller’s Sidney Strickland, head of the Laboratory of Neurobiology and Genetics, that showed that KA1 production explodes in the hippocampus during simulated stroke in mice, driving a cell-death cascade that begins when part of the brain is deprived of blood. Combined, the work suggests that the relatively understudied KA1 subunit plays an important role in a key area of the brain in both causing damage in an uncontrolled trauma such as a stroke and in protecting the brain from damage under the more controlled circumstances of chronic stress.

McEwen and colleagues have shown that healthy brains are remarkably resilient in the face of stress — brains replace their retracted neurons once the stress is removed. Perhaps, the researchers say, the same will prove true for depression. “One of the great hopes is that these changes in the hippocampus that happen with prolonged depression may not be signs of permanent irreversible damage but they may actually be signs of plasticity that we can treat with appropriate medications and also behavioral therapies,” McEwen says.
http://newswire.rockefeller.edu