Improved Antibiotic: Genes For Synthesizing Thiostrepton Identified

Researchers at the Georgia Institute of Technology have identified the genetic machinery responsible for synthesizing thiostrepton, a powerful antibiotic produced by certain bacteria. Though effective against the dangerous MRSA (methicillin-resistant Staphylococcus aureus) and vancomycin-resistant enterococci, thiostrepton currently has only limited applications in humans because it is not water soluble.dentification of the gene cluster responsible for producing thiostrepton sets the stage for genetic manipulations that could make the drug more useful by improving its water solubility, potentially providing a new tool in the high-stakes battle against bacteria. Beyond the possible medical applications, the research produced a scientific surprise: thiostrepton is derived from a genetically encoded peptide that undergoes no fewer than 19 different modifications, one of the most complex such processes known – and a surprising capability for a single-celled bacterium.

"We are interested in making derivatives of this peptide drug that retain their potency and are efficiently processed by biochemical machinery," said Wendy L. Kelly, an assistant professor in Georgia Tech's School of Chemistry and Biochemistry and the Parker Petit Institute for Bioengineering and Bioscience. "We want to put in substitutions to the genetic machinery that may create a more water soluble analog and could potentially be used for development of a new class of antibacterial agent."

Kelly, graduate student Lisa Pan and postdoctoral fellow Chaoxuan Li began their study of thiostrepton by having the genome of one bacterium that produces it -- Streptomyces laurentii – sequenced by a commercial laboratory. They then studied different parts of the genome, searching for the genes responsible for producing the drug.

"It was a combination of DNA sequencing, bioinformatic analysis of the encoded proteins and biochemical characterization," said Kelly. "We didn't really know where on the chromosome this would be localized. Instead of taking a single shot and looking only at one location, we used a shotgun strategy that gave us insight into many different regions on the chromosome at the same time."

Fortunately, in simple organisms like bacteria, genes responsible for a particular task tend to be located close together, so when the researchers found one relevant gene, they knew the rest would be nearby. The researchers produced a knockout mutant to confirm that the genes they had identified were the correct ones.

The mechanism by which the bacterium produces thiostrepton turned out to be of considerable interest. Because peptides produced directly by ribosomal synthesis tend to be comparably simple, researchers had expected the complex thiostrepton molecule to be produced by a non-ribosomal route.

However, the Georgia Tech team showed that the drug results from a process controlled by the ribosome – which makes it a good target for genetic manipulation.

"The fact that we have a gene that produces a peptide that undergoes post-translational modification makes this a simpler target for biosynthetic engineering," Kelly noted. "Before this finding, we didn't know that such extensive modifications could be made to a peptide. Finding this mechanism completely changes how we look at this and similar systems, and changes the potential for biosynthetically engineering effective new systems."

Kelly's research team will next seek to understand the complex pathway used to synthesize the drug, then attempt to modify the right component of that machinery to create a variant of thiostrepton that is water soluble.

"You can think about this in terms of an assembly line for manufacturing cars, with the changes occurring in stages during construction," she said. "The same would be true of a microorganism building up a complex molecule. Some modifications that occur later in the process may require certain key elements to be present first. We need to understand what modifications are necessary and what features of the structure are important for recognition and processing down the line."

Produced by certain terrestrial and marine bacteria, thiostrepton was identified in the 1950s, and first synthesized in the laboratory in 2004. Thiostrepton and related thiopeptide antibiotics fight bacteria by disabling their protein biosynthesis, and also have promising anti-malarial and anti-cancer activity.

Though researchers face many challenges in attempting to modify the genes and enzymes required to produce the drug, the potential benefits are significant.

"With the development of resistance and pathogens such as MRSA, there's a crisis developing in anti-microbial treatments," she noted. "If they were to become resistant to the few drugs that are currently available to fight them, they would become untreatable. There is a big push to identify new drugs for clinical use in humans that are effective against these strains."

With an undergraduate degree in pharmacy and graduate degrees in chemistry, Kelly has focused on natural systems that produce useful drugs.

"I have a profound appreciation for nature's chemistry and how nature makes complex metabolites from very simple building blocks," she said. "If you compare the kinds of transformations that can be done inside a bacterium against what a synthetic chemist can do, you see the power of nature in its ability to catalyze highly specialized reactions under very mild conditions."

Details of the work were published online in the Journal of the American Chemical Society on March 5. The research was sponsored by the Camille and Henry Dreyfus Foundation, the American Society of Pharmacognosy and Georgia Tech.

New Anti-cancer Drug: 200 Times More Active In Killing Tumor Cells

A team of 24 researchers from the U.S., Europe, Taiwan and Japan and led by University of Illinois scientists has engineered a new anti-cancer agent that is about 200 times more active in killing tumor cells than similar drugs used in recent clinical trials.he study appears this week in the Journal of the American Chemical Society.

The new agent belongs to a class of drugs called bisphosphonates. These compounds were originally developed to treat osteoporosis and other bone diseases, but were recently found to also have potent anti-cancer and immune boosting properties.

Drug developers have tried for years to design drugs to inhibit cell survival pathways in tumor cells, focusing on a protein called Ras since nearly a third of all human cancers involve a mutation in the Ras gene that causes cell signaling to go awry. These efforts have met with limited success.

Bisphosphonates act on other enzymes, called FPPS and GGPPS, which are upstream of Ras in the cell survival pathway. Inhibiting these enzymes appears to be a more effective strategy for killing cancer cells.

When used in combination with hormone therapy in a recent clinical trial, the bisphosphonate drug zoledronate significantly reduced the recurrence of breast cancer in premenopausal women with estrogen-receptor-positive breast cancer. Similar results were reported previously for hormone-refractory prostate cancer.

But zoledronate quickly binds to bone, reducing its efficacy in other tissues.

"We're trying to develop bisphosphonates that will be very active but won't bind to the bone, because if they bind to the bone they're not going to go to breast, lung or other tissues," said University of Illinois chemistry professor Eric Oldfield, who led the new study.

Oldfield's team also wanted to design a compound that would inhibit multiple enzymes in the tumor cell survival pathway, rather than just one, an approach analogous to the use of multi-kinase inhibitors in cancer therapy.

Andrew Wang, of Academia Sinica, Taipei, and Illinois chemist Rong Cao began by producing crystallographic structures of the target enzymes and drug candidates, allowing the researchers to identify those features that would enhance the drugs' ability to bind to the enzymes. Using this and other chemical data, Illinois chemistry department research scientist Yonghui Zhang engineered new bisphosphonate compounds that bound tightly to multiple enzyme targets, but not to bone.

One of the new compounds, called BPH-715, proved to be especially potent in cell culture and effectively inhibited tumor cell growth and invasiveness.

Tadahiko Kubo, of Hiroshima University, then found that BPH-715 also killed tumor cells in mice. And Socrates Papapoulos, of Leiden University, the Netherlands, showed that the compound had a very low chemical affinity for bone.

In humans, compounds like BPH-715 and zoledronate have an added benefit in fighting cancer: They spur the proliferation of immune cells called gamma delta T-cells, which aid in killing tumor cells.

"The new drugs are about 200 times more effective than the drugs used in recent clinical trials at killing tumor cells and in activating gamma delta T-cells to kill tumor cells," Oldfield said. "They also prevent tumor progression in mice much better than do existing bisphosphonate molecules."

World’s First Successful ViKY Robot-assisted Surgery For Pancreatic Tumors

This month Fox Chase Cancer Center performed the world's first successful minimally invasive distal pancreatectomy using the ViKY® system's revolutionary robotic, compact laparoscope holder. The technology, developed in France and tested on thousands of patients in Europe, made its debut in a cancer setting in the United States at Fox Chase. "Fox Chase is among only a handful of institutions worldwide using robotics or laparoscopy to treat patients with nearly all types of cancer," says Robert G. Uzzo, MD, FACS, chairman of the department of surgery at Fox Chase. "The use of technology, like the ViKY system, reinforces our Center's commitment to excellence in minimally invasive surgical techniques for the care of patients with both benign and cancerous conditions."

Fox Chase surgeon Andrew A. Gumbs, MD, who specializes in minimally invasive hepato-pancreatic and biliary (HPB) surgery, explains, "This system is so versatile that surgeons like me are able to use it for many different laparoscopic procedures, including those in the gastrointestinal, urologic, thoracic and gynecologic regions."

Typically with minimally invasive procedures, like a laparoscopic distal pancreatectomy, surgeons use both hands to manipulate the surgical tools and need an assistant to manipulate the endoscope—a thin, lighted tube equipped with a camera that allows the surgeon to view the surgical field.

Gumbs performed this first ever ViKY assisted minimally invasive distal pancreatectomy on a 65-year-old man who was diagnosed with two pancreatic cysts, one of which is potentially cancerous. Pathologists are currently evaluating the cyst.

"The new ViKY robotic laparoscope holder acts as an extra hand during surgery, giving me stability and steadiness," adds Gumbs. "The view of the surgical field is critical, so ViKY's pinpoint accuracy helps me perform more complex procedures laparoscopically." Unlike typical laparoscope holders, the ViKY system's holder is lightweight, easy to set up and use, and takes no floor space.

Standard treatment for pancreatic cancer is surgery to remove the head or tail of the pancreas. When patients present with pancreatic cancer localized to the tail of the pancreas (instead of the head), they undergo a distal pancreatectomy, in which the surgeon removes the tail of the pancreas and leaves the head attached. The remaining portion can function normally by producing and releasing digestive enzymes and hormones. Patients with pancreatic cancer are typically treated with surgery followed by radiation therapy and/or chemotherapy to reduce the risk of recurrence.

The ViKY system gave Gumbs precise control of the laparoscope while he performed the distal pancreatectomy. The endoscope moves according to the surgeon's orders, either through voice recognition or footswitch control.

Before the ViKY technology was available patients might have undergone open surgery. Depending on the complexity of the case, the surgeon may have considered open abdominal surgery, requiring a large incision and a lengthy recovery. Minimally invasive surgical techniques, like the surgery Dr. Gumbs performed, benefit patients in many ways, including a shorter hospital stay, faster recovery, quicker return to daily activity, less risk of infection and less scarring and bleeding.

Gumbs was the first American surgeon to complete a minimally invasive HPB fellowship at the Institut Mutualiste Montsouris in Paris, France. This is the hospital where the first published case of a single incision laparoscopic cholecystectomy in the world was done using the ViKY system. Gumbs is responsible for bringing the ViKY system to Fox Chase and will be training fellow surgeons on this technology.

The ViKY system is manufactured by Endocontrol Medical in La Tronche, France. Endocontrol is an innovative company offering robotic solutions for endoscopic surgeries. Endocontrol was created by Clement Vidal and Patrick Henri of Joseph Fourier University, Grenoble, France, a worldwide leader in computer assisted and robotic surgery.

Acetaldehyde In Alcohol: 'Hangover Chemical' May Be Overlooked Risk Factor For Cancer

New evidence by researchers at the Centre for Addiction and Mental Health (CAMH) and researchers in Germany shows that drinking alcohol is the greatest risk factor for acetaldehyde-related cancer. Heavy drinkers may be at increased risk due to exposure from multiple sources.Acetaldehyde is ubiquitous in daily life in Ontario. Widely present in the environment, it is inhaled from the air and tobacco smoke, ingested from alcohol and foods, and produced in the human body during the metabolism of alcoholic beverages. Research indicates that this organic chemical plays a significant role in the development of certain types of cancers (especially of the upper digestive tract), and it is currently classified as possibly carcinogenic by the International Agency for Research on Cancer of the World Health Organization.

New research from CAMH in Toronto and the Chemical and Veterinary Investigation Laboratory Karlsruhe (CVUA) in Germany recently provided the necessary methodology for calculating the risk for the ingestion of alcoholic beverages.

The team found that risk from ingesting acetaldehyde via alcoholic beverages alone may exceed usual safety limits for heavy drinkers. Their risk assessment study found that the average exposure to acetaldehyde from alcoholic beverages resulted in a life-time cancer risk of 7.6/10,000, with higher risk scenarios (e.g. contaminations in unrecorded alcohol) in the range of 1 in 1,000. As such, the life-time cancer risks for acetaldehyde from ingestion of alcoholic beverages greatly exceed the usual limits for cancer risks from the environment.

The research team noted, however, that this risk is compounded by the addition of acetaldehyde exposure from different sources. "The problem with acetaldehyde has been that although it has been recognized as toxic by Health Canada some years ago, most risk assessments to date were based on one source of exposure only" explained Dr. Jürgen Rehm, the lead scientist of the Toronto group and head of the Public Health and Regulatory Policies section at CAMH. "This has led to a negligence of the overall risk."

For example, in Toronto, even though there are limits for air exposure of acetaldehyde set by the responsible Public Health agency, these limits have been surpassed in the past. Alone, the risks associated with surpassing limits of acetaldehyde from the air may not yet be alarming, but for heavy drinkers and smokers, it adds to the acetaldehyde levels already received from these sources. This overall risk then surpasses established safety limits.

"Their risk assessment of acetaldehyde present as a congener in alcoholic beverages touches the tip of the iceberg," according to a Commentary on the CAMH/CVUA study in the journal Addiction.

New Lab Evidence Suggests Preventive Effect Of Herbal Supplement In Prostate Cancer

DHEA is a natural circulating hormone and the body's production of it decreases with age. Men take DHEA as an over-the-counter supplement because it has been suggested that DHEA can reverse aging or have anabolic effects since it can be metabolized in the body to androgens. Increased consumption of dietary isoflavones is associated with a decreased risk of prostate cancer.Red clover (Trifolium pretense) is one source of isoflavones. Both supplements may have hormonal effects in the prostate and little is known about the safety of these supplements.

In a recent report in Cancer Prevention Research, a journal of the American Association for Cancer Research, researchers report that DHEA levels can be manipulated in cells in the laboratory to understand its effects.

Julia Arnold, Ph.D., a staff scientist at the National Center for Complementary and Alternative Medicine (NCCAM) at the National Institutes of Health, said more research is necessary in an environment where men and women concerned about health problems tend to self-prescribe based on information they find on the Internet.

Towards this end, the NCCAM laboratory is studying signaling between human prostate cancer cells and their supporting stromal cells as they grow together in laboratory culture. "DHEA effects in the prostate tissues may depend on how these two cells types 'talk to each other' and further, it may be potentially harmful in tissues containing inflammation or with early cancer lesions because the cells can induce DHEA to become more androgenic," said Arnold.

Combining DHEA with transforming growth factor beta-1 increased testosterone production in the stromal cells and prostate specific antigen protein secretion two to four-fold and gene expression up to 50-fold in the cancer cells. When these cell cultures were treated with red clover isoflavones, the androgenic effects of DHEA were reversed.

"Something is happening in the prostate tissue microenvironment that is illustrating a potential cancer prevention effect from this supplement," said Arnold.

Red clover isoflavones may modify androgenic effects in the prostate but much more work in the laboratory and clinic is needed to validate these effects.

This sort of laboratory manipulation will allow scientists to understand the basic prostate biology as well as learn cellular and molecular mechanisms of over-the-counter supplements and other botanical or herbal agents. Arnold said NCCAM will continue to study DHEA with other supplements to determine any cancer preventive effects.

Catching The Common Cold Virus Genome

A new study by Brigham Young University researchers on the virus behind nearly half of all cold infections explains how and where evolution occurs in the rhinovirus genome and what this means for possible vaccines."There are a lot of different approaches to treating the cold, none of which seem to be effective," said Keith Crandall, professor of biology and co-author of the study. "This is partly because we haven't spent a lot of time studying the virus and its history to see how it's responding to the human immune system and drugs."

The BYU team studied genomic sequences available online and used computer algorithms to estimate how the rhinovirus is related to other viruses.

According to Nicole Lewis-Rogers, a postdoctoral fellow in the Biology Department and lead author on the study, the rhinovirus is similar to the polio virus, whose vaccine was announced in 1955. But while the polio virus has just three subspecies, the rhinovirus has more than 100 subspecies, which continually evolve.

"These viruses could be under the same constraints and yet change differently," Lewis-Rogers said. "That's why it is so hard to create a vaccine."

Through a computer program developed at BYU, Lewis-Rogers' team was able to identify the parts of the virus genome that enable resistance to drugs and the human immune system.

The immune system does a good job of recognizing viral contaminants and getting rid of them, as do new drugs, but the rhinovirus has responded to these defenses by changing its genome so that it is not so easily recognized.

"The virus is evolving solutions against the immune system and drugs," Crandall said. "The more we can learn about how the virus evolves solutions, the better we can rid the body of these infections."

Understanding where change occurs in the virus genome will help virologists who work to design drugs that target the rhinovirus.

"If you've got 10,000 bits of information, this narrows it down to a handful," Lewis-Rogers said. "Here is where you can start looking."

Lewis-Rogers and Crandall hope scientists will use these insights to build better drugs to combat the virus in the most effective way.

The study is reported in the April issue of the journal Molecular Biology and Evolution. BYU undergraduate Matthew Bendall is also a co-author on the study, which was funded by the USDA. Bendall will next pursue a master's in bioinformatics at BYU.

Broccoli May Help Protect Against Respiratory Conditions Like Asthma

Here's another reason to eat your broccoli: UCLA researchers report that a naturally occurring compound found in broccoli and other cruciferous vegetables may help protect against respiratory inflammation that causes conditions like asthma, allergic rhinitis and chronic obstructive pulmonary disease.Published in the March edition of the journal Clinical Immunology, the research shows that sulforaphane, a chemical in broccoli, triggers an increase of antioxidant enzymes in the human airway that offers protection against the onslaught of free radicals that we breathe in every day in polluted air, pollen, diesel exhaust and tobacco smoke. A supercharged form of oxygen, free radicals can cause oxidative tissue damage, which leads to inflammation and respiratory conditions like asthma.

"This is one of the first studies showing that broccoli sprouts — a readily available food source — offered potent biologic effects in stimulating an antioxidant response in humans," said Dr. Marc Riedl, the study's principal investigator and an assistant professor of clinical immunology and allergy at the David Geffen School of Medicine at UCLA.

"We found a two- to three-fold increase in antioxidant enzymes in the nasal airway cells of study participants who had eaten a preparation of broccoli sprouts," Riedl said. "This strategy may offer protection against inflammatory processes and could lead to potential treatments for a variety of respiratory conditions."

The UCLA team worked with 65 volunteers who were given varying oral doses of either broccoli or alfalfa sprout preparations for three days. Broccoli sprouts are the richest natural source of sulforaphane; the alfalfa sprouts, which do not contain the compound, served as a placebo.

Rinses of nasal passages were collected at the beginning and end of the study to assess the gene expression of antioxidant enzymes in cells of the upper airways. Researchers found significant increases of antioxidant enzymes at broccoli sprout doses of 100 grams and higher, compared with the placebo group.

The maximum broccoli sprout dosage of 200 grams generated a 101-percent increase of an antioxidant enzyme called GSTP1 and a 199-percent increase of another key enzyme called NQO1.

"A major advantage of sulforaphane is that it appears to increase a broad array of antioxidant enzymes, which may help the compound's effectiveness in blocking the harmful effects of air pollution," Riedl said.

According to the authors, no serious side effects occurred in study participants receiving broccoli sprouts, demonstrating that this may be an effective, safe antioxidant strategy to help reduce the inflammatory impact of free radicals.

Riedl notes that more research needs to be done to examine the benefits of sulforaphane for specific respiratory conditions. It is too early to recommend a particular dosage.

Riedl recommends including broccoli and other cruciferous vegetables as part of a healthy diet.

The study was supported by the National Institutes of Health, the National Institute of Environmental Health Sciences and the U.S. Environmental Protection Agency.

Other study authors include Dr. Andrew Saxon of the Hart and Louis Lyon Laboratory, division of clinical immunology and allergy in the department of medicine at the David Geffen School of Medicine at UCLA, and Dr. David Diaz-Sanchez of the human studies division of the U.S. Environmental Protection Agency.

Calculating Gene And Protein Connections In Parkinson's Disease Model

A novel approach to analyzing cellular data is yielding new understanding of Parkinson's disease's destructive pathways.Researchers have created an algorithm that meshes existing data to produce a clearer step-by-step flow chart of how cells respond to stimuli. Using this new method, Whitehead Institute and Massachusetts Institute of Technology scientists have analyzed alpha-synuclein toxicity to identify genes and pathways that can affect cell survival. Misfolded copies of the alpha-synuclein protein in brain cells are a hallmark of Parkinson's disease.

Until now, data on gene expression and protein production have not been consistently analyzed together, leaving gaps in researchers' understanding of how various genes and proteins interact to form a cell's response to a stimulus. This new method could speed the development of therapies for a variety of diseases, including Parkinson's disease.

The scientists have employed this new computational technique to analyze alpha-synuclein, a mysterious protein that is associated with Parkinson's disease.

Cells are constantly adapting to various stimuli, including changes in their environment and mutations, through an intricate web of molecular interactions. Knowledge of these changes is crucial for developing new treatments for diseases. To decipher how a cell responds to various stimuli, laboratories worldwide have been turning to new technologies that produce vast amounts of data. Such data typically exists in two major forms: genetic screen data (the results from deleting a gene from a cell's genome and seeing what observable traits appear in the cell) and information on the cellular levels of messenger RNA (mRNA, which is the template for proteins).

Historically, these two types of data have largely been analyzed independently of each other, revealing only glimpses of the cell's internal workings. Each type of data is actually biased toward identifying different aspects of cellular response, something that researchers had not realized until now. However, the new algorithm, known as ResponseNet, exploits these biases and allows for combined analysis.

In this combined analysis, both data types are integrated with molecular interactions data into a diagram that connects the experimentally identified proteins and genes. While this typically results in an extraordinarily complicated diagram, sometimes jokingly referred to as a "hairball", ResponseNet is designed to whittle the hairball down to the most probable pathways connecting various genes and proteins.

Esti Yeger-Lotem, a postdoctoral researcher in the laboratories of Whitehead Member Susan Lindquist and of Ernest Fraenkel at MIT's Biological Engineering department and co-author of the Nature Genetics article, says that by analyzing those probable pathways, a systems view of the cellular response emerges. "This allows for a more complete understanding of cellular response and can reveal hidden components of the response that may be targeted by drugs," she says.

According to Laura Riva, a postdoctoral researcher in MIT's biological engineering department and one of the designers of the algorithm, ResponseNet is potentially very useful for researchers.

"It is a powerful approach for interpreting experimental data because it can efficiently analyze tens of thousands of nodes and interactions," says Riva, who is also a co-author on the article. "The output of ResponseNet is a sparse network connecting some of the genetic data to some of the transcriptional data via intermediate proteins. Biologists can look at the network and understand which pathways are perturbed, and they can use it to generate testable hypotheses."

To demonstrate ResponseNet's capabilities, Yeger-Lotem entered the data from screens of 5,500 yeast strains (Saccharomyces cerevisiae). These strains are based on a yeast model that creates large amounts of the protein alpha-synuclein, thereby mimicking the toxic effects of alpha-synuclein accumulation in Parkinson's disease patients' brain cells.

Ernest Fraenkel, Assistant Professor of Biological Engineering at MIT, says that the alpha-synuclein data are an excellent test case for the algorithm, which has lead to new insights from existing data.

"The connection between alpha-synuclein and Parkinson's disease is enigmatic," says Fraenkel. "We have wonderful data from the yeast model, but despite this richness of data, so little is known about what alpha-synuclein really does in the cell."

Using these data, ResponseNet identified several links between alpha-synuclein toxicity and basic cell processes, including those used to recycle proteins and to usher the cell through its normal life cycle.

Surprisingly, ResponseNet also tied alpha-synuclein toxicity to a highly-conserved pathway targeted by cholesterol-lowering statin drugs and another pathway targeted by the immunosuppressing drug rapamycin.

To confirm ResponseNet's links and to test how these two pathways could affect alpha-synuclein toxicity, researchers added either rapamycin or the statin lovastatin to yeast model cultures. When the researchers added a low dose of rapamycin to the yeast model, the drug was toxic to the yeast. When lovastatin was added, the yeast reduced their growth rate, an indicator that the yeast had gotten sicker. However, when researchers added the molecule ubiquinone (also known as coenzyme Q10 or CoQ10), which is farther downstream in the statin network and possibly undersynthesized in alpha-synuclein-containing yeast, ubiquinone modestly suppressed alpha-synuclein toxicity.

All of these results validated the hypotheses based on ResponseNet's network.

"ResponseNet provides a wealth of new information," says Lindquist, who is also a Howard Hughes Medical Institute investigator and a professor of biology at MIT. "Some of the things we have found offer a promise to speed the development of new therapeutic strategies for Parkinson's disease. For the sake of the patients involved, let's hope they hold true in a human brain."

Full Citation: "Bridging high-throughput genetic and transcriptional data reveals cellular responses to alpha-synuclein toxicity"

Nature Genetics, online February 22, 2009

Teenage Boys Who Eat Fish At Least Once A Week Achieve Higher Intelligence Scores

Fifteen-year-old males who ate fish at least once a week displayed higher cognitive skills at the age of 18 than those who it ate it less frequently, according to a study of nearly 4,000 teenagers published in the March issue of Acta Paediatrica.Eating fish once a week was enough to increase combined, verbal and visuospatial intelligence scores by an average of six per cent, while eating fish more than once a week increased them by just under 11 per cent.

Swedish researchers compared the responses of 3,972 males who took part in the survey with the cognitive scores recorded in their Swedish Military Conscription records three years later.

"We found a clear link between frequent fish consumption and higher scores when the teenagers ate fish at least once a week" says Professor Kjell Torén from the Sahlgrenska Academy at the University of Gothenburg, one of the senior scientists involved in the study. "When they ate fish more than once a week the improvement almost doubled.

"These findings are significant because the study was carried out between the ages of 15 and 18 when educational achievements can help to shape the rest of a young man's life."

The research team found that:

* 58 per cent of the boys who took part in the study ate fish at least once a week and a further 20 per cent ate fish more than once a week.
* When male teenagers ate fish more than once a week their combined intelligence scores were on average 12 per cent higher than those who ate fish less than once a week. Teenagers who ate fish once a week scored seven per cent higher.
* The verbal intelligence scores for teenagers who ate fish more than once a week were on average nine per cent higher than those who ate fish less than once a week. Those who ate fish once a week scored four per cent higher.
* The same pattern was seen in the visuospatial intelligence scores, with teenagers who ate fish more than once a week scoring on average 11 per cent higher than those who ate fish less than once a week. Those who ate fish once a week scored seven per cent higher.

"A number of studies have already shown that fish can help neurodevelopment in infants, reduce the risk of impaired cognitive function from middle age onwards and benefit babies born to women who ate fish during pregnancy" says Professor Torén.

"However we believe that this is the first large-scale study to explore the effect on adolescents."

The exact mechanism that links fish consumption to improved cognitive performance is still not clear.

"The most widely held theory is that it is the long-chain polyunsaturated fatty acids found in fish that have positive effects on cognitive performance" explains Professor Torén.

"Fish contains both omega-3 and omega-6 fatty acids which are known to accumulate in the brain when the foetus is developing. Other theories have been put forward that highlight their vascular and anti-inflammatory properties and their role in suppressing cytokines, chemicals that can affect the immune system."

In order to isolate the effect of fish consumption on the study subjects, the research team looked at a wide range of variables, including ethnicity, where they lived, their parents' educational level, the teenagers' well-being, how frequently they exercised and their weight.

"Having looked very carefully at the wide range of variables explored by this study it was very clear that there was a significant association between regular fish consumption at 15 and improved cognitive performance at 18" concludes lead author Dr Maria Aberg from the Centre for Brain Repair and Rehabilitation at the University of Gothenburg.

"We also found the same association between fish and intelligence in the teenagers regardless of their parents' level of education."

The researchers are now keen to carry out further research to see if the kind of fish consumed - for example lean fish in fish fingers or fatty fish such as salmon - makes any difference to the results.

"But for the time being it appears that including fish in a diet can make a valuable contribution to cognitive performance in male teenagers" says Dr Aberg.

Evidence Appears To Show How And Where Brain's Frontal Lobe Works

A Brown University study of stroke victims has produced evidence that the frontal lobe of the human brain controls decision-making along a continuum from abstract to concrete, from front to back.Abstract actions can be controlled at an abstract level, such as deciding to make a sandwich, or at more concrete and specific levels, such as choosing a sequence of movements that make the sandwich.

The scientific data supports preexisting theories that abstract decisions about action take place in the front of the frontal lobe, the back portion controls the capacity for concrete decisions, and the progression from front to back forms a gradient from abstract to concrete.

The Brown researchers are among the first to show that specific areas of the frontal cortex are needed for different levels of abstract decision.

The finding, to be detailed March 1 in the journal Nature Neuroscience, represents a huge leap in comprehending how the brain supports higher level cognition and intelligent behavior. It could lead to advances in everything from the treatment of strokes to understanding how humans develop thought. Researchers from the University of California–Berkeley also participated in the study.

“It is among the strongest evidence to date for a systemic organization of the frontal cortex,” said lead author David Badre, an assistant professor of cognitive and linguistic sciences at Brown University.

The frontal cortex of brain has been long known to affect the internal control of behavior. It controls the capacity to plan, reason, conduct higher-level thinking and connect what we know about the world to how we behave.

Badre and his collaborators came to their conclusion by studying stroke victims who suffered damage to different parts of the frontal lobe. The patients all suffered a stroke at least six months prior to testing. All were screened with an MRI or CT scan to determine where any lesions existed in the brain post-stroke.

The scientists recruited 11 patients — seven men and four women, ranging from age 45 to 73. A 12th patient was recruited but could not perform any of the tests involved.

Researchers gave the patients four different tests that ultimately required selecting a finger-press response. For example, the first test would show a color such as red, which required an index finger push. Blue would trigger the middle finger. The test would then become more difficult by adding more alternate finger presses.

Patients faced greater challenges in selecting a response as subsequent, progressive tests became more complex, with more abstract options.

Badre and colleagues found that damage at a given location affected more abstract decisions but left intact the capacity for more concrete decisions. “If there is damage in a given spot, it will affect all higher (decision-making) functions but not lower functions,” Badre said.

The National Institutes of Health, Veterans Administration Research Service and a National Research Service Award supported the research.