Smart Economy

Free Radicals and Type 2 Diabetes

Battle of the bulge occurs in the liver

(Medical Xpress)—An international team of scientists led by Monash University researchers has shown how free radicals contribute to type 2 diabetes, obesity and fatty liver disease.                     

Type 2 diabetes and non-alcoholic fatty liver disease are key complications of obesity as 80 per cent of patients with type 2 diabetes are obese, and 75 per cent of patients who are obese or have type 2 diabetes also have fatty liver disease.

The team, led by Professor Tony Tiganis from the Department of Biochemistry and Molecular Biology at Monash, has found that free radical molecules called Reactive Oxygen Species (ROS) wage a battle with enzymes called protein tyrosine phosphatases, initiating a cascade of events with devastating consequences.

The findings, published today in the prestigious journal Cell Metabolism, explain how selective insulin resistance – a pathological feature of type 2 diabetes – occurs in the liver. The study identifies the molecular culprits involved, and reveals how they contribute to disease progression.

"We have shown for the very first time that these free radicals inactivate protein tyrosine phosphatases in the liver to activate rogue pathways that promote fatty liver disease and exacerbate the development of obesity and type 2 diabetes," Professor Tiganis said.

Professor Tiganis' team found in lab studies that obesity promoted ROS generation that inactivated a phosphatase called PTPN2. This inactivation in turn exacerbated obesity and fatty liver disease progression.

While there is more work to be done to understand the causes of fatty liver disease, Professor Tiganis has plans to test two potential therapeutic approaches. One involves inactivating a protein in the liver, and the other will use a selective anti-oxidant to 'mop up' excess free radicals that would otherwise inactivate PTPN2.

While free radicals play important roles in disease, Professor Tiganis advises against taking anti-oxidants indiscriminately.

"Although we need to undertake further studies in humans, preclinical studies indicate that ROS also play important roles in biology," he said.

 

Explore further: Protein maybe key to halting obesity related disease

 

Journal reference: Cell Metabolism

Provided by Monash University

Research reveals 2 key mechanisms of oxidative stress regulation

 

Published on March 7, 2014 at 1:35 AM         ·      

Regulation of oxidative stress is critical to cell survival. New preclinical research from Roswell Park Cancer Institute (RPCI) has revealed two key mechanisms by which oxidative stress is regulated in normal and cancerous cells.

Oxidative stress occurs when a cell is not able to adequately remove reactive oxygen species (ROS), or reactive molecules that result from the metabolism of oxygen. To alleviate these toxically high levels of ROS, cells activate NF-E2-related transcription factor 2 (Nrf2), which normally resides in the cytoplasm. Under conditions of oxidative stress, however, Nrf2 relocates to the nucleus, where it induces transcription of antioxidant genes.

For many years, ROS detoxification was considered the major function of Nrf2. Reciprocally, activation of Nrf2 was considered the major and universal mechanism for ROS detoxification.

Writing in the journal Molecular Cell, a team led by Mikhail Nikiforov, PhD, a Professor of Oncology and member of the Department of Cell Stress Biology at RPCI, has demonstrated that under certain conditions, Nrf2 behaves in ways that are directly opposite to its normal activities. These scientists have shown that if intracellular ROS exceed a critical threshold, Nrf2 induces expression of the transcription factor Klf9 (Kruppel-like factor 9), which in turn further increases ROS levels by suppressing cellular antioxidant genes, ultimately leading to cell death. The team verified this previously unrecognized feed-forward mechanism of ROS regulation in vivo using an animal model of idiopathic pulmonary fibrosis, a terminal disease of the lungs.

Reactive oxygen species play a dual role in tumorigenesis. While low ROS levels promote tumor cell proliferation and increase genetic instability, high amounts of ROS are detrimental to cell proliferation or survival, inhibiting both healthy and diseased cells. The team's findings identify Klf9 as a molecular "switch" between the anti- and pro-oxidative functions of Nrf2.

"Tumor cells exhibit increased generation of reactive oxygen species as a consequence of high metabolic activity. Consequently, tumors often develop adaptive mechanisms to suppress high levels of ROS, so we looked for ways to exploit their weakness in the face of ROS increase," notes Dr. Nikiforov. "Our findings suggest that Klf9 depletion could be beneficial for malignancies where high amounts of ROS hinder tumor progression, including colorectal and gynecologic cancers. Our data may also support a role for Klf9 as a general tumor suppressor and provide further insights into the mechanism by which tumors acquire resistance to higher levels of ROS."

Activation of Klf9 may prove to be an effective complement to therapies that induce oxidative stress as a mechanism of cell killing, including cisplatinum, arsenic trioxide and the experimental agent elesclomol. Dr. Nikiforov and his team have begun subsequent studies to elucidate the role of Klf9 and its targets in tumor progression and drug resistance of several difficult-to-treat cancers, including melanoma and multiple myeloma.

Source:

Roswell Park Cancer Institute

Why all antioxidants are not made the same-bacteria metabolize most of them before the can act as antioxidants

Why all antioxidants are not made the same

 

...Most botanical antioxidants/supplements are degraded /metabolized by gut bacteria and bacteria your saliva, therefore of little practical value. Carbon-60 or hydrated fullerenes –a natural product and the highest anti-oxidant in the world are not metabolized by bacteria. That's why in vivo tests(in the body) and in vitro (in the lab) tests may not produce the same results or often conflicting results with many botanical antioxidants--Walter Derzko

 

 Some Health Benefits Of Berries May Not Make It Past Your Mouth

 COLUMBUS, Ohio – Research has suggested that compounds that give colorful fruits their rich hues, especially berries, promote health and might even prevent cancer. But for the first time, scientists have exposed extracts from numerous berries high in those pigments to human saliva to see just what kinds of health-promoting substances are likely to survive and be produced in the mouth.

 It’s too early to name the best berry for health promotion based on this initial work. But the researchers have discovered that two families of pigments that provide berries with their colors, called anthocyanins, are more susceptible to degradation in the mouth than are the other four classes of these pigments.

 The Ohio State University study also showed that bacteria living in the mouth are responsible for most of the breakdown of these compounds that occurs in saliva. Researchers are investigating whether it’s the berry pigments themselves, or instead the products of their degradation, that actually promote health.

 

Scientists say that these early findings will contribute to the further development of confectionaries, gums and other delivery devices for the prevention and possibly the treatment of conditions such as periodontal disease and oral cancers.

 

The researchers exposed extracts of anthocyanin pigments from blueberries, chokeberries, black raspberries, red grapes and strawberries to the saliva collected from 14 people. Black raspberries, in particular, have been shown in numerous previous studies to have chemopreventive effects on tumors in the mouth, esophagus and colon, mostly in animal studies. Their high anthocyanin content has been linked to those benefits.

 

“All fruits are unique because their chemical composition, or fingerprint, varies,” said Mark Failla, professor of human nutrition at Ohio State and interim chair of the Department of Human Sciences. “There are many different edible berries. Some might be better for providing health-promoting effects within the oral cavity, whereas others may be more beneficial for colonic health. We simply do not know at this time.

“Increased intake of fruits and vegetables is associated with decreased risk of some chronic diseases. An understanding of the metabolism of these compounds, and the relative activities of the compounds in the consumed fruit and their metabolic products, is needed to make scientifically sound dietary recommendations and to develop effective delivery vehicles for the mouth,” Failla said.

 The research is published in a recent issue of the journal Food Chemistry.

 Failla and colleagues asked 14 healthy individuals between the ages of 21 and 55 years to collect saliva in the morning before they had eaten breakfast or brushed their teeth. Research participants later collected additional saliva samples before and after they had rinsed their mouths with an antibacterial liquid.

 The five fruits selected for study allowed the scientists to test the six distinct families of the anthocyanin pigments. Researchers purified the anthocyanins from each berry type and added the extracts to saliva.

 The extent of the pigment degradation in saliva was primarily a function of the chemical structure of a given anthocyanin, said Failla, also an investigator in Ohio State’s Comprehensive Cancer Center and Food Innovation Center.

 Two families of anthocyanins consistently degraded when exposed to saliva: delphinidin and petunidin. Four other families were more stable: cyanidin, pelargonidin, peonidin and malvidin.

“Our observations suggest that the bacteria within one’s oral cavity are a primary mediator of pigment metabolism. The bacteria are converting compounds that are present in the foods into metabolites,” Failla said. “One area of great interest is whether the health-promoting benefits associated with eating anthocyanin-rich fruits like berries are provided by the pigment itself, the natural combinations of the pigments in the fruit, or the metabolites produced by bacteria in the mouth and other regions of the gastrointestinal tract.”

Email this to a friend

 

 

 

 ________________________________________

“There are many different edible berries. Some might be better for providing health-promoting effects within the oral cavity, whereas others may be more beneficial for colonic health.”

________________________________________

There is context for this study that further complicates the understanding of anthocyanins’ benefits. Multiple studies have led to the conclusion that anthocyanins themselves are very poorly absorbed by the body.

“If anthocyanins are the actual health-promoting compound, you would want to design food products, confectionaries and gels containing mixtures of anthocyanins that are stable in the mouth. If, on the other hand, the metabolites produced by the metabolism of anthocyanins are the actual health-promoting compounds, there will be greater interest in fruits that contain anthocyanins that are less stable in the oral cavity,” Failla said. “We lack such insights at this time.”

The extent to which the anthocyanins were degraded varied among the 14 people whose saliva was used in the study. However, two families of anthocyanins consistently degraded the most in all volunteers. Failla said the observed variation among individuals is likely related to differences in the microbial community that resides in each person’s mouth.

 This research group is continuing the work, examining which bacteria are most involved in the metabolism of anthocyanins and testing the stability of the pigments in berry juices in the mouths of human volunteers rather than in test tubes containing their saliva.

 This work was supported in part by the Ohio Agricultural Research and Development Center.

 Co-authors include Kom Kamonpatana of the Interdisciplinary Ph.D. Program in Nutrition; Monica Giusti and Ken Riedl of the Department of Food Science and Technology; Chureeporn Chitchumroonchokchai of the Department of Human Nutrition; and Maria MorenoCruz and Purnima Kumar of the Department of Periodontology, all at Ohio State. All but MorenoCruz are also investigators in the Food Innovation Center.

 #

 Contact: Mark Failla, (614) 247-2412; [email protected]

 Written by Emily Caldwell, (614) 292-8310; [email protected]

Reversal of type 1 diabetes in mice may eventually help humans

 

 

CINCINNATI—Investigators at the University of Cincinnati (UC) have found a therapy that reverses new onset Type 1 diabetes in mouse models and may advance efforts in combating the disease among humans.

The study, led by William Ridgway, MD, was presented Saturday, June 14, 2014, at the American Diabetes Association's 74th Scientific Sessions in San Francisco.

Type 1 diabetes is usually diagnosed in children and young adults and affects about 5 percent of all people with diabetes, according to the American Diabetes Association. In Type 1 diabetes, the body does not produce sufficient insulin, which is central to glucose metabolism: without insulin, blood glucose rises. 

There is no cure for Type 1 diabetes though it can be controlled with insulin therapy. Symptoms of the disease include frequent urination, excessive thirst and weight loss even though you are eating more.

Researchers say the incidence of Type 1 diabetes and autoimmunity in general has risen rapidly since the mid-20th century, possibly the result of under-stimulation of innate immune systems which trigger autoimmunity in children and young adults. In Type 1 diabetes, autoimmunity causes the body's T-cells to attack its insulin-producing beta cells.

Previously, it has been reported that non-obese diabetic mice have defects in innate immune cells and that TLR4, a toll-like receptor, plays a protective role in preventing Type 1 diabetes.

Ridgway, Alice W. and Mark A. Brown Professor and Director of the division of immunology, allergy and rheumatology at UC, says his team of researchers used an agonistic monoclonal antibody, UT18, to boost the activity of TLR4 and reverse new onset diabetes in a high percentage of newly diabetic non-obese mice.

"We have shown that by using an antibody to stimulate a specific molecule in the innate immune system we can reverse—with a high rate of success—new onset diabetes in mice that have  already developed the symptoms of diabetes," says Ridgway. "The cause of this reversal is a preservation of the endocrine pancreatic beta cells that produce insulin. These cells are preserved from the autoimmune attack which is the hallmark of Type 1 diabetes."

The key to reversing Type 1 diabetes in mice, says Ridgway, is catching the disease at its onset, which is typically within a very short time window. The time frame would be longer in humans, but it is still a relatively short time from new onset to end-stage Type 1 diabetes, says Ridgway.

Ridgway says this approach differs from most in combating Type 1 diabetes because his team's therapies in mice do not directly interact with T-cells. He says treatment of autoimmunity has often been directed at suppressing an over-zealous adaptive immune response by eliminating auto-reactive T-cells.

"We are targeting a different part of the immune system," says Ridgway. "There are two arms of the immune system. One is called the adaptive immune system and the other is the innate immune system. Basically the T-cells and B-cells are in your adaptive immune system and they respond to many different antigens. The innate system tends to have a stereotypical response. We are targeting a receptor that is found mostly on the innate immune cells, such as dendritic cells.

"This same molecular TLR4 pathway operates in humans in many similar ways; though there are some differences, it is possible this new pathway of targeting the immune system could be tested in humans," says Ridgway.

Additional study will be required, but the therapy may hold promise because one agonistic anti-TLR4 agent is already FDA approved and others are under development, says Ridgway.

Contact: Cedric Ricks [email protected] 513-558-4657 University of Cincinnati Academic Health Center

Research suggests benefits of canola oil for people with Type 2 diabetes

 

Those on canola bread diet saw both a reduction in blood glucose levels and significant reduction in LDL cholesterol

		IMAGE:   Dr. David Jenkins, head of the Clinical Nutrition and Risk Factor Modification Centre of St. Michael's Hospital, compared people with Type 2 diabetes who ate either a low glycemic index... Click here for more information.

TORONTO, June 14, 2014—Canola is Canada's oil and new research from St. Michael's Hospital suggests it should also be one of the oils of choice for people with Type 2 diabetes. Dr. David Jenkins, head of the hospital's Clinical Nutrition and Risk Factor Modification Centre, compared people with Type 2 diabetes who ate either a low glycemic index diet that included bread made with canola oil, or a whole wheat diet known to reduce the risk of cardiovascular disease.

His study, published today (Saturday, June 14) in the journal Diabetes Care, found that those on the canola bread diet experienced both a reduction in blood glucose levels and a significant reduction in LDL, or "bad," cholesterol.

Even more exciting, he said, was the finding that the canola bread diet seemed to have the most significant impact on people who needed help the most – those whose HbA1c test measuring blood glucose over the previous two or three months was highest.

Dr. Jenkins, who is a professor of both nutritional sciences and medicine at the University of Toronto, said the reduction in LDL cholesterol observed in his study of 141 people could translate into a 7 per cent reduction in cardiovascular events. He said the benefit could also be translated into an additional 20mg dose of one of the cholesterol-reducing drugs known as statins—a doubling of a standard dose.

The word canola is a contraction of Canada and ola, meaning oil. It was developed from rapeseed at the University of Manitoba in the 1970s. Canola oil contains only 7 per cent saturated fat, less than half that of olive oil, widely touted for its health benefits.

Dr. Jenkins said another interesting finding of the study was that patients on the whole wheat diet seemed to have better blood flow after 12 weeks than those on the canola bread diet, as measured by the EndoPat test that uses a cuff on the arm similar to a blood pressure test. He said the significance of that finding was not entirely clear, but this positive result may be an indication of why whole wheat foods have consistently been shown to reduce the risk of cardiovascular disease.

Dr. Jenkins and his colleagues developed the concept of the glycemic index in the early 1980s as a way of explaining how different carbohydrates affect blood glucose and to find out which foods were best for people with diabetes. High GI foods—such as white bread, most breakfast cereals, potatoes and rice — produce a large rise in blood glucose and insulin, which may damage eyes, kidneys and heart. The carbohydrates in low GI foods—including pasta, beans, lentils,  berries, apples and certain whole grains such as barley and oats –are  broken down more slowly, so that people get more gentle raises in blood glucose and insulin and so get less tissue damage to eyes and kidneys etc. 

Other studies have linked low GI diets with a reduction in both diabetes and cardiovascular events, and have shown monounsaturated fats such as canola and olive oil reduced the risk of cardiovascular disease. Dr. Jenkins said the combination of a low GI diet supplemented with canola oil had not been tested before on people with Type 2 diabetes.

###

This research was funded by the Canola Council of Canada, Agriculture and Agri-Food Canada, Loblaw Companies, and the Canada Research Chairs Program.

About St. Michael's Hospital

St. Michael's Hospital provides compassionate care to all who enter its doors. The hospital also provides outstanding medical education to future health care professionals in more than 23 academic disciplines. Critical care and trauma, heart disease, neurosurgery, diabetes, cancer care, and care of the homeless are among the hospital's recognized areas of expertise. Through the Keenan Research Centre and the Li Ka Shing International Healthcare Education Center, which make up the Li Ka Shing Knowledge Institute, research and education at St. Michael's Hospital are recognized and make an impact around the world. Founded in 1892, the hospital is fully affiliated with the University of Toronto. 

For more information or to interview Dr. Jenkins, contact: 

Leslie Shepherd Manager, Media Strategy, Phone: 416-864-6094 or 647-300-1753 [email protected]

St. Michael's Hospital

Inspired Care. Inspiring Science.

http://www.stmichaelshospital.com

Follow us on Twitter: http://www.twitter.com/stmikeshospital

 

---

Are female hormones playing a key role in the male obesity epidemic?

 

An imbalance of female sex hormones among men in Western nations may be contributing to high levels of male obesity, according to new research from the University of Adelaide.

In a paper published in the online journal PLOS ONE, researchers from the University's School of Medical Sciences suggest that obesity among Western men could be linked with exposure to substances containing the female sex hormone estrogen – substances that are more often found in affluent societies, such as soy products and plastics.

The research was conducted by University of Adelaide medical student James Grantham and co-authored by Professor Maciej Henneberg, Wood Jones Professor of Anthropological and Comparative Anatomy.

Mr Grantham compared obesity rates among men and women from around the world with measures such as Gross Domestic Product to determine the impact of affluence on obesity.  He found that while it was normal for women in the developing world to have significantly greater levels of obesity than men, the developed world offers quite a different picture.

"Hormonally driven weight gain occurs more significantly in females than in males, and this is very clear when we look at the rates of obesity in the developing world," Mr Grantham says.

"However, in the Western world, such as in the United States, Europe and Australia, the rates of obesity between men and women are much closer.  In some Western nations, male obesity is greater than female obesity.

"While poor diet is no doubt to blame, we believe there is more to it than simply a high caloric intake," Mr Grantham says.

Professor Henneberg says: "Exposure to estrogen is known to cause weight gain, primarily through thyroid inhibition and modulation of the hypothalamus.  Soy products contain xenoestrogens, and we are concerned that in societies with a high dietary saturation of soy, such as the United States, this could be working to 'feminize' the males.  This would allow men in those communities to artificially imitate the female pattern of weight gain.

"Another well-established source of xenoestrogen is polyvinyl chloride, known as PVC.  This product is in prominent use in most wealthy countries, from plastic medical devices to piping for our water supplies."

Professor Henneberg says micro-evolutionary changes may be occurring within Western societies that could also be leading to changes in testosterone and estrogen in men.  "This would certainly explain the various concerns about sperm count reductions among men in developed nations," he says.

Professor Henneberg and Mr Grantham say further research is needed to better understand whether or not environmental factors are leading to a "feminization" of men in the Western world.

###

Media Contacts:

Professor Maciej Henneberg Wood Jones Professor of Anthropological and Comparative Anatomy School of Medical Sciences The University of Adelaide [email protected]

James Grantham Medical student and lead author The University of Adelaide [email protected]

Good bacteria armed with antibiotic resistance protect gut microbiome

 

 

Researchers from Case Western Reserve University in Cleveland have discovered that populating the gastrointestinal (GI) tracts of mice with Bacteroides species producing a specific enzyme helps protect the good commensal bacteria from the harmful effects of antibiotics. Their research is published ahead of print in Antimicrobial Agents and Chemotherapy.

Antibiotics are powerful weapons against pathogens, but most are relatively indiscriminate, killing the good bacteria, along with the bad. Thus, they may render patients vulnerable to invasion, particularly by virulent, antibiotic-resistant pathogens that frequently populate hospitals.

The novel aspect of the research is that the enzyme produced by these bacteria, beta-lactamase, is a major cause of antibiotic resistance, says first author, Usha Stiefel. Interestingly, the enzyme is not only protecting the bacteria that produce it but also the rest of the bacteria making up the intestinal microbiome.

In the study, the investigators established populations of beta-lactamase producing Bacteroides in some mice, but not others. They then gave all the mice ceftriaxone, a beta-lactam antibiotic, for three days and then oral doses of vancomycin-resistant enterococcus, or Clostridium difficile, both of which are virulent GI pathogens.

The mice that had been populated with Bacteroides maintained their diverse species of commensal gut bacteria, free of pathogens, while the control mice saw their commensals decimated by antibiotics, enabling establishment of the pathogens.

"When patients in the hospital or nursing home setting receive antibiotics, it is doubly dangerous when they lose their native colonic bacteria, because healthcare settings are full of resistant or particularly virulent bacteria, and so patients are especially vulnerable to acquiring these bacteria within their intestinal tracts," says Stiefel.

Since the Bacteroides, which comprise roughly one quarter of the intestinal microbiome, are absent elsewhere in the body, the investigators believe that the beta-lactamase will not interfere with treatment of infections in other organ systems, such as in the respiratory tract, or the blood, explains Stiefel.

"The results of our study are exciting because they show how it might be possible to take antibiotics without suffering from the loss of your colonic microbiome and then becoming colonized by virulent pathogens," says Stiefel. For example, beta-lactamase enzymes could be given orally as drugs, to protect the gut bacteria from systemic antibiotics. Alternatively, as with the mice, patients' GI tracts might be populated with antibiotic-degrading bacteria.

One weakness of the strategy is that while it could protect against acquiring a GI infection, C. difficile, for example, it could not be used to combat such an infection.

"The recognition of the importance of an intact and diverse microbiome has probably best been demonstrated by the successful treatment of Clostridium difficile colitis by fecal microbiota transplantation, or 'stool transplant,'" says Stiefel. "If you have an intact intestinal microbiome, you simply are going to be resistant to acquiring many types of infection."

"If we can find ways to preserve the microbiome in hospitalized patients who are receiving antibiotics, we are on our way to preventing a large proportion of hospital-acquired infections," says Stiefel.

###

 

The manuscript can be found online at http://bit.ly/asmtip0614d.  The final version of the article is scheduled for the August 2014 issue of Antimicrobial Agents and Chemotherapy.

Antimicrobial Agents and Chemotherapy is a publication of the American Society for Microbiology (ASM).  The ASM is the largest single life science society, composed of over 39,000 scientists and health professionals. Its mission is to advance the microbiological sciences as a vehicle for understanding life processes and to apply and communicate this knowledge for the improvement of health and environmental and economic well-being worldwide.

Carbon 60 or Hydrated Fullerenes -the highest antioxident in the world

Excess Free Radicals in the body (called oxidative stress) triggers many diseases, but it's easy to prevent or in some cases reverse. To neutralize excess free radicals in the body, eat antioxidant foods daily, with high ORAC values (see ORAC table http://www.oracvalues.com/sort/orac-value ) and drink Hydrated Fullerene or C-60 water-the highest antioxidant in the world. For information contact me

 

Tangled Path of Alzheimer's-Linked Brain Cells Mapped in Mice

 

"Transportation" may be at the heart of the disease

Release Date: June 4, 2014

Fast Facts:

• Cholinergic neurons, a type of extremely large brain cells, are found in all mammals and are the first cells to degenerate in people with Alzheimer’s disease.
• By studying laboratory mice, scientists have now mapped the complete size and structure of cholinergic neurons for the first time.
• Understanding the structure of cholinergic neurons should help researchers better understand what goes wrong in Alzheimer’s disease.

1 2

The paths taken by a single cholinergic neuron as it branches through a thin section of the forebrain of a mouse

Nathans Lab, eLife

By studying laboratory mice, scientists at The Johns Hopkins University have succeeded in plotting the labyrinthine paths of some of the largest nerve cells in the mammalian brain: cholinergic neurons, the first cells to degenerate in people with Alzheimer’s disease.

“For us, this was like scaling Mount Everest,” says Jeremy Nathans, Ph.D., professor of molecular biology and genetics, neuroscience, and ophthalmology at the Johns Hopkins University School of Medicine. “This work reveals the amazing challenges that cholinergic neurons face every day. Each of these cells is like a city connected to its suburbs by a single, one-lane road, with all of the emergency services located only in the city. You can imagine how hard it would be in a crisis if all of the emergency vehicles had to get to the suburbs along that one road. We think something like this might be happening when cholinergic neurons trying to repair the damage done by Alzheimer’s disease.”

Each cholinergic neuron, Nathans explains, has roughly 1,000 branch points. If lined up end to end, one neuron’s branches would add up to approximately 15 times the length of the mouse brain. But all of the branches are connected by a single, extremely thin “pipeline” to one hub — the cell body — that provides for the needs of the branches. The challenge of moving material through this single pipeline could make it very difficult for cholinergic neurons to combat the challenges that come with a disorder like Alzheimer’s disease, he says. Now, by mapping the branches and pipelines, scientists will likely get a better fix on what happens when the neurons fail to meet the challenges.

A summary of the research was published online in the journal eLife on May 7.

Cholinergic neurons are among the largest neurons in the mammal brain. Named for their release of a chemical messenger called acetylcholine, they number only in the thousands in mouse brains, a tiny fraction of the 50 to 100 million total neurons. Their cell bodies are located at the base of the brain near its front end, but their branches extend throughout the cerebral cortex, the outermost, wrinkled layer of “grey matter” that is responsible for the mind’s most advanced intellectual functions. Therefore, although there are relatively few cholinergic neurons, they affect a very large part of the brain, Nathans says.

Due to the technical challenge of visualizing the complicated paths of hundreds of tiny branches from a single neuron tangled within millions of other neurons, the actual size and shape of individual cholinergic neurons — and the territory they cover — had been unknown until now, Nathans says. Using genetic engineering methods, the Nathans team programmed several cholinergic neurons per mouse to make a protein that could be seen with a colored chemical reaction. Critical to the success of the work was the ability to limit the number of cells making the protein — if all of the cholinergic neurons made the protein, it would have been impossible to distinguish individual branches.

Because microscopes cannot see through thick tissue, Nathans and his team preserved the mouse brains and then thinly sliced them to produce serial images. The branching path of each neuron was then painstakingly reconstructed from the serial images and analyzed. In adult mice, he says, the average length of the branches of a single cholinergic neuron, lined up end to end, is 31 cm (12 inches), varying from 11 to 49 cm (4 to 19 inches). The average length of a mouse brain is only 2 cm — a bit less than one inch. Although each cholinergic neuron, on average, contains approximately 1,000 branch points, they vary significantly in the extent of the territory that they cover.

The researchers used the same techniques to study the cholinergic neurons of mice with a rodent form of Alzheimer’s disease and found that the branches were fragmented. They also found clumps of material that may have been debris from the disintegrating branches.

Although the cholinergic neurons of human brains have not been individually traced, Nathans’ team was able to calculate that the average cholinergic neuron in the human brain has a total branch length of approximately 100 meters, a bit longer than a football field. “That is a really long pipeline, especially if one considers that the pipes have diameters of only 30 thousandths of a millimeter, far narrower than a human hair,” says Nathans.

He adds, “Although our study only defined a few simple, physical properties of these neurons, such as size and shape, it has equipped us to form and test better hypotheses about what goes wrong with them during disease.”

Other authors of the report include Hao Wu and John Williams of the Johns Hopkins University School of Medicine.

This work was supported by grants from the Human Frontier Science Program, the Howard Hughes Medical Institute and the Brain Science Institute of The Johns Hopkins University.

Distance From a Conflict May Promote Wiser Reasoning- Solomon’s Paradox bias

 

If you’re faced with a troubling personal dilemma, such as a cheating spouse, you may think about it more wisely if you consider it as an outside observer would, according to research forthcoming in Psychological Science, a journal of the Association for Psychological Science.

“These results are the first to demonstrate a new type of bias within ourselves when it comes to wise reasoning about an interpersonal relationship dilemma,” says psychology researcher and study author Igor Grossmann of the University of Waterloo in Canada. “We call the bias Solomon’s Paradox, after the king who was known for his wisdom, but who still failed at making personal decisions.”

Grossmann and Ethan Kross from the University of Michigan asked study participants, all of whom reported being in monogamous romantic relationships, to reflect on a relationship conflict. They were asked to vividly imagine a scenario in which either their partner or a friend’s partner had been unfaithful, and were then asked to answer a set of questions about the scenario.

The questions were designed to tap into dimensions of wise reasoning, such as the ability to recognize the limits of one’s own knowledge, search for a compromise, consider the perspectives of others, and recognize the possible ways in which the scenario could unfold.

Results from the experiments indicated that participants who were asked to reason about a friend’s relationship conflict made wiser responses than those who were asked to reason about their own relationship conflict.

In a second experiment, Grossmann and Kross investigated whether personal distance might make a difference. The procedure was similar to the first experiment, but this time they explicitly asked participants to take either a first-person perspective (“put yourself in this situation”) or a third-person perspective (“put yourself in your friend’s shoes”) when reasoning about the conflict.

The results supported those from the first experiment: Participants who thought about their own relationship conflict from a first-person perspective showed less wise reasoning than those who thought about a friend’s relationship conflict.

But taking an outsider’s perspective seemed to eliminate this bias: Participants who thought about their own relationship conflict through a friend’s eyes were just as wise as those who thought about a friend’s conflict.

Interestingly, results from a third experiment that compared data from younger adults (ages 20-40) and older adults (ages 60-80) indicated that, contrary to the adage that wisdom comes with age, older participants were wiser in reasoning about their own relationship conflict than their younger counterparts.

Together, these findings suggest that distancing oneself from a personal problem by approaching it as an outsider may be the key to wise reasoning:

“We are the first to demonstrate that there is a simple way to eliminate this bias in reasoning by talking about ourselves in the third person and using our name when reflecting on a relationship conflict,” says Grossmann. “When we employ this strategy, we are more likely to think wisely about an issue.”

This research was supported by the Rackham Predoctoral Fellowship and the Canadian Social Sciences and Humanities Research Council Insight Grant (both to I. Grossmann).

 

               

            June 9, 2014