“The ultimate aim is to develop a method which allows humans to unconsciously relate with some parts of the virtual environment more intensely than with others, and that they are encouraged only by their own physiological responses to the virtual reality shown”, Christoph Groenegress, co-author of the work and researcher at the University of Barcelona explains to SINC.

The system, the details of which were recently published in the journal The Visual Computer, uses sensors and wireless devices to measure three physiological parameters in real time: heart rate, respiration, and the galvanic (electric) skin response. Immediately, the data is processed with a software programme that is used to control the behaviour of a virtual character who is sitting in a waiting room.

The heart rate is reflected in the movement of the character’s feet; respiration in the rising of their chest (exaggerated movements so that it can be noticed); and the galvanic skin response in the more or less reddish colour of the face.

The researchers conducted an experiment to see if the people whose physiological parameters were recorded had any preference as regards the virtual actor who was to use them, without them knowing in advance. But the result was negative, “probably because other factors also influence the choice such as the character’s appearance or their situation in the scene”. The team is now studying how to solve this problem.

To tell stories and in rehabilitation

The scientists point out that the unconscious processes can be a useful tool for telling stories –in a video-game, for example- or for arousing interest in participants when carrying out a sequence of tasks, such as patients undergoing rehabilitation.

“We maintain that the linking of subjective corporal states to a virtual reality can improve the sensation of realism that a person has of this reality and, eventually, create a stronger link between humans and this virtual reality”, Groenegress concludes.

References:

Christoph Groenegress, Bernhard Spanlang y Mel Slater. “The physiological mirror - a system for unconscious control of a virtual environment through physiological activity”. The Visual Computer 26 (6-8): 649�, 2010. DOI: 10.1007/s00371-010-0471-9.

Contact: SINC
info@plataformasinc.es
34-914-251-820
FECYT - Spanish Foundation for Science and Technology

For severe migraine sufferers, psychological treatments build on the benefits of drug therapy, according to a new study1 by Elizabeth Seng and Dr. Kenneth Holroyd from Ohio University in the US. Their comparison of the effects of various treatment combinations for severe migraine – drug therapy with or without behavioral management – shows that those patients receiving the behavioral management program alongside drug therapy are significantly more confident in their ability to use behavioral skills to effectively self-manage migraines. And surprisingly, the increase in confidence in self-management abilities is greatest among those who feel that they have very little control over their condition before treatment starts. Seng’s and Holroyd’s findings are published online in Springer’s journal Annals of Behavioral Medicine.

Seng and Holroyd analyzed data for 176 participants in the US Treatment of Severe Migraine Trial. Treatment programs included acute drug therapy for all, with either β-blockers or placebo - each with or without behavioral migraine management. The behavioral migraine management program consisted of demonstrations of migraine management skills during four monthly clinic visits, which were then applied between sessions by participants through workbooks, audiotape lessons, and guided home practice.

Their analyses showed that the addition of behavioral migraine management to drug therapy dramatically increased participants’ confidence in their ability to effectively self-manage migraine, compared to migraine drug therapy alone. Behavioral management also increased participants’ belief that migraines can be influenced by one’s own behavior and decreased the belief that migraines are primarily influenced by chance or fate.

The authors conclude: “Our exploratory analyses offer an optimistic message: brief psychological interventions for migraine management can effectively increase sufferers’ confidence in self-management and can be long-lasting.” Psychological interventions enhanced drug therapy, enabling participants to take a more active role in their treatment by using behavioral skills to manage migraines.

Reference

1. Seng EK & Holroyd KA (2010). The dynamics of changes in self-efficacy and local of control expectancies in the behavioral and drug treatment of severe migraine. Annals of Behavioral Medicine; DOI 10.1007/s12160-010-9223-3

Contact: Renate Bayaz
Renate.Bayaz@springer.com
Springer

LA JOLLA, CA – August 30, 2010 –– An international team led by scientists from The Scripps Research Institute, the Swiss Tropical Institute, the Genomics Institute of the Novartis Research Foundation and the Novartis Institute for Tropical Diseases has discovered a promising new drug candidate that represents a new class of drug to treat malaria. Clinical trials for the compound are planned for later this year.

The research was published on September 3, 2010, in the prestigious journal Science.

“We’re very excited by the new compound,” said Elizabeth Winzeler, a Scripps Research associate professor and member of the Genomics Institute of the Novartis Research Foundation (GNF) who led the research with Thierry Diagana of the Novartis Institute of Tropical Diseases. “It has a lot of encouraging features as a drug candidate, including an attractive safety profile and potential treatment in a single oral dose.”

The Problem with Malaria

Malaria is a nasty and often fatal disease, which may lead to kidney failure, seizures, permanent neurological damage, coma, and death. The disease is caused by Plasmodium parasites, transmitted through the bite of infected mosquitoes.

Despite a century of effort to globally control malaria, the disease remains endemic in many parts of the world. According to the World Health Organization, in 2008 there were 247 million cases of malaria and nearly one million deaths – mostly among children living in Africa. The need for new treatments is made more urgent by the spread of drug-resistance to current medications.

While some 40 percent of the world’s population lives in malaria-infected areas, little economic incentive for pharmaceutical companies to develop new treatments exists, since malaria-infected areas correspond with the some of the world’s most impoverished nations.

To help surmount this barrier, concerned individuals have formed public-private partnerships to help spur research on much-needed treatments. The current study is the result of one such partnership. In addition to in-kind contributions by the pharmaceutical company Novartis (including its decade-old Novartis Malaria Initiatives) and the scientific expertise of scientists in academic laboratories around the world, the research was made possible by the support of the nonprofit organizations Medicines for Malaria Venture, the Wellcome Trust, and the W. M. Keck Foundation, as well as funding from government agencies in the United States (the National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID) and Singapore (Agency for Science, Technology, and Research (A*STAR)).

In Pursuit of a New Drug

The impetus for the new study began in the Scripps Research Winzeler laboratory about seven years ago when Winzeler received funding from the Keck Foundation to develop new antimalarial drugs by pursuing target-based drug discovery methods (designing a drug based on known molecular interactions). The approach was not yielding many interesting compounds, so Winzeler and her collaborators at GNF decided to take a different tack.

Noting that serendipity and observation played a role in all previous breakthrough antimalarials (for example, the drug artemisinin was derived from an herb used in traditional Chinese medicine), the team decided to pursue cell-based screening. The Winzeler lab at GNF then developed a high-throughput screen to look for compounds active against the malaria parasite Plasmodium falciparum. Scientists at Novartis, which had compiled a library of 12,000 purified natural products, then offered their library for the screen.

The first screen returned a set of 275 compounds with anti-malarial activity. Subsequent screens weeded out those with little activity against multi-drug resistant parasites and those toxic for mammalian cells. Seventeen compounds remained in the running.

An evaluation of the remaining compounds’ toxicity and pharmacokinetic profiles provided additional information to evaluate their potential drug candidates. One compound—belonging to a chemical class of molecules called spiroindolones, which had never before been associated with anti-malarial activity—stood out as particularly promising.

Novartis Institute for Tropical Medicine’s project team head Bryan Yeung noted, “Of the remaining compound classes, the spirotetrahydro-beta-carbolines or spiroindolones displayed the desired physicochemical properties for drug development, as well as a mechanism of action distinct from the currently used therapies based on aminoquinolines and artemisinin derivatives.”

In an effort based at the Novartis Institute of Tropical Diseases in Singapore, the chemistry team synthesized and evaluated some 200 derivatives of this molecule to optimize its safety profile and pharmacokinetic properties. At the end of several hundred rounds of medicinal chemistry and efficacy testing at the Swiss Tropical and Public Health Institute, the team advanced NITD609 as the best candidate for proceeding to clinical trials.

Shining Light in the Black Box

The new study, however, doesn’t stop there. To gain insight into how NITD609 worked, Winzeler applied a distinctive and elegant evolutionary approach.

Winzeler noted, “One of the disadvantages of doing cellular screening has been chemists will say, ‘You don’t know what the target is. You don’t know if the parasites are going to become resistant to it. It’s a huge black box.’ It has been extremely difficult to find the genes involved in malarial drug resistance using traditional methods. So what we’ve been doing in my lab is developing ways to find single-base changes in drug-exposed genomes.”

In this case, Case McNamara at GNF, a lead author, took a parasite and cloned it to create two identical organisms. One was allowed to reproduce in regular culture. The other was placed in a culture with a sub-lethal dose of the anti-malarial drug candidate. After three to four months and many generations, the parasites in the culture with NITD609 started to display low-level drug resistance.

At that point, the team used an advanced tiling array to compare the 26 million base pairs of coding sequence in the genome of the drug-exposed organisms to the genome of the control organisms.

“We were expecting hundreds or thousands of mutations because we grew the parasites for many generations,” Winzeler said. “We got only a handful.”

When McNamara analyzed the genomes of the six resistant clones, it turned out that all of the mutant strains had at least one mutation mapping to a single gene, pfatp4. This suggests that the protein PfATP4 is either the target for the new drug candidate or is involved in the parasite’s resistance to it in some other way.

“PfATP4 is a cation transporting ATPase, so it is a very well validated drug target,” said Winzeler. “That class of proteins, for example, is the target of antacids. It hasn’t really been explored in malaria. This is one of the first cases where an evolution study has been used to identify the action of a compound in a parasite cell.”

The first authors of the paper, “Spiroindolones, a new and potent chemotype for the treatment of malaria,” are Matthias Rottmann of the Swiss Tropical and Public Health Institute and the University of Basel, McNamara, and Yeung. In addition to Winzeler, Diagana, Rottmann, McNamara, and Yeung, authors of the paper are: Marcus C.S. Lee and David A. Fidock of the Columbia University Medical Center; Bin Zou, Jocelyn Tan, Suresh B. Lakshminarayana, Anne Goh, Veronique Dartois, and Thomas H. Keller of the Novartis Institute for Tropical Diseases; Bruce Russell, Rossarin Suwanarusk, and Laurent Renia of A*STAR; Patrick Seitz, Hans-Peter Beck, and Reto Brun of the Swiss Tropical and Public Health Institute and the University of Basel; David M. Plouffe and Steven B. Cohen of GNF; Neekesh V. Dharia, Kathryn R. Spencer, Gonzalo E. González-Páez, and Tim Jegla of Scripps Research; Esther K. Schmitt of the Natural Products Unit of Novartis Pharma AG; and Francois Nosten of Mae Sot (Thailand), Mahidol University (Thailand), and the University of Oxford (Great Britain).

About The Scripps Research Institute

The Scripps Research Institute is one of the world’s largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Scripps Florida is located in Jupiter, Florida.

Contact: Mika Ono
mikaono@scripps.edu
858-784-2052
Scripps Research Institute

Cortisol is considered to be a stress hormone. Its secretion is increased during times of stress. Traditionally it’s been measured in serum, urine and saliva, but that only shows stress at the time of measurement, not over longer periods of time. Cortisol is also captured in the hair shaft.

“Intuitively we know stress is not good for you, but it’s not easy to measure,” explains Dr. Koren, who holds the Ivey Chair in Molecular Toxicology at Western’s Schulich School of Medicine & Dentistry. “We know that on average, hair grows one centimetre (cm) a month, and so if we take a hair sample six cm long, we can determine stress levels for six months by measuring the cortisol level in the hair.”

In the study, hair samples three cm long were collected from 56 male adults who were admitted to the Meir Medical Centre in Kfar-Saba, Israel suffering heart attacks. A control group, made up of 56 male patients who were hospitalized for reasons other than a heart attack, was also asked for hair samples. Higher hair cortisol levels corresponding to the previous three months were found in the heart attack patients compared to the control group.

The prevalence of diabetes, hypertension, smoking and family history of coronary artery disease did not differ significantly between the two groups, although the heart attack group had more cholesterol problems. After accounting for the known risk factors, hair cortisol content emerged as the strongest predictor of heart attack.

“Stress is a serious part of modern life affecting many areas of health and life,” says Dr. Koren. “This study has implications for research and for practice, as stress can be managed with lifestyle changes and psychotherapy.”

The study was supported by Physician Services Inc. and the Canadian Institutes of Health Research.

Contact: Kathy Wallis
kwallis3@uwo.ca
519-661-2111 x81136
University of Western Ontario

Did you know the Institute of Health and Medical Research (INSERM) and University of Montpellier financed professionals indicated that regulating ‘good’ and ‘bad’ levels of cholesterol can help stop mental problems among seniors?

In a freshly released issue of the journal Biological Psychiatry, written in July 2010, leading researcher Dr. Marie-Laure Ancelin of INSERM (Institut National de la Santé et de la Recherche Médicale http://www.inserm.fr) described that gender specific regulation of levels of cholesterol can help reduce depression in the seniors.

French analysts followed a large number of women and men aged sixty five and older for seven years.

They discovered that depression in women was associated with lower levels of “good” high-density lipoprotein cholesterol (HDL-C), which puts them at higher risk for cardiovascular disease, including heart stroke.

In contrast, depressive disorder in men was linked with low levels of “bad” low-density lipoprotein cholesterol (LDL-C). This association was strongest in men with a hereditary vulnerability to depression related to a serotonin transporter gene.

Therefore, proper regulation of HDL-C and LDL-C levels can aid stop depression in the seniors, the researchers concluded.

The analysis was published in the July 15 issue of the journal Biological Psychiatry (Reference: http://www.biologicalpsychiatryjournal.com/article/S0006-3223(10)00393-8/abstract).

Major diet sources of cholesterol include cheese, egg yolks, beef, pork, poultry, and shrimp. Plant products such as flax seeds and peanuts incorporate cholesterol-like substances called phytosterols.

Total cholesterol means the sum of HDL (High-density lipoprotein), LDL (Low-density lipoprotein), and VLDL (Very-low-density lipoprotein). Usually, only the total, HDL, and triglycerides are measured.

It is suggested to have cholesterol tested more frequently than 5 years if a person has total cholesterol of 200 mg/dL or higher, or if a man over age forty five or a woman over age 50 has HDL (good) cholesterol less than 40 mg/dL, or occur other risk factors for coronary disease and stroke.

So…exactly what can you do to rise your HDL (good) and reduce your LDL (bad) levels?

1. Exercising can substantially increase HDL cholesterol while lowering LDL cholesterol.

2. Cigarette smoking has been shown to lower HDL while raising LDL cholesterol.

3. Processed, trans fats at the same time raise LDL cholesterol and lower HDL cholesterol.

4. Monounsaturated fats such as those found in essential olive oil and avocados increase HDL and lower LDL.

5. Fatty fish like salmon and sardines contain omega-3 fats that raise HDL and lower LDL.

6. Whole, intact grains contain dietary fiber and niacin, both of which raise HDL and may lower LDL.

Now it’s all to you…

About me - Betty Doyle shares knowledge for the anti depression pills blog. It’s a nonprofit site dedicated to her personal depression journey. The blog focuses on giving energy and hope to any individual who is suffering from depressive disorder and promotes those individuals to find the energy to fight back against the effects of depression. By doing this she wants to aid alleviate some of the stigma mental illness depression can cause and help people perception of mood difficulties.

The device, which would include thousands of microscopic filters as well as a bioreactor to mimic the metabolic and water-balancing roles of a real kidney, is being developed in a collaborative effort by engineers, biologists and physicians nationwide, led by Shuvo Roy, PhD, in the UCSF Department of Bioengineering and Therapeutic Sciences.

The treatment has been proven to work for the sickest patients using a room-sized external model developed by a team member in Michigan. Roy’s goal is to apply silicon fabrication technology, along with specially engineered compartments for live kidney cells, to shrink that large-scale technology into a device the size of a coffee cup. The device would then be implanted in the body without the need for immune suppressant medications, allowing the patient to live a more normal life.

“This device is designed to deliver most of the health benefits of a kidney transplant, while addressing the limited number of kidney donors each year,” said Roy, an associate professor in the UCSF School of Pharmacy who specializes in developing micro-electromechanical systems (MEMS) technology for biomedical applications. “This could dramatically reduce the burden of renal failure for millions of people worldwide, while also reducing one of the largest costs in U.S. healthcare.”

The team has established the feasibility of an implantable model in animal models and plans to be ready for clinical trials in five to seven years.

End-stage renal disease, or chronic kidney failure, affects more than 500,000 people per year in the United States alone, and currently is only fully treated with a kidney transplant. That number has been rising between 5-7 percent per year, Roy said, in part because of the kidney damage associated with diabetes and hypertension.

Yet transplants are difficult to obtain: a mere 17,000 donated kidneys were available for transplant last year, while the number of patients on the transplant waiting list currently exceeds 85,000, according to the Organ Procurement ant Transplant Network.

Roughly 350,000 patients are reliant on kidney dialysis, Roy explained, which comes at a tremendous cost. The Medicare system alone spends $25 billion on treatments for kidney failure – more than 6 percent of the total budget – while the disease affects only 1 percent of Medicare recipients, he said. That cost includes almost $75,000 per patient each year for dialysis, according to the U.S. Renal Data System.

Dialysis also takes a human toll. A typical dialysis schedule is three sessions per week, for 3 to 5 hours per session, in which blood is pumped through an external circuit for filtration. This is exhausting for patients and only replaces 13 percent of kidney function, Roy said. As a result, only 35 percent of patients survive for more than 5 years.

With the limited supply of donors, that means thousands of patients die each year waiting for a kidney.

The implantable device aims to eradicate that problem. The two-stage system uses a hemofilter to remove toxins from the blood, while applying recent advances in tissue engineering to grow renal tubule cells to provide other biological functions of a healthy kidney. The process relies on the body’s blood pressure to perform filtration without needing pumps or an electrical power supply.

The project exemplifies the many efforts under way at UCSF to build collaborations across scientific disciplines that accelerate the translation of academic research into real solutions for patients, according to Mary Anne Koda-Kimble, PharmD, dean of the UCSF School of Pharmacy.

“This is a perfect example of the work we are doing at UCSF to address some of the most critical medical issues of our time, both in human and financial costs,” Koda-Kimble said. “This project shows what can be accomplished by teams of scientists with diverse expertise, collaborating to profoundly and more quickly improve the lives of patients worldwide.”

The creation of the Department of Bioengineering and Therapeutic Sciences – a joint department in the UCSF schools of Pharmacy and Medicine – was itself an effort to promote translational research at UCSF by forming collaborations across biomedical specialties. Roy is also a founding faculty member of the UCSF Pediatric Device Consortium, which aims to accelerate the development of innovative devices for children health, and a faculty affiliate of the California Institute for Quantitative Biosciences (QB3) at UCSF.

His team is collaborating with 10 other teams of researchers on the project, including the Cleveland Clinic where Roy initially developed the idea, Case Western Reserve University, University of Michigan, Ohio State University, and Penn State University.

The first phase of the project, which has already been completed, focused on developing the technologies required to reduce the device to a size that could fit into the body and testing the individual components in animal models. In the second and current phase, the team is doing the sophisticated work needed to scale up the device for humans. The team now has the components and a visual model and is pursuing federal and private support to bring the project to clinical use.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

Follow UCSF on Twitter at http://twitter.com/ucsfnews

Contact: Kristen Bole
kristen.bole@ucsf.edu
415-502-6397
University of California - San Francisco

The glandular tissue of the breast contains two main cell types, outer “basal” cells and inner “luminal” cells. The basal layer consists mostly of differentiated cells with a small population of mammary stem cells. The luminal layer contains differentiated cells and several types of cells which are intermediates between the luminal cells and stem cells. The different cell types can be identified and separated on the basis of specific molecular markers.

“In breast cancer, it has been proposed that different tumor subtypes may originate from different stem and intermediate cells, with more aggressive ‘basal-like’ breast cancers originating from basal stem cells and less aggressive breast cancers from the luminal intermediates,” explains senior study author, Dr. Matthew J. Smalley from The Breakthrough Breast Cancer Research Centre at the Institute of Cancer Research in London. “Strikingly, the vast majority of breast tumors with mutations in BRCA1, a breast cancer susceptibility gene, have basal-like characteristics, suggesting a stem cell origin.”

More recently, however, it was demonstrated that increases in abnormal luminal intermediate cells are associated with BRCA1 mutations and that there are similarities between the genes switched on in normal human luminal intermediate cells and basal-like breast cancer cells. “To resolve the true origin of BRCA1 breast cancer, we designed the first direct comparison of the effects of creating identical BRCA1-associated tumor predisposing events in basal stem versus luminal intermediate cells,” says Dr. Smalley.

Specifically, the researchers deleted the BRCA1 gene in mouse basal stem cells or luminal intermediate cells. They discovered that although BRCA1 deletion caused tumors to form from both basal stem cells and luminal intermediate cells, only the latter had features that were identical to both human BRCA1 tumors and the majority of human basal-like breast cancers not associated with BRCA1 mutations.

Taken together, these findings suggest that the majority of so-called basal-like breast cancers are derived from luminal intermediate cells and not from basal stem cells as was originally expected. “Our results highlight luminal intermediate cells as a key to understanding the origins of basal-like breast cancer,” concludes Dr. Smalley. “This has important implications for treatment and prevention strategies for this aggressive disease.”

The reseachers include Gemma Molyneux, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK; Felipe C. Geyer, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK; Fiona-Ann Magnay, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK; Afshan McCarthy, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK; Howard Kendrick, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK; Rachael Natrajan, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK; Alan MacKay, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK; Anita Grigoriadis, Breakthrough Breast Cancer Research Unit, Guy’s Hospital, King’s Health Partners AHSC, London, UK; Andrew Tutt, Breakthrough Breast Cancer Research Unit, Guy’s Hospital, King’s Health Partners AHSC, London, UK; Alan Ashworth, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK; Jorge S. Reis-Filho, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK; and Matthew J. Smalley, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.

Contact: Cathleen Genova
cgenova@cell.com
617-397-2802
Cell Press

Now, a research team at the University of Georgia has shown for the first time that a gene called Myc (pronounced “mick”) may be far more important in the development and persistence of stem cells than was known before. Myc is traditionally thought of as a cancer-causing gene, or oncogene, but recent studies from the UGA team have established critical roles for it in stem cell biology. The discovery has important implications for the basic understanding of developmental processes and how stem cells can be used for therapeutic purposes.

“This new research has uncovered a really unexpected role for Myc,” said Stephen Dalton, GRA Eminent Scholar of Molecular Cell Biology and Georgia Cancer Coalition Distinguished Scientist at UGA. “Our work here represents the first mechanistic characterization of how Myc controls the pluripotent stem cell state.”

The research was published today in the journal Cell Stem Cell. Other authors of the paper include Keriayn Smith and Amar Singh of the Dalton lab at UGA. Smith left recently to begin a postdoc at the University of North Carolina. Dalton also is a member of the department of biochemistry and molecular biology in the Franklin College of Arts and Sciences and is affiliated with the UGA Cancer Center and the Biomedical and Health Sciences Institute.

In previous work, Dalton and his colleagues showed that Myc is critical for stem cell maintenance and that it affects widespread changes in gene expression. This latter function is crucial when stem cells differentiate into more specific cell types. In the new research, Dalton’s team showed that Myc sustains the important pluripotency process by repressing a “master regulator” gene called GATA6.

“Pluripotency is the inherent property of a cell to create all cell types, from an embryo to an adult organism,” said Dalton. “It’s an extremely important biological process, and knowing how it is controlled is crucial not only from a basic developmental perspective but also so that we can harness the potential of stem cells for the development of therapies, including those for diabetes, cardiovascular disease and a range of neurological disorders. Through a detailed understanding of early development, we hope to apply this information so that pluripotent stem cells can be differentiated into therapeutically useful cell types. These cells can then be used in a clinical setting to cure degenerative diseases and treat acute injury.”

The finding that Myc inhibits GATA6 came as a big surprise to the Dalton team and points out that researchers have only seen the tip of the “molecular iceberg” in terms of what Myc does in stem cells. It now seems likely that understanding Myc’s role in further detail will reshape current ideas about the basic biology of stem cells.

Dalton’s new work addressed the uncertainty about how Myc maintains the pluripotency of stem cells by examining what happens when two forms of Myc—c-Myc and N-Myc—are inactivated in pluripotent stem cells. What he found was that either c- or N-Myc is sufficient to maintain pluripotency, but that the absence of both triggers the differentiation of pluripotent stem cells. Myc is therefore acting as a “brake” to restrain differentiation. When the “differentiation brake” is removed, cells lose their stem cell properties, and, potentially, they can become any one of over a hundred different cell types.

Pluripotent stem cells can now be made from skin fibroblasts and even from blood samples. (Fibroblasts are cells common in connective tissues of animals and play an important role in the healing of wounds, among many functions.) The conversion of mature fibroblast or blood cells back to pluripotent stem cells is called “reprogramming.” Myc also has a critical role in this process. The ability to make stem cells from a patient’s blood or skin is going to revolutionize medicine as it opens the way for patient-specific stem cells that would circumvent problems associated with immune rejection, said Dalton.

“During the reprogramming of cells, Myc represses genes associated with the differentiated state and primes them for the expression of stem cell genes,” he said. “We now speculate that during the early reprogramming stage, Myc serves to change the cell cycle so that stem cells can divide for long periods of time without aging. This is also what Myc does in cancer cells.”

Dalton said that there is an intriguing relationship between normal stem cells and cancer cells. Since Myc is crucial for maintenance of stem cells and for the development of cancer, pluripotent stem cells represent a good model for tumor biologists. Cancer is thought to be initiated by rogue stem cells found in different tissues, further highlighting the link between stem cell biology, cancer and Myc.

“This is clearly going to be a major area of research for many years to come,” Dalton said.

The research was supported by grants to Dalton from the National Institute of Child Health and Development and the National Institute for General Medical Sciences.

Contact: Stephen Dalton
sdalton@uga.edu
706-542-9857
University of Georgia

The discovery could lead to development of a simple dietary remedy for many of the more than 23 million Americans suffering from diabetes and other conditions.

Writing in the advance online edition of the September 3 issue of the journal Cell, Jerrold Olefsky, MD, and colleagues identified a key receptor on macrophages abundantly found in obese body fat. Obesity and diabetes are closely correlated. The scientists say omega-3 fatty acids activate this macrophage receptor, resulting in broad anti-inflammatory effects and improved systemic insulin sensitivity.

Macrophages are specialized white blood cells that engulf and digest cellular debris and pathogens. Part of this immune system response involves the macrophages secreting cytokines and other proteins that cause inflammation, a method for destroying cells and objects perceived to be harmful. Obese fat tissue contains lots of these macrophages producing lots of cytokines. The result can be chronic inflammation and rising insulin resistance in neighboring cells over-exposed to cytokines. Insulin resistance is the physical condition in which the natural hormone insulin becomes less effective at regulating blood sugar levels in the body, leading to myriad and often severe health problems, most notably type 2 diabetes mellitus.

Olefsky and colleagues looked at cellular receptors known to respond to fatty acids. They eventually narrowed their focus to a G-protein receptor called GPR120, one of a family of signaling molecules involved in numerous cellular functions. The GPR120 receptor is found only on pro-inflammatory macrophages in mature fat cells. When the receptor is turned off, the macrophage produces inflammatory effects. But exposed to omega-3 fatty acids, specifically docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the GPR120 receptor is activated and generates a strong anti-inflammatory effect.

“It’s just an incredibly potent effect,” said Olefsky, a professor of medicine and associate dean of scientific affairs for the UC San Diego School of Medicine. “The omega-3 fatty acids switch on the receptor, killing the inflammatory response.”

The scientists conducted their research using cell cultures and mice, some of the latter genetically modified to lack the GPR120 receptor. All of the mice were fed a high-fat diet with or without omega-3 fatty acid supplementation. The supplementation treatment inhibited inflammation and enhanced insulin sensitivity in ordinary obese mice, but had no effect in GPR120 knockout mice. A chemical agonist of omega-3 fatty acids produced similar results.

“This is nature at work,” said Olefsky. “The receptor evolved to respond to a natural product – omega-3 fatty acids – so that the inflammatory process can be controlled. Our work shows how fish oils safely do this, and suggests a possible way to treating the serious problems of inflammation in obesity and in conditions like diabetes, cancer and cardiovascular disease through simple dietary supplementation.”

However, Olefsky said more research is required. For example, it remains unclear how much fish oil constitutes a safe, effective dose. High consumption of fish oil has been linked to increased risk of bleeding and stroke in some people.

Should fish oils prove impractical as a therapeutic agent, Olefsky said the identification of the GPR120 receptor means researchers can work toward developing an alternative drug that mimics the actions of DHA and EPA and provides the same anti-inflammatory effects.

Co-authors of the paper are Da Young Oh, Saswata Talukdar, Eun Ju Bae, Hidetaka Morinaga, WuQuiang Fan, Pingping Li and Wendell J. Lu, all in the Department of Medicine, Division of Endocrinology and Metabolism at the University of California, San Diego; Takeshi Imamura, Division of Pharmacology, Shiga University of Medical Science; and Steven M. Watkins, Lipomics Technologies, Inc.

Funding for this research came, in part, from a National Institutes of Health grant and the Eunice Kennedy Shriver NICHD/NIH.

Download video of Olefsky discussing the research at: http://vmg.ucsd.edu/download/vmg_pub/HS%20Media%20Release/Olefsky%20Omega%203%20Fatty%20Acids/

Contact: Scott LaFee
slafee@ucsd.edu
619-543-6163
University of California - San Diego

Whether teenagers who smoked pot will use other illicit drugs as young adults has more to do with life factors such as employment status and stress, according to the new research. In fact, the strongest predictor of whether someone will use other illicit drugs is their race/ethnicity, not whether they ever used marijuana.

Conducted by UNH associate professors of sociology Karen Van Gundy and Cesar Rebellon, the research appears in the September 2010, issue of the Journal of Health and Social Behavior in the article, “A Life-course Perspective on the ‘Gateway Hypothesis.’ ”

“In light of these findings, we urge U.S. drug control policymakers to consider stress and life-course approaches in their pursuit of solutions to the ‘drug problem,’ ” Van Gundy and Rebellon say.

The researchers used survey data from 1,286 young adults who attended Miami-Dade public schools in the 1990s. Within the final sample, 26 percent of the respondents are African American, 44 percent are Hispanic, and 30 percent are non-Hispanic white.

The researchers found that young adults who did not graduate from high school or attend college were more likely to have used marijuana as teenagers and other illicit substances in young adulthood. In addition, those who used marijuana as teenagers and were unemployed following high school were more likely to use other illicit drugs.

However, the association between teenage marijuana use and other illicit drug abuse by young adults fades once stresses, such as unemployment, diminish.

“Employment in young adulthood can protect people by ‘closing’ the marijuana gateway, so over-criminalizing youth marijuana use might create more serious problems if it interferes with later employment opportunities,” Van Gundy says.

In addition, once young adults reach age 21, the gateway effect subsides entirely.

“While marijuana use may serve as a gateway to other illicit drug use in adolescence, our results indicate that the effect may be short-lived, subsiding by age 21. Interestingly, age emerges as a protective status above and beyond the other life statuses and conditions considered here. We find that respondents ‘age out’ of marijuana’s gateway effect regardless of early teen stress exposure or education, work, or family statuses,” the researchers say.

The researchers found that the strongest predictor of other illicit drug use appears to be race-ethnicity, not prior use of marijuana. Non-Hispanic whites show the greatest odds of other illicit substance use, followed by Hispanics, and then by African Americans.

The University of New Hampshire, founded in 1866, is a world-class public research university with the feel of a New England liberal arts college. A land, sea, and space-grant university, UNH is the state’s flagship public institution, enrolling more than 12,200 undergraduate and 2,200 graduate students.

The American Sociological Association (www.asanet.org), founded in 1905, is a nonprofit membership association dedicated to serving sociologists in their work, advancing sociology as a science and profession, and promoting the contributions to and use of sociology by society. The Journal of Health and Social Behavior is a quarterly, peer-reviewed journal of the ASA.

The research article described above is available by request for members of the media. Contact Daniel Fowler, ASA’s Media Relations and Public Affairs Officer, at pubinfo@asanet.org or (202) 527-7885.

Contact: Karen Van Gundy
karen.vangundy@unh.edu
603-862-1896
University of New Hampshire