Archive for the ‘Gene Therapy Research’ Category

ScienceDaily (Sep. 2, 2012) Scientists have restored the sense of smell in mice through gene therapy for the first time -- a hopeful sign for people who can't smell anything from birth or lose it due to disease.

The achievement in curing congenital anosmia -- the medical term for lifelong inability to detect odors -- may also aid research on other conditions that also stem from problems with the cilia. Those tiny hair-shaped structures on the surfaces of cells throughout the body are involved in many diseases, from the kidneys to the eyes.

The new findings, published online in Nature Medicine, come from a team at the University of Michigan Medical School and their colleagues at several other institutions.

The researchers caution that it will take time for their work to affect human treatment, and that it will be most important for people who have lost their sense of smell due to a genetic disorder, rather than those who lose it due to aging, head trauma, or chronic sinus problems. But their work paves the way for a better understanding of anosmia at the cellular level.

"Using gene therapy in a mouse model of cilia dysfunction, we were able to rescue and restore olfactory function, or sense of smell," says senior author Jeffrey Martens, Ph.D., an associate professor of pharmacology at U-M. "Essentially, we induced the neurons that transmit the sense of smell to regrow the cilia they'd lost."

The mice in the study all had a severe genetic defect that affected a protein called IFT88, causing a lack of cilia throughout their bodies. Such mice are prone to poor feeding and to early death as a result. In humans, the same genetic defect is fatal.

The researchers were able to insert normal IFT88 genes into the cells of the mice by giving them a common cold virus loaded with the normal DNA sequence, and allowing the virus to infect them and insert the DNA into the mouse's own cells. They then monitored cilia growth, feeding habits, and well as signals within and between the nerve cells, called neurons, that are involved in the sense of smell.

Only 14 days after the three-day treatment, the mice had a 60 percent increase in their body weight, an indication they were likely eating more. Cell-level indicators showed that neurons involved in smelling were firing correctly when the mice were exposed to amyl acetate, a strong-smelling chemical also called banana oil.

"At the molecular level, function that had been absent was restored," says Martens.

"By restoring the protein back into the olfactory neurons, we could give the cell the ability to regrow and extend cilia off the dendrite knob, which is what the olfactory neuron needs to detect odorants," says postdoctoral fellow and first author Jeremy McIntyre, Ph.D.

Read the original:
Can’t smell anything? Discovery may give you hope

2 September 2012 Last updated at 21:22 ET By James Gallagher Health and science reporter, BBC News

Gene therapy has been used to give mice born without a sense of smell the ability to sniff their surroundings, an international team of researchers say.

The mice had a genetic disease which affected microscopic hairs in their body - called cilia - which can detect chemicals in the air.

Researchers hope their findings will lead to treatments for diseased cilia, which can cause blindness, deafness and kidney disease in people.

The study is in Nature Medicine.

Microscopic cilia stick out from many cells in the body. A range of genetic disorders called ciliopathies result in damaged cilia which can be fatal or severely debilitating. One symptom can be a lifetime without a sense of smell, called congenital anosmia.

A groups of researchers, lead by the University of Michigan, looked at mice with a mutation in their Ift88 gene, which meant they struggled to produce cilia and could not smell.

The group created a virus which was capable of infecting cells with a working version of the Ift88 gene. This was injected into the nose on three consecutive days. This was able to restore the cilia and a sense of smell.

Prof Philip Beales from University College London was involved in the study. He told the BBC: "It is a proof of concept that has shown we can get that gene back into these cells, produce the right protein, produce cilia and function as expected.

He said the mice were then able to use their sense of smell to seek out food. However, it is hoped a similar approach could be used for other symptoms of the disorders.

Read the original:
Mice 'smell again' after therapy

Public release date: 2-Sep-2012 [ | E-mail | Share ]

Contact: Kara Gavin kegavin@umich.edu 734-764-2220 University of Michigan Health System

ANN ARBOR, Mich. Scientists have restored the sense of smell in mice through gene therapy for the first time -- a hopeful sign for people who can't smell anything from birth or lose it due to disease.

The achievement in curing congenital anosmia -- the medical term for lifelong inability to detect odors -- may also aid research on other conditions that also stem from problems with the cilia. Those tiny hair-shaped structures on the surfaces of cells throughout the body are involved in many diseases, from the kidneys to the eyes.

The new findings, published online in Nature Medicine, come from a team at the University of Michigan Medical School and their colleagues at several other institutions.

The researchers caution that it will take time for their work to affect human treatment, and that it will be most important for people who have lost their sense of smell due to a genetic disorder, rather than those who lose it due to aging, head trauma, or chronic sinus problems. But their work paves the way for a better understanding of anosmia at the cellular level.

"Using gene therapy in a mouse model of cilia dysfunction, we were able to rescue and restore olfactory function, or sense of smell," says senior author Jeffrey Martens, Ph.D., an associate professor of pharmacology at U-M. "Essentially, we induced the neurons that transmit the sense of smell to regrow the cilia they'd lost."

The mice in the study all had a severe genetic defect that affected a protein called IFT88, causing a lack of cilia throughout their bodies. Such mice are prone to poor feeding and to early death as a result. In humans, the same genetic defect is fatal.

The researchers were able to insert normal IFT88 genes into the cells of the mice by giving them a common cold virus loaded with the normal DNA sequence, and allowing the virus to infect them and insert the DNA into the mouse's own cells. They then monitored cilia growth, feeding habits, and well as signals within and between the nerve cells, called neurons, that are involved in the sense of smell.

Only 14 days after the three-day treatment, the mice had a 60 percent increase in their body weight, an indication they were likely eating more. Cell-level indicators showed that neurons involved in smelling were firing correctly when the mice were exposed to amyl acetate, a strong-smelling chemical also called banana oil.

Read this article:
Can't smell anything? This discovery may give you hope

YAHOO:

Talent manager Annabelle Rama will fly to Germany in September to undergo therapy - stem cell therapy, that is. This has been a promise made by her son Richard Gutierrez who's footing the bill. "Early this year pa lang ay napagplanuhan na 'yung pagpapa-stem cell ng nanay ko at prinomise ko sa kanya na pag-iipunan ko, prinomise ko sa kanya na ako ang magti-treat sa kanya," Richard said on the first episode of "H.O.T. TV," Aug. 5.

He noted, "'Yung mom ko hindi mahilig 'yan na pumunta sa mga doctor, hindi mahilig magpa-check-up."

Looking forward

This early, Annabelle is already excited about her trip and the upcoming treatment.

"Kaya ako excited pumunta kasi unang-una mataas ang aking sugar, mataas ang aking cholesterol, tapos me problema pa ako sa high blood, blood pressure ko. Siguro nga kailangan kong pumunta ng Germany," she said, noting that the condition of her friends, talent manager Lolit Solis and actress Lorna Tolentino, have improved tremendously after going through stem cell therapy.

"Nakita ko ang mukha ni Lolis pumuputi ang mukha niya, eh at saka mukha siyang fresh na fresh. Lalo na si LT, nakita ko rin siya. Mukhang gumanda naman siya. Basta lahat ng kaibigan kong galing doon, nakakausap ko, sabi nila ay talagang gumaling daw sila. 'Yung kanilang napi-feel na mabigat sa katawan dahil sa sakit nila ay nawawala lahat," she said.

Exorbitant fees?

Annabelle had already inquired about the fees of stem cell procedure in the country and she feels it's exorbitant.

"Kasi sa Piipinas may pinagtatanungan na ako, umabot ng mga four million pesos 'yung naitanong ko kaya parang na-discourage akong magpagamot kasi nga ganoon kamahal."

More:
Annabelle Rama to undergo stem cell treatment to improve health

By David Farrier

Some of the world's top scientists are meeting in Rotorua to figure out how to feed future generations in a world with a booming population.

Organisers say the ABIC 2012 conference aims to promote debate about genetic engineering, and they only had to step outside to find people wanting to debate it with them.

It is the 12th International Conference for Agricultural Biotechnology.

The gathering is of some of the best brains in the world when it comes to the art of growing plants. But it's also much bigger than that.

Now we see agriculture branching out, says ABIC Foundation chairman Dr Jerome Konecsni. We're looking at agriculture as a source of energy, as a source of medicines.

The conference comes as the World Bank notes global food prices soaring by 10 percent in July, with the price of maize reaching an all-time high.

It's very important because the task of feeding the world of tomorrow is probably one of the most formidable jobs we have to do, says Dr Clive James, agricultural scientist.

Outside, a protest of around 30 people rallied, unhappy with talk of genetic modification.

All we're wanting in there is for scientists to find a middle path between the control of science and respect that people want GM-free production, says protest organiser Jon Carapiet.

Read the original:
GM-food conference draws critics

September 1, 2012

redOrbit Staff & Wire Reports Your Universe Online

African-American and European men have an increased risk of prostate cancer due to changes in one of their immune system genes, claims a new study published online in the journal Cancer Epidemiology, Biomarkers & Prevention.

Researchers from the University of Illinois at Chicago (UIC) College of Medicine, as well as colleagues from Northwestern University and Washington, D.C.s Howard University Hospital, isolated changes in the IL-16 gene, an immune system protein, the school reported in an August 31 statement.

Previously identified changes in the gene for IL-16 were associated with prostate cancer in men of European descent. But the same changes in the genes coded sequence called polymorphisms did not confer the same risk in African Americans, the university said.

Doubt was cast on IL-16s role in prostate cancer when researchers were unable to confirm that the IL-16 polymorphisms identified in whites were also important risk factors in African Americans, they added.

Using a new technique known as imputation, which the school describes as a form of statistical extrapolation, the research team was able to discover new patterns of association, which in turn showed them new locations within the gene where they could search for polymorphisms. With that knowledge, they were able to find changes in a different part of the IL-16 gene that were both linked to prostate cancer and unique to African-American males.

According to the UIC statement, polymorphisms occur as a result of DNA mutations and are prevalent in the ancestry of different populations. Lead researcher Rick Kittles, an associate professor of medicine in hematology/oncology at the university, explained that searching for polymorphisms associated with diseases like prostate cancer is more difficult in African-Americans than in Caucasians, as the former race is said to be far more genetically diverse than the latter.

Kittles said that the research provides us with a new potential biomarker for prostate cancer, adding that it confirms the importance of IL-16 in prostate cancer and leads us in a new direction. Very little research has been done on IL-16, so not much is known about it. We now need to explore the functional role of IL-16 to understand the role it is playing in prostate cancer.

The research was supported by grants from the US Department of Defense and the National Cancer Institute/National Institutes of Health.

Excerpt from:
Genetic Link To Prostate Cancer Found In Europeans, African-Americans

DUBLIN--(BUSINESS WIRE)--

Research and Markets (http://www.researchandmarkets.com/research/vrslm2/neuroprotection) has announced the addition of Jain PharmaBiotech's new report "Neuroprotection - Drugs, Markets and Companies" to their offering.

This report describes the role of neuroprotection in acute disorders such as stroke and injuries of the nervous system as well as in chronic diseases such as neurodegenerative disorders because many of the underlying mechanisms of damage to neural tissues are similar in all these conditions and several products are used in more than one disorder. Over 500 products have been investigated for neuroprotective effects including those from the categories of free radical scavengers, anti-excitotoxic agents, apoptosis (programmed cell death) inhibitors, anti-inflammatory agents, neurotrophic factors, metal ion chelators, ion channel modulators and gene therapy. Some of the agents are old established pharmaceuticals whereas others are new biotechnology products.

Pathomechanisms of diseases are described with steps at which neuroprotective therapies are directed. Diseases covered include cerebrovascular disorders, traumatic brain injury, spinal cord injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy and ischemic optic neuropathy as well as retinal degeneration. Although anesthetics such as propofol are neuroprotective as well, neuroprotection during surgery and anesthesia is discussed with the aim of preventing and treating complications that result in CNS damage.

The report contains a profile of 133 companies that have a neuroprotective product or products along with 114 collaborations. Some of the products in development at academic institutions that do not have a commercial sponsor are also included. Although an up-to-date search of the literature was performed and selected 850 references are included, a considerable amount of information has not been published anywhere else. Clinical trials of various neuroprotective agents are described and failures of trials are analyzed with suggestions for improving the selection of drugs and design of trials. The report is supplemented with 66 tables and 11 figures.

Market analysis of currently used products that have a neuroprotective effect are analyzed for the year 2011. Some of these products are approved for other indications but are known to have a neuroprotective effect. With the approval of new products and takeover of markets for obsolete symptomatic therapies, the neuroprotection market value will rise by the year 2016 when it will constitute a major and important component of the CNS market. Forecasts are made until 2021. By that time neuroprotection will be an established part of the neurological practice and measures will be available to achieve this effectively.

Key Topics Covered:

1. Introduction

2. Neuroprotective Agents

3. Neuroprotection in Cerebrovascular Disease

Read more from the original source:
Research and Markets: Neuroprotection - Drugs, Markets and Companies - Updated 2012 Report

CTVNews.ca Staff Published Saturday, Sep. 1, 2012 7:05AM EDT

Are women genetically programmed to have sunnier dispositions than men? Some U.S. researchers think they might.

Scientists with the U.S. governments National Institutes of Health, the University of South Florida and elsewhere think they have narrowed in on one of the genes that fuels happiness. But it seems the gene only has an effect in women, not men.

The researchers found the gene after analyzing the DNA of 193 women and 152 men, who were asked to score their own levels of happiness. Women with low expression of the MAO-A, or monoamine oxidase-A gene, reported much more happiness than those with no expression.

That finding was made after the researchers controlled for other factors that can affect happiness, such as income and education level. Interestingly, though, the researchers found no link with the gene in men.

The MAO-A gene works similarly to antidepressant medications: it regulates the activity of an enzyme called monoamine which breaks down "feel good" neurochemicals, such as serotonin and dopamine. A dysfunctional MAO-A gene has been linked to increased aggression levels in both mice and humans.

Lead author, Dr. Henian Chen, an associate professor in the Department of Epidemiology and Biostatistics at USF, says he was surprised that low expression of this gene was linked to greater happiness in women.

He notes that low expression has actually been linked to psychological problems such as alcoholism, aggressiveness and antisocial behavior.

"Its even called the warrior gene by some scientists. But, at least for women, our study points to a brighter side of this gene," he said in a statement.

Chen thinks that the low-expression version of the MAO-A gene promotes higher levels of monoamine, which allows larger amounts of these neurotransmitters to stay in the brain and boost mood.

Read more from the original source:
Researchers narrow in on women's 'happiness gene'

Phosphorus uptake gene 'could boost rice yields'

Joel Adriano and Iman Zarei

30 August 2012 | EN

Other crops, including corn, could also benefit from the newly discovered rice gene, say experts

Flickr/IRRI Images

[MANILA] A rice gene that could significantly raise the rate of phosphorus uptake in rice varieties has been discovered by a team of international researchers, who claim that it could increase rice yields by up to 20 per cent.

The gene is called PSTOL1, which stands for Phosphorus Starvation Tolerance. It enhances the root growth of rice plants, enabling them to acquire more phosphorous and other nutrients locked in soils.

Sigrid Heuer, a senior scientist at the International Rice Research Institute (IRRI) in the Philippines, and leader of the team that published the study in Nature last week (22 August), said low phosphorus availability in soils affects about half of the world's farmlands. Affected soils require additional applications of phosphorous fertiliser to make them productive.

However, the global demand for such fertiliser is increasing. As a result, prices have almost tripled since 2005. For poor farmers who cannot afford the high prices, yields remain very low.

The discovery of the PSTOL1 gene will make it easier for breeders to develop new rice varieties with enhanced phosphorus uptake using breeding techniques, such as marker-assisted selection, since they will have confidence that the new varieties contain the gene.

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Phosphorus uptake gene 'could boost rice yields'

Public release date: 31-Aug-2012 [ | E-mail | Share ]

Contact: Jeanne Galatzer-Levy jgala@uic.edu 312-996-1583 University of Illinois at Chicago

Prostate cancer in African-American men is associated with specific changes in the IL-16 gene, according to researchers at the University of Illinois at Chicago College of Medicine.

The study, published online in the journal Cancer Epidemiology, Biomarkers & Prevention, establishes the association of IL-16 with prostate cancer in men of both African and European descent.

"This provides us with a new potential biomarker for prostate cancer," says principal investigator Rick Kittles, UIC associate professor of medicine in hematology/oncology.

Previously identified changes in the gene for IL-16, an immune system protein, were associated with prostate cancer in men of European descent. But the same changes in the gene's coded sequence -- called "polymorphisms" -- did not confer the same risk in African Americans.

Doubt was cast on IL-16's role in prostate cancer when researchers were unable to confirm that the IL-16 polymorphisms identified in whites were also important risk factors in African Americans, Kittles said.

Kittles and his colleagues used a technique called imputation -- a type of statistical extrapolation -- that allowed them to see new patterns of association and identify new places in the gene to look for polymorphisms. They found changes elsewhere in the IL-16 gene that were associated with prostate cancer and that were unique to African Americans.

Polymorphisms result from DNA mutations and emerge in the ancestral history of different populations. People of African descent are much more genetically diverse than whites, Kittles said, making the search for polymorphisms associated with disease more difficult.

Although the effect of the particular changes to the gene appear to be different in men of African versus European descent, it is likely that several of the polymorphisms in the gene alter the function of the IL-16 protein.

See the article here:
Genetic link to prostate cancer risk in African Americans found

The Australian diagnostics company Genetic Technologies (GENE)(GTG.AX) is giving up gains from Wednesday, down 6% on the day to $3.48. The middle of the week saw immense momentum on the stock from traders, driving share price from $3.18 to $4.20 before beginning a descent that lasted through Thursday and into this morning. Gains on Wednesday were triggered when the Australian banking firm Lodge Partners initiated coverage of Genetic Technologies with a `Buy` rating, followed by news of a patent infringement suit from GENE against the Reproductive Genetics Institute. GENE markets BREVAgen, a diagnostic tool for determining genetic predisposition to breast cancer in women and is the exclusive marketer of Rosetta Genomics` (ROSG) miRview set of assays in Australia, New Zealand, and Singapore. Genetic Technologies had losses of $1.15 per share in fiscal 2012 - ended June 30 - but expects to improve revenue through sales of BREVAgen, saying that market penetration so far is in-line with similar products; the assay is now available in 48 states. GENE is beginning to even out as trader involvement dissipates and is trading on the low end of its 52-week range. Investor chatter points to Roche`s (RHHBY) Investor Day on the 5th as a catalyst for companies in the field of personalized medicine, like Genetic Technologies, however, this kind of trade is very speculative. PropThink identified another company that will benefit from Roche`s conference next week, however, and that report on Halozyme Therapeutics (HALO) is availablehere.

Or, click hereto see this article at PropThink.com.

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PropThink: Genetic Technologies' Wednesday Gains Unsustainable, Declining Without Momentum

SAN DIEGO--(BUSINESS WIRE)--

Pathway Genomics Corporation, a San Diego-based genetic testing laboratory, has announced a clinical trial with theVeterans Affairs San Diego Healthcare System (VASDHS). Launched this summer, researchers at VASDHS have begun a prospective randomized clinical trial ofPathway Fit, the companys premier saliva-based nutrigenetic test. The trial is focused on the genetic associations of weight loss and weight regain in veterans enrolled inMOVE!, a national weight management program designed by theVA National Center for Health Promotion and Disease Prevention (NCP).

The trial aims to determine if veterans can lose more weight by linking genetic changes with evidence-based lifestyle suggestions as part of Pathway Fit, said Dr. Karen Herbst, the trials lead investigator and staff physician in the endocrinology division of VASDHS. Veterans will learn what diet best matches their genetic-based phenotypes and metabolism, what kind of eating behaviors they may have, and the genetic changes that provide information on how their bodies respond to exercise. The overall goal is to help veterans modify their behavior in order to achieve a superior outcome.

The trial comes at a time when an estimated72.5 million Americanssuffer from obesity, and approximately70 percent of U.S. veteransare overweight or obese, many with co-morbidities, including post-traumatic stress disorder (PTSD). If the trial is successful, Dr. Herbst and her colleagues would like to expand the study to additional VA medical centers across the United States.

We are pleased to be collaborating with the VA in this effort to serve our nations veterans and help them achieve or maintain optimum health and wellness, said Dr. Michael Nova, Pathways chief medical officer. This alignment can provide a model of the vital role genetic information can play in behavior change and personalized medicine.

Pathway has recentlyseen positive results in a trialof Pathway Fit.

Pathway Genomics collaborated with theCalifornia Schools Voluntary Employee Benefits Association (VEBA)in a study that evaluated the weight loss results of 179 overweight California school employees. After six months, the data showed that overweight employees provided with results of their Pathway Fit genetic test had significant weight loss success some lost up to 40 pounds when compared to employees who had tried to lose weight, under similar conditions, without the genetic information.Pathway Fit is now available to all adult VEBA members, of which approximately 40,000 have weight problems and could benefit from the test.

About Pathway Genomics

Pathway Genomics owns and operates an on-sitegenetic testinglaboratory that is accredited by the College of American Pathologists (CAP), accredited in accordance with the U.S. Health and Human Services Clinical Laboratory Improvement Amendments (CLIA) of 1988, and licensed by the state of California. Using only a saliva sample, the company incorporates customized and scientifically validated technologies to generate personalized reports, which address a variety of medical issues, including an individuals carrier status for recessive genetic conditions, food metabolism and exercise response, prescription drug response, and propensity to develop certain diseases such as heart disease, type 2 diabetes and cancer. For more information about Pathway Genomics, visit http://www.pathway.com.

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Pathway Genomics Helps Veterans Combat Obesity Epidemic Using Genetic Testing

Oregon Health & Science University has scheduled a Sept. 22 memorial to celebrate the life of Dr. Robert Koler, a pioneer in genetics research.

Koler made important early discoveries in the field of genetically inherited blood disorders and anticipated early on the role that molecular biochemistry would play in curing disease. He also helped steer the university toward its current focus on genetics-based research.

"He believed that genetics was the way to the future," says former OHSU President Peter Kohler, who will speak at Koler's memorial.

The service starts at 2 p.m. in the OHSU Auditorium (Old Library Building), 3181 S.W. Sam Jackson Park Rd.

Koler, a provost emeritus and professor emeritus of medicine and molecular and medical genetics, died Aug. 2 at the age of 88.

Born in Wyoming on Valentine's Day, 1924, Koler and his family moved to Eugene where he studied at the University of Oregon during World War II. He married in 1945, and in 1947 he completed an accelerated Army training program at the university's medical school in Portland, the precursor to OHSU. During the Korean War; Koler worked as an Army captain and hospital physician in Japan.

Returning to the medical school in Oregon, he studied under noted hematologist Edwin Osgood, and in the 50s began working with Richard Jones, doing first-of-their kind studies of genetically inherited blood disorders.

Long before genetics became widely viewed as a way to cure disease, Koler preached its importance. After a 1960 sabbatical studying genetics at the Galton Institute in London he pushed the medical school to offer basic courses in genetics. Genetics became a division, then a full-fledged OHSU department in 1981, that he was selected to head. He later served in a variety of administrative jobs while continuing to push for genetics research.

After he retired in 1989, he offered to work as an advisor to then-OHSU vice-president Lesley Hallick, but turned down any pay, saying his retirement pay was enough.

"The mission of the instititution is what he loved," Hallick said.

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Sept. 22 memorial service scheduled for Robert Koler, Oregon Health & Science University genetics research pioneer

Researchers built up portrait from finger-bone fragment of Denisovan who lived and died in a Siberian cave

Scientists have reconstructed the entire genetic makeup of a girl who lived and died in a Siberian cave more than 50,000 years ago. The young woman belonged to a long extinct group of humans called Denisovans their existence known only from meagre fossil remains uncovered at the Denisova cave in the Altai mountains in 2008. They are thought to have occupied much of Asia tens of thousands of years ago. Previous tests on the remains found they were more closely related to Neanderthals than modern humans.

Writing in the journal Science, researchers in the U.S. and Germany describe how they sequenced the girls genome with an accuracy once considered impossible with such ancient specimens. The final sequence matched the quality of modern genetic tests on living people.

They sequenced single strands of DNA taken from a little finger bone found at the scene. The bone fragments, and two fossilised teeth, are the only remains of the Denisovans.

Studies on the girls genes suggest she had dark skin, brown hair and brown eyes, but other genetic factors help shed light on the Denisovans more broadly. Comparison of genetic material inherited separately from the girls mother and father points to a population with very low genetic diversity, probably a consequence of the Denisovans starting off as a small group of pioneers and expanding rapidly.

Svante Paabo, at the Max Planck Institute for Evolutionary Anthropology in Leipzig, said there was now no difference in what we can learn genetically about a person that lived 50,000 years ago and from a person today, provided that we have well-enough preserved bones.

The team from Leipzig and Harvard Medical School in Boston compared the Denisovan genome with similar sequences from Neanderthals and 11 modern humans from around the world. This revealed evidence for inbreeding, with Denisovan DNA living on in some populations alive today. Its clear that Denisovan material has contributed three to five per cent of the genomes of people in Australia and New Guinea and aboriginal people from the Philippines, and some of the islands nearby, said David Reich, a Harvard geneticist who worked on the study. The research highlighted scores of gene variants that are found in modern humans but not in Denisovans. Eight mutations that have arisen since our ancestors split from Denisovans are involved in brain function and nerve connectivity, for example.

This is perhaps, in the long term for me, the most fascinating thing about this: what it will tell us in the future about what makes us special in the world, relative to the Denisovans and Neanderthals, said Mr. Paabo.

Another 34 mutations found only in modern humans are associated with diseases, including four that affect the skin and eyes. Guardian Newspapers Limited, 2012

Originally posted here:
Genetics of 50,000-year-old girl reconstructed

ScienceDaily (Sep. 1, 2012) Flying high, or down in the dumps -- individuals suffering from bipolar disorder alternate between depressive and manic episodes. Researchers from the University of Bonn and the Central Institute of Mental Health in Mannheim have now discovered, based on patient data and animal models, how the NCAN gene results in the manic symptoms of bipolar disorder.

The results have been published in the current issue of The American Journal of Psychiatry.

Individuals with bipolar disorder are on an emotional roller coaster. During depressive phases, they suffer from depression, diminished drive and often, also from suicidal thoughts. The manic episodes, however, are characterized by restlessness, euphoria, and delusions of grandeur. The genesis of this disease probably has both hereditary components as well as psychosocial environmental factors.

The NCAN gene plays a major part in how manias manifest

"It has been known that the NCAN gene plays an essential part in bipolar disorder," reports Prof. Dr. Markus M. Nthen, Director of the Institute of Human Genetics at the University of Bonn. "But until now, the functional connection has not been clear." In a large-scale study, researchers led by the University of Bonn and the Central Institute of Mental Health in Mannheim have now shown how the NCAN gene contributes to the genesis of mania. To do so, they evaluated the genetic data and the related descriptions of symptoms from 1218 patients with differing ratios between the manic and depressive components of bipolar disorder.

Comprehensive data from patients and animal models

Using the patients' detailed clinical data, the researchers tested statistically which of the symptoms are especially closely related to the NCAN gene. "Here it became obvious that the NCAN gene is very closely and quite specifically correlated with the manic symptoms," says Prof. Dr. Marcella Rietschel from the Central Institute of Mental Health in Mannheim. According to the data the gene is, however, not responsible for the depressive episodes in bipolar disorder.

Manic mice drank from sugar solution with abandon

A team working with Prof. Dr. Andreas Zimmer, Director of the Institute of Molecular Psychiatry at the University of Bonn, examined the molecular causes effected by the NCAN gene. The researchers studied mice in which the gene had been "knocked out." "It was shown that these animals had no depressive component in their behaviors, only manic ones," says Prof. Zimmer. These knockout mice were, e.g., considerably more active than the control group and showed a higher level of risk-taking behavior. In addition, they tended to exhibit increased reward-seeking behavior, which manifested itself by their unrestrained drinking from a sugar solution offered by the researchers.

Lithium therapy also effective against hyperactivity in mice

See the rest here:
Flying high: Researchers decipher manic gene

DUBLIN--(BUSINESS WIRE)--

Research and Markets (http://www.researchandmarkets.com/research/9fkkzb/cell_therapy_tec) has announced the addition of Jain PharmaBiotech's new report "Cell Therapy - Technologies, Markets and Companies" to their offering.

This report describes and evaluates cell therapy technologies and methods, which have already started to play an important role in the practice of medicine. Hematopoietic stem cell transplantation is replacing the old fashioned bone marrow transplants. Role of cells in drug discovery is also described. Cell therapy is bound to become a part of medical practice.

Stem cells are discussed in detail in one chapter. Some light is thrown on the current controversy of embryonic sources of stem cells and comparison with adult sources. Other sources of stem cells such as the placenta, cord blood and fat removed by liposuction are also discussed. Stem cells can also be genetically modified prior to transplantation.

Cell therapy technologies overlap with those of gene therapy, cancer vaccines, drug delivery, tissue engineering and regenerative medicine. Pharmaceutical applications of stem cells including those in drug discovery are also described. Various types of cells used, methods of preparation and culture, encapsulation and genetic engineering of cells are discussed. Sources of cells, both human and animal (xenotransplantation) are discussed. Methods of delivery of cell therapy range from injections to surgical implantation using special devices.

Cell therapy has applications in a large number of disorders. The most important are diseases of the nervous system and cancer which are the topics for separate chapters. Other applications include cardiac disorders (myocardial infarction and heart failure), diabetes mellitus, diseases of bones and joints, genetic disorders, and wounds of the skin and soft tissues.

Regulatory and ethical issues involving cell therapy are important and are discussed. Current political debate on the use of stem cells from embryonic sources (hESCs) is also presented. Safety is an essential consideration of any new therapy and regulations for cell therapy are those for biological preparations.

The cell-based markets was analyzed for 2011, and projected to 2021. The markets are analyzed according to therapeutic categories, technologies and geographical areas. The largest expansion will be in diseases of the central nervous system, cancer and cardiovascular disorders. Skin and soft tissue repair as well as diabetes mellitus will be other major markets.

The number of companies involved in cell therapy has increased remarkably during the past few years. More than 500 companies have been identified to be involved in cell therapy and 284 of these are profiled in part II of the report along with tabulation of 274 alliances. Of these companies, 154 are involved in stem cells. Profiles of 70 academic institutions in the US involved in cell therapy are also included in part II along with their commercial collaborations. The text is supplemented with 55 Tables and 11 Figures. The bibliography contains 1,050 selected references, which are cited in the text.

Key Topics Covered:

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Research and Markets: Cell Therapy - Technologies, Markets and Companies - Updated 2012 Report

Public release date: 30-Aug-2012 [ | E-mail | Share ]

Contact: Hilary Glover hilary.glover@biomedcentral.com 44-020-319-22370 BioMed Central

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States and is thought to affect almost three million people in the UK. New research published in BioMed Central's open access journal Genome Medicine has identified genes whose activity is altered with increasing lung damage and, using a database of drug effects on gene activity (the Connectivity Map), finds that the compound Gly-His-Lys (GHK) affects the activity of these genes. When tested on human cells from lungs damaged by emphysema, GHK was able to restore normal gene activity and repair cell function.

The strongest cause of COPD is smoking, and at least 25% of smokers will develop this disease. Tobacco smoke and other irritants cause oxidative stress and chronic inflammation, which over time results in emphysema, the destruction of lung alveolar cells. Without these cells, the lungs are not able to efficiently exchange oxygen for carbon dioxide, leaving the patient continuously short of breath and with low levels of oxygen in their blood.

In a ground breaking, multi-centre, study funded by the National Institute of Health (NIH), researchers used cells taken from lungs donated by patients undergoing double lung transplant, whose own lungs were irrevocably damaged by COPD. Profiling of these samples showed that 127 genes had changes in activity that was associated with worsening disease severity within the lung. As would be expected from the nature of the disease, several genes associated with inflammation, such as the genes involved in signalling to B-cells (the immune system cells which make antibodies), showed increased activity.

In contrast genes involved in maintaining cellular structure and normal cellular function, along with the growth factors TGF and VEGF, were down-regulated and showed decreased activity. This included genes which control the ability of the cells to stick together (cell adhesion), produce the protein matrix which normally surrounds the cells, and which promote the normal association between lung cells and blood vessels.

Dr Avrum Spira and Dr Marc Lenburg, who co-led this study from the Boston University School of Medicine, explained, "When we searched the Connectivity Map database, which is essentially a compendium of experiments that measure the effect of therapeutic compounds on every gene in the genome, we found that how genes were affected by the compound GHK, a drug known since the 1970s, was the complete opposite of what we had seen in the cells damaged by emphysema."

Dr Joshua Campbell explained, "What got us especially excited was that previous studies had shown that GHK could accelerate wound repair when applied to the skin. This made us think that GHK could have potential drug's as a therapy for COPD."

Prof James Hogg, from the University of British Columbia continued, "When we tested GHK on cells from the damaged lungs of smokers with COPD, we saw an improvement in the structure of their actin cytoskeleton and in cell adhesion, especially to collagen. GHK also restored the ability of cells to reorganise themselves to repair wounds and construct the contractile filaments essential for alveolar function."

GHK is a natural peptide found in human plasma, but the amount present decreases with age. While more testing needs to be done on its effects in COPD, these early results are very promising. Therapeutic studies with GHK in animal models of COPD are now underway with the ultimate goal of moving this compound into clinical trials. As more gene activity signatures are discovered, this method of matching drug to disease may provide a rapid method for discovering potential uses for existing drugs and compounds.

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How gene profiling in emphysema is helping to find a cure

Latest Mental Health News

WEDNESDAY, Aug. 29 (HealthDay News) -- A "happy" gene that affects females but not males may explain why women are often happier than men, research suggests.

In the new study, researchers analyzed data from 193 women and 152 men who were assessed for happiness and underwent DNA testing as part of a long-term study of mental health.

The team focused on the "monoamine oxidase A" (MAOA) gene, which regulates an enzyme that breaks down brain neurotransmitters such as serotonin and dopamine, "feel-good" chemicals targeted by many antidepressants.

One version of the MAOA gene raises levels of monoamine, which allows larger amounts of these neurotransmitters to remain in the brain and boost mood.

The researchers found that women with the low-expression version of the MAOA gene were much happier than other women. Compared to women with no copies of the low-expression version, those with one copy scored higher on the happiness scale and those with two copies scored even higher.

A large number of men carried the low-expression version of the MAOA gene, but they were no happier than those without it, the investigators found.

The study was released online in advance of print publication in the journal Progress in Neuro-Psychopharmacology & Biological Psychiatry.

"This is the first happiness gene for women," lead author Dr. Henian Chen, an associate professor in the department of epidemiology and biostatistics in the College of Public Health, at University of South Florida, said in a university news release.

"I was surprised by the result, because low expression of MAOA has been related to some negative outcomes like alcoholism, aggressiveness and antisocial behavior. It's even called the warrior gene by some scientists, but, at least for women, our study points to a brighter side of this gene," Chen said.

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Scientists ID 'Happy' Gene in Women

ScienceDaily (Aug. 30, 2012) Two papers led by scientific teams from the Cancer Genetics Program at Beth Israel Deaconess Medical Center (BIDMC) shed new light on the genetic mechanisms underlying cellular energy and metabolism and, at the same time, highlight both the challenges and opportunities of genetic approaches to cancer treatment.

Appearing in the September 2012 issues of The Journal of Clinical Investigation (JCI) and Nature Medicine, the new findings reveal surprising insights into how PML regulates metabolism via the fatty acid oxidation (FAO) pathway and, in the process, uncover paradoxical roles for this tumor suppressor gene.

"The real story lies in the juxtaposition of these two papers, the way they jointly illuminate the braided function of PML in the FAO pathway," says the papers' senior author Pier Paolo Pandolfi, MD, PhD, Director of Cancer Genetics at BIDMC and George C. Reisman Professor of Medicine at Harvard Medical School. The Pandolfi laboratory has been studying the PML (promyelocytic leukemia protein) tumor suppressor gene, for more than 20 years.

Fatty-acid oxidation is the fat-burning metabolic process that is of importance to the energy of all cells. The two studies examined the impact of the FAO process in different biomedical situations including obesity, breast cancer and hematopoetic stem cell maintenance. Importantly, both publications determined that the FAO pathway could be a target for pharmacologic treatments.

The JCI paper defines the mechanism by which PML regulates FAO (involving the regulation of peroxisome proliferator-activated receptors or PPARs). According to first author Arkaitz Carracedo, PhD, a former postdoctoral fellow in the Pandolfi laboratory and currently Ikerbasque Research Professor at the research institute CIC bioGUNE, Bizkaia, Spain, the findings demonstrate that alterations in this pathway result in excessive fat accumulation and obesity in genetically engineered mouse models. In other words, when PML is highly expressed, cellular metabolism is enhanced and the mice were able to briskly burn fat and avoid gaining weight. Conversely, when PML was lost, the animals grew obese.

But, the team also made the paradoxical discovery that PML's enhanced cellular metabolism appeared to provide breast cancer cells with the energy needed to survive. These findings are further supported by data showing PML is highly expressed in a subset of breast cancers with poor prognosis, notes Carracedo. Instead of maintaining its function as a tumor suppressor and keeping breast cancer cells under control, PML is providing breast cancer with a survival advantage. These findings aligned with work by other labs that have found a relationship between high PML expression and breast cancers with poor prognosis.

In the second paper, in the September 2012 issue of Nature Medicine, Keisuke Ito, MD PhD, together with co-lead author Arkaitz Carracedo, looked at PML's role in regulating hematopoetic stem cells (HSCs), again through the FAO pathway, and defined for the first time the contribution of lipid metabolism to maintaining the function of HSCs.

HSCs replenish blood cells throughout the lifespan of an organism, and so they are critical to the aging process, explains Ito, also a former postdoctoral fellow in the Pandolfi laboratory and currently a member of the faculty at the Albert Einstein College of Medicine. The authors discovered that inhibition of fatty acid oxidation could represent an effective therapy for leukemia, as well as other forms of cancer -- but that it simultaneously posed a risk to the replenishment of HSCs. "Our results uncover a crucial metabolic requirement involving PPAR-delta signaling and FAO for preservation of the delicate equilibrium between HSC maintenance and function," the authors write. The findings have straightforward therapeutic implications for the improvement of both the efficacy of bone marrow transplantation (BMT) and the treatment of hematological malignancies.

"These two studies highlight both the opportunities and complexities of genetic approaches to human disease," notes Pandolfi. "Our next logical step will be to identify a potential path for therapeutic intervention through the opposing Scylla and Charybdis-like threats and benefits of this pathway," he says, referring to the two sea monsters that sailors of mythology had to navigate. "Through pharmacological dosage and scheduling, we will come up with a way to reap the benefits of PML and FAO regulation, while reducing or even eliminating its risks. The opportunity is there since we have drugs that can modulate both PML levels and FAO, and we have begun testing these concepts right away in our "mouse hospital."

In addition to Pandolfi and Carracedo, coauthors of the JCI paper include BIDMC investigators Dror Weiss, Manoj Bhasin, Andrew C. Adams, Maria Sundvall, Su Jung Song, Keisuke Ito, Ainara Egia, Towia Libermann, and Elefteria Maratos-Flier; Harvard Medical School investigators Vincent C.J. de Boer, Gaelle Laurent, Lydia S. Finley, and Marcia C. Haigis; Dana-Farber Cancer Institute investigators Zachary Gerhart-Hines, and Pere Puigserver; Amy K. Leliaert and Zachary T. Schafer of the University of Notre Dame; and Andrea L. Richardson of Brigham and Women's Hospital.

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Diverse metabolic roles for PML tumor suppressor gene

AARHUS, Denmark--(BUSINESSWIRE)--

CLC bio, the world's leading bioinformatics software developer, has been awarded a share of a EU-funded clinical research grant, PATHSEEK, worth $ 2 million out of a total project budget of $ 10 million.

As part of the grant, CLC bio will develop a user-friendly and computationally efficient solution for pathogen identification, host biomarker identification, pathogen variant characterization and molecular epidemiology in a clinical setting, as well as build a flexible computational back-end.

VP of R&D at CLC bio, Dr. Roald Forsberg, comments, "Current platforms in diagnostic laboratories are limited by the amount of time required for generating a result and by the limited sequence information available for pathogens. To overcome these limitations were going to develop a disruptive diagnostic technological pathogen sequencing platform which utilizes our world-leading bioinformatics expertise to enable scientists to go from a patient sample to a result, in less than 48 hours."

CEO of CLC bio, Thomas Knudsen, adds, "From the start, it has been one of CLC bios core strategies to do active research within the bioinformatics field and letting that research be a primary driver of our software development. We're currently part of and coordinating 10 different research projects, of which half are funded by the EU. This underlines our successful strategy and we plan to be part of even more research grants in the future."

About PATHSEEK

PATHSEEK is a 3-year study led by Professor Judy Breuer at University College London, which will demonstrate the potential of next generation sequencing technologies in clinical microbiology labs, to enable the detection of pathogens directly from clinical samples and the early detection of drug resistant mutations. The study will look at infections with clear unmet clinical needs or which pose a global risk, including, HIV, Mycobacterium tuberculosis, hepatitis B (HBV) and C (HCV) and influenza A. PATHSEEK will also investigate two host pharmacogenomics biomarkers which predict response to therapy for HCV and HIV.

The partners in PATHSEEK include University College London (UK), Erasmus Universitair Medisch Centrum Rotterdam (NL), Oxford Gene Technology (UK), and CLC bio (DK).

About CLC bio

http://www.clcbio.com/about

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CLC bio Part of $ 10M EU PATHSEEK Project

April Flowers for redOrbit.com Your Universe Online

An international consortium of researchers from Uppsala University, Swedish University of Agricultural Sciences and Texas A&M University have discovered a mutation in a single gene in horses that is critical for the ability to perform ambling gaits and pacing that has a major effect on performance in harness racing. The study, published in Nature, is a breakthrough for understanding spinal cord neuronal circuitry and locomotion in vertebrates.

A complex coordination of muscle contractions carried out by neuronal circuits in our spinal cords allow us to walk and run, but how does this work at the level of nerve cells and molecules?

There is a great variability in the pattern of locomotion for horses, including the three naturally occurring gaits: walk, trot and canter/gallop. Some horses, however, have additional gaits such as ambling gaits or pace. For instance, Icelandic Horses can tolt (ambling gait) and flying pace. The team decided to investigate the genetic basis for these locomotive differences.

Gus Cothran, a professor in the Animal Genetic Lab of the College of Veterinary Medicine & Biomedical Sciences at Texas A&M, and the team used a process called whole genome SNP analysis to study the genes of 70 Icelandic horses that had either four gaits or five, with the pace being the fifth gait.

The team sequenced the DMRT3 gene of the test horses and found that in almost every case of gaited horses, there was mutation in the DMRT3 that caused a premature stop codon which causes the protein product of the gene to be terminated before the whole protein is completed. This alters the function of the protein, which leads to the differences associated with the gait.

We suspected a strong genetic component, but were almost shocked when we discovered that a single gene, DMRT3, largely explained the genetic difference between pacers and non-pacers, explains Lisa Andersson one of the PhD students involved in the project.

A separate group of researchers from Uppsala University, led by Klas Kullander, found that this particular gene, DMRT3, is expressed in a previously unknown type of neuron in the spinal cord of mice. The characteristics of these neurons, including their location, suggested that these neurons could take part in the neuronal circuitry that coordinates movement.

When the two groups of scientists compared their data, they realized an important biological finding was imminent.

At that moment, we realized that our discovery did not only extend our understanding of spinal neuronal circuits in mice, but that we had discovered a tangible population of nerve cells that also seemed to be critical for the control of gaits in horses. The new type of nerve cell is dependent on DMRT3, and is tentatively named after this gene, said Kullander.

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Single Gene Has Impact On Gait Of Horses And Mice

ScienceDaily (Aug. 30, 2012) The WTX gene is mutated in approximately 30 percent of Wilms tumors, a pediatric kidney cancer. Like many genes, WTX is part of a family. In this case, WTX has two related siblings, FAM123A and FAM123C. While cancer researchers are learning more of WTX and how its loss contributes to cancer formation, virtually nothing is known of FAM123C or FAM123A, the latter of which is a highly abundant protein within neurons, cells that receive and send messages from the body to the brain and back to the body.

A UNC-led team of scientists used sophisticated technologies to identify and describe the protein interactions that distinguish each member of the WTX family. They found that unlike WTX and FAM123C, FAM123A interacts with a specific set of proteins that regulates cell adhesion and migration, processes essential to normal cell functioning and which, when mutated, contribute to human diseases such as cancer or Alzheimer's.

The report is the first to associate a member of the WTX gene family with cell adhesion and migration. Ben Major, PhD, and his research team believe that because FAM123A is so highly expressed in neurons, their findings raise the possibility that FAM123A controls neuron migration and neuronal activity, both of which play critical roles in development, neuro-degeneration and learning. Dr. Major, study senior author, is an assistant professor of cell biology and physiology in the UNC School of Medicine and a member of UNC Lineberger Comprehensive Cancer Center.

Their report appears in the September 4, 2012 online edition of Science Signaling.

The specific set of proteins the scientists discovered within the FAM123A complex are known microtubules-associated proteins. Microtubules, one component of a cell's cytoskeleton, are rigid hollow rods approximately 25 nm in diameter, about 3000 times thinner than a human hair. Microtubules are dynamic structures that undergo continual assembly and disassembly within the cell. They function both to determine cell shape and to control a variety of cell movements, including some forms of cell locomotion.

Dr. Major explains, "Since FAM123A and WTX are closely related proteins, anything we learn about FAM123A helps us know more about WTX, the tumor suppressor gene lost in pediatric kidney cancer. Unlike WTX, FAM123A binds to a specific set of proteins that are famous for regulating microtubules, a critical component within the cell's cytoskeleton or cellular 'scaffolding.' It's important to understand how different cellular cytoskeletal networks communicate and coordinate with each other. This communication is required for normal development and life.

"When the cytoskeleton is not functioning properly, a myriad of diseases arise, including certain cancers and cancer metastases. In cancer, cells can't move to new areas of the body without being able to squeeze between and crawl around surrounding cells and tissues, which ultimately allows the cell to move away from the primary tumor. Such movement requires complicated and intricate coordination between the cytoskeleton and the rest of the cell. Our work shows that FAM123A is critical for this communication."

Dr. Major and his research team use a powerful new technology to study protein complexes. He says, "Proteins never work alone, rather they bind each other to collectively carry out a specific task. An important challenge in cancer research today is determining which of the more than 30,000 proteins in a cell come together to form complexes." Dr. Major and colleagues can purify a specific protein from cancer cells and then, using sophisticated technologies called mass spectrometry, they identify the associated proteins.

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Cancer gene family member functions key to cell adhesion and migration

The California mouse (Peromyscus californicus) is a species of rodent in the family Cricetidae found in northwestern Mexico and central to southern California. Most rodents are polygamous, but the California mouse pair bonds, making it a model organism for researchers studying the genetics and implications of partner fidelity. Credit: The University of California, Berkeley

In the foothills of the Santa Cruz Mountains two closely related species of mice share a habitat and a genetic lineage, but have very different social lives. The California mouse (Peromyscus californicus) is characterized by a lifetime of monogamy; the deer mouse (Peromyscus maniculatus) is sexually promiscuous.

Researchers at the University of California Berkeley recently showed how these differences in sexual behavior impact the bacteria hosted by each species as well as the diversity of the genes that control immunity. The results were published in the May 2012 edition of PLoS One.

Monogamy is a fairly rare trait in mammals, possessed by only five percent of species. Rarely do two related, but socially distinguishable, species live side-by-side. This makes these two species of mice interesting subjects for Matthew MacManes, a National Institutes of Health-sponsored post-doctoral fellow at UC Berkeley.

Through a series of analyses, MacManes and researchers from the Lacey Lab examined the differences between these two species on the microscopic and molecular levels. They discovered that the lifestyles of the two mice had a direct impact on the bacterial communities that reside within the female reproductive tract. Furthermore, these differences correlate with enhanced diversifying selection on genes related to immunity against bacterial diseases.

Bacteria live on every part of our bodies and have distinctive ecologies. The first step of MacManes project involved testing the bacterial communities that resided in the vaginas of both species of micethe most relevant area for a study about monogamous and promiscuous mating systems.

Next, MacManes performed a genetic analysis on the variety of DNA present, revealing hundreds of different types of bacteria present in each species. He found that the promiscuous deer mouse had twice the bacterial diversity as the monogamous California mouse. Since many bacteria cause sexually transmitted infections (like chlamydia or gonorrhea), he used the diversity of bacteria as a proxy for risk of disease. Results of the study were published in Naturwissenschaften in October 2011.

But this wasn't the end of the exploration.

"The obvious next question was, does the bacterial diversity in the promiscuous mice translate into something about the immune system, or how the immune system functions?" MacManes asked.

MacManes hypothesized that selective pressures caused by generation after generation of bacterial warfare had fortified the genomes of the promiscuous deer mouse against the array of bacteria it hosts.

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Researchers use Ranger supercomputer to identify genetic differences related to social lives of mammals

Public release date: 30-Aug-2012 [ | E-mail | Share ]

Contact: Kristen Woodward kwoodwar@fhcrc.org 206-667-5095 Fred Hutchinson Cancer Research Center

SEATTLE African Americans have higher blood levels of a protein associated with increased heart-disease risk than European Americans, despite higher "good" HDL cholesterol and lower "bad" triglyceride levels. This contradictory observation now may be explained, in part, by a genetic variant identified in the first large-scale, genome-wide association study of this protein involving 12,000 African American and Hispanic American women.

Lead researcher Alexander Reiner, M.D., an epidemiologist at Fred Hutchinson Cancer Research Center, and colleagues describe their findings online ahead of the Sept. 7 print issue of the American Journal of Human Genetics.

Specifically, the researchers looked for genetic signposts associated with elevated levels of C-reactive protein, or CRP a marker of inflammation that is linked with increased risk of heart disease, diabetes and some cancers.

"Most previous studies examining the genetic determinants of elevated CRP have focused on tens of thousands of white individuals of European descent," said Reiner, a member of the Hutchinson Center's Public Health Sciences Division. "Since minorities African Americans and Hispanic Americans in particular tend to have higher CRP levels than other U.S. racial and ethnic groups, it's important to understand whether genetic factors might contribute to these differences."

Reiner and colleagues identified several genetic factors linked to CRP that are relatively specific to African Americans. They found a variation in TREM2, a family of genes on chromosome 6p21 that are expressed in white blood cells and appear to be important for regulating the degree of inflammation generated when white blood cells respond to infection or tissue injury.

"TREM genes were recognized relatively recently to be involved in inflammation and autoimmune disorders. Our finding adds further support to the importance of this gene family in generating and regulating inflammatory responses," said Reiner, who is also a professor of epidemiology at the University of Washington School of Public Health.

They also discovered that approximately 20 previously identified genetic factors associated with elevated CRP in whites are also shared among African Americans and Hispanic Americans genes that involve pathways related to innate immunity as well as metabolism of fat and sugar.

Identifying the genetic variants that regulate CRP levels may help researchers settle a point of scientific controversy: whether chronic, low-grade inflammation causes cardiovascular disease or whether it is just a reaction to the disease process of atherosclerosis, also known as hardening of the arteries.

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New genetic risk factor for inflammation identified in African-American women

Public release date: 30-Aug-2012 [ | E-mail | Share ]

Contact: Bonnie Prescott bprescot@bidmc.harvard.edu 617-667-7306 Beth Israel Deaconess Medical Center

BOSTON -- Two papers led by scientific teams from the Cancer Genetics Program at Beth Israel Deaconess Medical Center (BIDMC) shed new light on the genetic mechanisms underlying cellular energy and metabolism and, at the same time, highlight both the challenges and opportunities of genetic approaches to cancer treatment.

Appearing in the September 2012 issues of The Journal of Clinical Investigation (JCI) and Nature Medicine, the new findings reveal surprising insights into how PML regulates metabolism via the fatty acid oxidation (FAO) pathway and, in the process, uncover paradoxical roles for this tumor suppressor gene.

"The real story lies in the juxtaposition of these two papers, the way they jointly illuminate the braided function of PML in the FAO pathway," says the papers' senior author Pier Paolo Pandolfi, MD, PhD, Director of Cancer Genetics at BIDMC and George C. Reisman Professor of Medicine at Harvard Medical School. The Pandolfi laboratory has been studying the PML (promyelocytic leukemia protein) tumor suppressor gene, for more than 20 years.

Fatty-acid oxidation is the fat-burning metabolic process that is of importance to the energy of all cells. The two studies examined the impact of the FAO process in different biomedical situations including obesity, breast cancer and hematopoetic stem cell maintenance. Importantly, both publications determined that the FAO pathway could be a target for pharmacologic treatments.

The JCI paper defines the mechanism by which PML regulates FAO (involving the regulation of peroxisome proliferator-activated receptors or PPARs). According to first author Arkaitz Carracedo, PhD, a former postdoctoral fellow in the Pandolfi laboratory and currently Ikerbasque Research Professor at the research institute CIC bioGUNE, Bizkaia, Spain, the findings demonstrate that alterations in this pathway result in excessive fat accumulation and obesity in genetically engineered mouse models. In other words, when PML is highly expressed, cellular metabolism is enhanced and the mice were able to briskly burn fat and avoid gaining weight. Conversely, when PML was lost, the animals grew obese.

But, the team also made the paradoxical discovery that PML's enhanced cellular metabolism appeared to provide breast cancer cells with the energy needed to survive. These findings are further supported by data showing PML is highly expressed in a subset of breast cancers with poor prognosis, notes Carracedo. Instead of maintaining its function as a tumor suppressor and keeping breast cancer cells under control, PML is providing breast cancer with a survival advantage. These findings aligned with work by other labs that have found a relationship between high PML expression and breast cancers with poor prognosis.

In the second paper, in the September 2012 issue of Nature Medicine, Keisuke Ito, MD PhD, together with co-lead author Arkaitz Carracedo, looked at PML's role in regulating hematopoetic stem cells (HSCs), again through the FAO pathway, and defined for the first time the contribution of lipid metabolism to maintaining the function of HSCs.

HSCs replenish blood cells throughout the lifespan of an organism, and so they are critical to the aging process, explains Ito, also a former postdoctoral fellow in the Pandolfi laboratory and currently a member of the faculty at the Albert Einstein College of Medicine. The authors discovered that inhibition of fatty acid oxidation could represent an effective therapy for leukemia, as well as other forms of cancer but that it simultaneously posed a risk to the replenishment of HSCs. "Our results uncover a crucial metabolic requirement involving PPAR-delta signaling and FAO for preservation of the delicate equilibrium between HSC maintenance and function," the authors write. The findings have straightforward therapeutic implications for the improvement of both the efficacy of bone marrow transplantation (BMT) and the treatment of hematological malignancies.

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New research uncovers diverse metabolic roles for PML tumor suppressor gene