Wednesday, December 8, 2010

STEM CELLS FROM AMNIOTIC FLUID

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High hopes rest on stem cells: one day, they may be used to treat many diseases. To date, embryos are the main source of these cells, but this raises ethical problems. Scientists at the Max Planck Institute for Molecular Genetics in Berlin have now managed to convert amniotic fluid cells into pluripotent stem cells. These amniotic fluid-derived iPS cells are hardly distinguishable from embryonic stem cells - however, they "remember" where they came from.

The special abilities of embryonic stem cells can today be used in multiple "grown-up" cells (e.g. skin and hair cells). This is done by reprogramming the cells and converting them to "induced pluripotent stem cells" (iPS cells). These then possess the typical properties of embryonic stem cells, meaning they can generate any of the cell types of the human body (pluripotency), and they can multiply endlessly.

The scientists have shown that the amniotic fluid iPS cells can form different human cell types. They have also discovered that induced pluripotent stem cells can remember the original cell type from which they were generated. During cellular reprogramming, various genes that control the development of stem cells are apparently switched on or remain active. This confirms other current research results, which show that iPS cells derived from distinct tissues are prone to follow their pre-destined developmental path upon spontaneous differentiation. "We don't know just yet whether this donor-cell type memory will have an impact on possible medical treatment, or which type of somatic cell-derived iPS cell will be most suitable for treatment", cautions Katharina Wolfrum of the Max Planck Institute for Molecular Genetics.

Amniotic fluid cells have a number of advantages over other cell types. For one thing, amniotic fluid cells are routinely harvested in antenatal examinations to enable the early detection of disease. In most cases, more cells are obtained than are actually needed. In addition, the amniotic fluid mixture contains different types of cells from the unborn child, including stem-cell-like cells. As they are not very old, they have fewer environmentally-induced mutations, making them genetically more stable. "This may mean that it is possible to reprogram these amniotic fluid cells faster and more easily than other cell types, making amniotic fluid-derived iPS cells an interesting complement to embryonic stem cells", explains James Adjaye of the Max Planck Institute in Berlin.

Moreover, amniotic fluid cells could be extracted for cellular reprogramming before the birth of a child and be prepared for their intended use while the pregnancy is still ongoing. "This would make it possible to test which drugs work for a baby and whether they are tolerated, before that baby is born. Moreover, in the future, sick newborns can be treated with cells from their own body", says Adjaye.

(Photo: Max Planck Institute for Molecular Genetics)

Max Planck Institute

GENES LINK PUBERTY TIMING AND BODY FAT IN WOMEN

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Scientists have discovered 30 new genes that control the age of sexual maturation in women. Notably, many of these genes also act on body weight regulation or biological pathways related to fat metabolism.

The study, which appears in Nature Genetics, was a collaborative effort by the international ReproGen consortium, which included 175 scientists from 104 worldwide institutions, including Boston University School of Medicine (BUSM) and Boston University School of Public Health.

Menarche, the onset of first menstruation in girls, indicates the attainment of reproductive capacity and is a widely used marker of pubertal timing. Age of menarche varies widely and is highly dependent on nutritional status. Early menarche is associated with many adverse health outcomes later in life, including breast cancer, endometrial cancer, obesity, type 2 diabetes and cardiovascular disease, as well as shorter adult stature.

To identify loci for age at menarche, the researchers performed a meta-analysis of 32 genome-wide association studies on more than 87,000 women from the U.S., Europe and Australia and performed replication studies in nearly 15,000 additional women. In addition to the known loci at LIN28B and 9q31.2, the researchers identified 30 new menarche loci and found suggestive evidence for a further 10 loci. According to the researchers, the new loci included four previously associated with body mass index, three in or near other genes implicated in energy homeostasis and three in or near genes implicated in hormonal regulation. Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to timing of menarche.

“Our study found genes involved in hormone regulation, cell development and other biological pathways associated with mechanisms age at menarche, which shows that the timing of puberty is controlled by a complex range of biological processes,” said senior author Joanne Murabito, MD ScM, an associate professor of medicine at BUSM and Clinic Director and Investigator of the Framingham Heart Study.

“Several of the genes for menarche have been associated with body weight and obesity in other studies suggesting some women may have a genetic susceptibility to weight gain and early puberty. It is important to understand that these ‘genetic factors’ can be modified by changes in lifestyle. Efforts to reduce or prevent childhood obesity should in turn help reduce the early onset of puberty in girls,” added Murabito.

The next steps according to the researchers are to examine the findings in women of other race/ethnic groups, as well as to examine whether these genetic loci influence growth and to determine whether the associations are driven by measures of body fatness. This future work will help to unravel the biologic mechanism underlying the associations.

The researchers are extremely grateful to all study participants including women participating in the Framingham Heart Study for making this research possible. The investigators would also like to acknowledge the support provided by the National Institute on Aging and the National Heart, Lung and Blood Institute.

Boston University

FINDINGS SUGGEST NEW CAUSE, POSSIBLE TREATMENT FOR MULTIPLE SCLEROSIS

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Researchers have found evidence that an environmental pollutant may play an important role in causing multiple sclerosis and that a hypertension drug might be used to treat the disease.

The toxic substance acrolein was elevated by about 60 percent in the spinal cord tissues of mice with a disease similar to multiple sclerosis, said Riyi Shi, a medical doctor and a professor of neuroscience and biomedical engineering in Purdue University's Department of Basic Medical Sciences, School of Veterinary Medicine, Center for Paralysis Research and Weldon School of Biomedical Engineering.

The research results represent the first concrete laboratory evidence for a link between acrolein (pronounced a-KRO-le-an) and multiple sclerosis, he said.

"Only recently have researchers started to understand the details about what acrolein does to the human body," Shi said. "We are studying its effects on the central nervous system, both in trauma and degenerative diseases such as multiple sclerosis."

The toxic compound is found in air pollutants including tobacco smoke and auto exhaust. Acrolein also is produced within the body after nerve cells are damaged. Previous studies by this research team found that neuronal death caused by acrolein can be prevented by administering the drug hydralazine, an FDA-approved medication used to treat hypertension.

The new findings show that hydralazine also delays onset of multiple sclerosis in mice and reduces the severity of symptoms by neutralizing acrolein.

"The treatment did not cause any serious side effects in the mice," Shi said. "The dosage we used for hydralazine in animals is several times lower than the standard dosing for oral hydralazine in human pediatric patients. Therefore, considering the effectiveness of hydralazine at binding acrolein at such low concentrations, we expect that our study will lead to the development of new neuroprotective therapies for MS that could be rapidly translated into the clinic."

The researchers also learned the specific chemical signature of the drug that binds to acrolein and neutralizes it, potentially making it possible to create synthetic alternatives with reduced side effects. The studies are detailed in a paper appearing online this month in the journal Neuroscience. The paper was written by doctoral students Gary Leung, Wenjing Sun and Lingxing Zheng; graduate research assistant Melissa Tully, who is an MD-Ph.D. student at Purdue and the Indiana University School of Medicine; postdoctoral researcher Sarah Brookes; and Shi.

In multiple sclerosis, the myelin insulation surrounding nerve cells is destroyed and the nerve fibers themselves are damaged.

"We think that acrolein is what degrades myelin, so if we can block that effect then we can delay the onset of MS and lessen the symptoms," Shi said.

Acrolein induces the production of free radicals, compounds that cause additional injury to tissues after disease or physical trauma.

"We've discovered that acrolein may play a very important role in free radical injury, particularly in multiple sclerosis," Shi said.

The elevated acrolein levels in the MS mice were cut in half when treated with hydralazine. The drug represents a potential long-term therapy to slow the disease's progress.

"To our knowledge, this is the first evidence that acrolein acts as a neurotoxin in MS and also the first time anyone has demonstrated hydralazine to be a neuroprotective drug," Shi said.

Other researchers had previously shown that acrolein damages liver cells and that the damage can be alleviated by hydralazine, leading the Purdue researchers to study its possible effects on spinal cord tissues.

Further research will be conducted, and Shi's group has identified other potential compounds for binding acrolein. The research team, in a possible future collaboration with the Indiana University School of Medicine, also is working to improve the sensitivity of detection methods to measure acrolein levels in people with multiple sclerosis.

(Photo: Purdue University/Michel Schweinsberg)

Purdue University

TECHNOLOGY USES AUTO EXHAUST HEAT TO CREATE ELECTRICITY, BOOST MILEAGE

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Researchers are creating a system that harvests heat from an engine's exhaust to generate electricity, reducing a car's fuel consumption.

The effort is funded with a $1.4 million, three-year grant from the National Science Foundation and the U.S. Department of Energy. A Purdue University team is collaborating with General Motors, which is developing a prototype using thermoelectric generators, or TEGs, said Xianfan Xu, a Purdue professor of mechanical engineering and electrical and computer engineering.

TEGs generate an electric current to charge batteries and power a car's electrical systems, reducing the engine's workload and improving fuel economy.

The prototype, to be installed in the exhaust system behind the catalytic converter, will harvest heat from gases that are about 700 degrees Celsius, or nearly 1,300 degrees Fahrenheit, Xu said.

Current thermoelectric technology cannot withstand the temperatures inside catalytic converters, where gases are about 1,000 degrees Celsius, he said. However, researchers also are working on new thermoelectrics capable of withstanding such high temperatures, a step that would enable greater fuel savings.

The project begins Jan.1. The first prototype aims to reduce fuel consumption by 5 percent, and future systems capable of working at higher temperatures could make possible a 10 percent reduction, said Xu, whose work is based at the Birck Nanotechnology Center in Purdue's Discovery Park.

The research team, led by Xu, involves Purdue faculty members Timothy Fisher, a professor of mechanical engineering; Stephen Heister, a professor of aeronautics and astronautics; Timothy Sands, the Basil S. Turner Professor of Engineering, a professor of materials engineering and electrical and computer engineering, and executive vice president for academic affairs and provost; and Yue Wu, an assistant professor of chemical engineering.

The thermoelectric material is contained in chips a few inches square that will be tailored for their specific location within the system.

"They are optimized to work best at different temperatures, which decrease as gas flows along the system," Xu said.

The researchers are tackling problems associated with the need to improve efficiency and reliability, to integrate a complex mix of materials that might expand differently when heated, and to extract as much heat as possible from the exhaust gases.

Thermoelectric materials generate electricity when there is a temperature difference.

"The material is hot on the side facing the exhaust gases and cool on the other side, and this difference must be maintained to continually generate a current," said Xu, who has been collaborating with GM in thermoelectric research for about a decade.

A critical research goal is to develop materials that are poor heat conductors.

"You don't want heat to transfer rapidly from the hot side to the cool side of the chip," Xu said. "You want to maintain the temperature difference to continuously generate current."

Researchers at GM are using a thermoelectric material called skutterudite, a mineral made of cobalt, arsenide, nickel or iron.

"The biggest challenge is system-level design - how to optimize everything to get as much heat as possible from the exhaust gas," Xu said. "The engine exhaust has to lose as much heat as possible to the material."

Rare-earth elements, such as lanthanum, cesium, neodymium and erbium, reduce the thermal conductivity of skutterudite. The elements are mixed with skutterudite inside a furnace. Because using pure rare-earth elements is costly, researchers also are working to replace them with alloys called "mischmetals."

The work builds on previous research at Purdue involving the National Science Foundation, the Defense Advanced Research Projects Agency, the Air Force Office of Scientific Research and the Rolls-Royce University Technology Center.

Findings, as well as teaching- and research-oriented materials from the project will be provided via websites including Purdue's nanoHUB and thermalHUB Web portals. The research will provide graduate and undergraduate students with training in interdisciplinary areas and industrial experience through internships.

Thermoelectric technologies also might be used in other applications such as harnessing waste heat to generate electricity in homes and power plants and for a new type of solar cell and solid-state refrigerator, Xu said.

(Photo: Purdue University/Mark Simons)

Purdue University

IN FENDING OFF DISEASES, PLANTS AND ANIMALS ARE MUCH THE SAME

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It may have been 1 billion years since plants and animals branched apart on the evolutionary tree, but down through the ages they have developed strikingly similar mechanisms for detecting microbial invasions and resisting diseases.

This revelation was arrived at over a period of 15 years by teams of researchers from seemingly disparate fields who have used classical genetic studies to unravel the mysteries of disease resistance in plants and animals, according to a historical overview that will appear in the Nov. 19 issue of the journal Science.

The report, written by Pamela Ronald, a UC Davis plant pathologist, and Bruce Beutler, an immunologist and mammalian geneticist at The Scripps Research Institute, describes how researchers have used common approaches to tease apart the secrets of immunity in species ranging from fruit flies to rice. It also forecasts where future research will lead.

“Increasingly, researchers will be intent on harnessing knowledge of resistance and immune responses to advance plant and animal health,” said Ronald, who was a co-recipient of the 2008 U.S. Department of Agriculture’s National Research Initiative Discovery Award for work on the genetic basis of flood tolerance in rice.

“Some of the resistance mechanisms that researchers will discover will likely serve as new drug targets to control deadly bacteria for which there are currently no effective treatments,” she said.

At the heart of this research saga are receptors -- protein molecules usually found on cell membranes -- that recognize and bind to specific molecules on invading organisms, signaling the plant or animal in which the receptor resides to mount an immune response and fend off microbial infection and disease.

Beutler and Ronald have played key roles in this chapter of scientific discovery. In 1995, Ronald identified the first such receptor -- a rice gene known as known as Xa21 -- and in 1998, Beutler identified the gene for the first immune receptor in mammals -- a mouse gene known as TLR4.

Their overview in Science includes illustrated descriptions of the disease-resistance or immunity pathways in the mouse, Drosophila fruit fly, rice and a common research plant known as Arabidopsis. These represent the immune defense systems of vertebrates, insects, monocotyledons (grasslike plants) and dicotyledons (plants such as beans that have two seed leaves.)

The researchers note that plant biologists led the way in discovering receptors that sense and respond to infection. The 1980s brought about an intense hunt for the genes that control production of the receptor proteins, followed by an “avalanche” of newly discovered receptor genes and mechanisms in the 1990s.

Another milestone included discovery in 2000 of the immune receptor in Arabidopsis known as FLS2 -- which demonstrated that a plant receptor could bind to a molecule that is present in many different microbial invaders.

The review also discuses how plant and animal immune responses have evolved through the years and which mechanisms have remained the same.

While the past 15 years have been rich in significant discoveries related to plant and animal immunity, Beutler and Ronald are quick to point out that researchers have just scratched the surface.

“If you think of evolution as a tree and existing plant and animal species as the leaves on the tips of the tree’s branches, it is clear that we have examined only a few of those leaves and have only a fragmentary impression of what immune mechanisms exist now and were present in the distant past,” said Beutler, an elected member of the U.S. National Academy of Sciences.

He and Ronald predict that, as results from new gene sequencing projects become available, scientists will likely find that some plant and animal species emphasize specific resistance mechanisms while having little use for others.

For example, the researchers point out that the Drosophila’s immune system depends on only one immunologically active receptor, known as the Toll receptor, to sense invasion by fungi and gram-positive bacteria. In contrast, Arabidopsis has dozens of sensors to protect against microbial infections, and rice has hundreds.

Ronald and Beutler project that many surprises will be uncovered by future research as it probes the disease-resistance mechanisms of other species.

(Photo: UC Davis/iStock)

UC Davis

BACTERIA USE TOXIC DARTS' TO DISABLE EACH OTHER, ACCORDING TO UCSB SCIENTISTS

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In nature, it's a dog-eat-dog world, even in the realm of bacteria. Competing bacteria use "toxic darts" to disable each other, according to a new study by UC Santa Barbara biologists. Their research is published in the journal Nature.

"The discovery of toxic darts could eventually lead to new ways to control disease-causing pathogens," said Stephanie K. Aoki, first author and postdoctoral fellow in UCSB's Department of Molecular, Cellular, and Developmental Biology (MCDB). "This is important because resistance to antibiotics is on the rise."

Second author Elie J. Diner, a graduate student in biomolecular sciences and engineering, said: "First we need to learn the rules of this bacterial combat. It turns out that there are many ways to kill your neighbors; bacteria carry a wide range of toxic darts."

The scientists studied many bacterial species, including some important pathogens. They found that bacterial cells have stick-like proteins on their surfaces, with toxic dart tips. These darts are delivered to competing neighbor cells when the bacteria touch. This process of touching and injecting a toxic dart is called "contact dependent growth inhibition," or CDI.

Some targets have a biological shield. Bacteria protected by an immunity protein can resist the enemy's disabling toxic darts. This immunity protein is called "contact dependent growth inhibition immunity." The protein inactivates the toxic dart.

The UCSB team discovered a wide variety of potential toxic-tip proteins carried by bacteria cells –– nearly 50 distinct types have been identified so far, according to Christopher Hayes, co-author an associate professor at MCDB. Each bacterial cell must also have immunity to its own toxic dart. Otherwise, carrying the ammunition would cause cell suicide.

Surprisingly, when a bacterial cell is attacked –– and has no immunity protein –– it may not die. However, it often ceases to grow. The cell is inactivated, inhibited from growth. Similarly, many antibiotics do not kill bacteria; they only prevent the bacteria from growing. Then the body flushes out the dormant cells.

Some toxic tips appear to function inside the targeted bacteria by cutting up enemy RNA so the cell can no longer synthesize protein and grow. Other toxic tips operate by cutting up enemy DNA, which prevents replication of the cell.

"Our data indicate that CDI systems are also present in a broad range of bacteria, including important plant and animal pathogens such as E. coli which causes urinary tract infections, and Yersinia species, including the causative agent of plague," said senior author David Low, professor of MCDB. "Bacteria may be using these systems to compete with one another in the soil, on plants, and in animals. It's an amazingly diverse world."

The team studied the bacteria responsible for soft rot in potatoes, called Dickeya dadantii. This bacteria also invades chicory leaves, chrisanthemums, and other vegetables and plants.

(Photo: George Foulsham, Office of Public Affairs, UCSB)

UCSB

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