New Method to Prevent Heart Attacks

Wednesday, March 17, 2010

Cardiovascular disease is by far the absolute most common national disease in Sweden and a little more than 26,000 people are treated every year at hospitals due to acute cardiac infarction, according to the Heart and Lung Foundation. KTH researcher Matilda Larsson at the School of technology and health at KTH has recently defended her thesis and her research aims at developing methods which can as early as possible assess the risk of cardiovascular disease.

The earlier the risk of cardiovascular disease can be identified, the easier it will be to avoid acute cardiac infarction which will save lives. But even if research and health care has been improved considerably over the past few years, cardiovascular disease even in the future will be one of the most common reasons for sickness and mortality in Sweden. That is why Matilda Larsson's research is, to say the least, of vital importance.

"One of the problems that we face today is that the methods used for risk assessment are new, and they need to be fine-tuned. The people that use the technology that is available must have considerable experience in being able to interpret the data they receive," says Matilda Larsson.

To rectify this problem, Matilda Larsson has developed the existing ultrasound technology so that the information is more easily accessible.

"By visualising the data, the doctor will find it easier to interpret the results," says Matilda Larsson.

The usual method is that the doctor measures the heart's blood flow and how the cardiac valves operate. With the Speckle tracking method, Matilda Larsson and her colleagues study how the ultrasound image's greyscale pattern changes, and she can also measure the movement patterns and deformation of the heart and the vascular tissue.

"The long-term objective is to have access to a sensitive method which can predict myocardial infarction at an early stage," says Matilda Larsson.
Her thesis is called "Quantification and visualisation of cardiovascular function using ultrasound" and she has applied for a patent for a method used within this area.

Matilda Larsson originally comes from Ostervala between Gavle and Uppsala, but she will not be returning there for quite some time.

"Now I will continue as a post doctoral student at the university in Leuven, Belgium, where I conducted some of my thesis work. We will study movements and deformation of the carotis," says Matilda.

Fruit flies and test tubes open new window on Alzheimer's disease

Tuesday, March 16, 2010

A team of scientists from Cambridge and Sweden have discovered a molecule that can prevent a toxic protein involved Alzheimer's disease from building up in the brain. They found that in test tube studies the molecule not only prevents the protein from forming clumps but can also reverse this process. Then, using fruit flies with Alzheimer's disease, they showed that the same molecule effectively "cures" the insects of the disease.

Alzheimer's disease is the most common neurodegenerative disorder and is linked to the misfolding and aggregation of a small protein known as the amyloid β (Aβ) peptide. Previous studies in animal models have shown that aggregation of Aβ damages neurones (brain cells) causing memory impairment and cognitive deficits similar to those seen in patients with Alzheimer's disease. The mechanisms underlying this damage are, however, still not understood.

The new molecule - designed by scientists in Sweden - is a small protein known as an Affibody (an engineered binding protein). In this new study, researchers at the University of Cambridge and the Swedish University of Agricultural Sciences found that in test-tube experiments this protein binds to the Aβ peptide, preventing it from forming clumps and breaking up any clumps already present.

In a second experiment, they studied the effect of this Affibody in a Drosophila (fruit fly) model of Alzheimer's disease previously developed at Cambridge.

Working with fruit flies that develop the fly equivalent of Alzheimer's because they have been genetically engineered to produce the Aβ protein, they crossed these flies with a second line of flies genetically engineered to produce the Affibody.

They found that offspring - despite producing the Aβ protein - did not develop the symptoms of Alzheimer's disease.

According to lead author Dr Leila Luheshi of the Department of Genetics at University of Cambridge: "When we examined these flies we found that the Affibody not only prevented and reversed the formation of Aβ clumps, it also promoted clearance of the toxic Aβ clumps from the flies' brains."

"Finding a way of preventing these clumps from forming in the brain, and being able to get rid of them, is a promising strategy for preventing Alzheimer's disease. Affibody proteins give us a window into the Alzheimer's brain: by helping us understand how these clumps damage brain cells, they should help us unravel the Alzheimer's disease process."

According to Professor Torleif Hard of the Swedish University of Agricultural Sciences and one of the senior authors of the study: "Our work shows that protein engineering could open up new possibilities in Alzheimer's therapy development."

Researchers Identify Gene that May Play Role in Atherosclerosis

Monday, March 15, 2010

To understand the role of inflammation in cardiovascular and other diseases, it is essential to identify and characterize genes that induce an inflammatory response in the body -- and the genes that regulate them.

A study published online this week in the journal Proceedings of the National Academy of Sciences suggests that a gene called Hu antigen R (HuR) plays a critical role in inducing and mediating an inflammatory response in cells experiencing mechanical and chemical stresses. The study was supported by the National Institutes of Health.

The findings may open up new possibilities for developing treatments of metabolic diseases associated with inflammation, such as atherosclerosis. Atherosclerosis typically occurs in branched or curved regions of arteries where plaques form because of cholesterol build-up. Inflammation can alter the structure of plaques so that they become more likely to rupture, causing a blood vessel blockage and leading to heart attack or stroke.

"This is the first systematic study showing that HuR not only responds to external stimuli as a stress-sensitive gene, but it also regulates other stress-sensitive genes," said senior author Gang Bao, the Robert A. Milton Chair in Biomedical Engineering in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.

The study results show that HuR promotes the expression of genes that support atherosclerosis and inhibits the expression of genes that combat atherosclerosis.

"We found that suppressing expression of HuR inhibited the inflammatory response of cells, which shows that designing drugs that block HuR function may reduce the risk of plaques rupturing," explained Bao.

Bao guided Won Jong Rhee, a former postdoctoral fellow in his laboratory, to conduct a series of experiments investigating the biology, behavior and pathways of HuR.

The researchers first studied how the HuR gene responds to different flow environments and chemical treatments. They exposed human umbilical vein endothelial cells to disturbed flow -- which occurs in artery regions where plaques form -- and found that the cells expressed higher levels of HuR than when they experienced a static or laminar flow environment. This finding was validated in tissue experiments with results showing increased amounts of HuR in regions of a mouse aorta that were exposed to disturbed flow.

Then the researchers treated endothelial cells with statins, medications used to treat atherosclerosis by reducing the number of cholesterol-containing low-density lipoprotein (LDL) molecules in the blood and inhibiting inflammation. The results indicated a decreased level of HuR with statin treatment.

After establishing HuR as a stress-sensitive gene regulated by external stimuli, including flow and statin treatment, the researchers conducted experiments to determine whether HuR regulates the expression of other stress-sensitive genes. They found that reducing the level of HuR in cells increased the levels of two genes that combat atherosclerosis -- Kruppel-like factor 2 (Klf2) and endothelial nitric oxide synthase (eNOS). The reduction in HuR also decreased the expression of bone morphogenic protein-4 (BMP-4), a gene that supports atherosclerosis.

Reducing the level of HuR in cells also significantly inhibited many inflammatory responses of the endothelial cells, including the expression of two potential atherosclerosis drug targets: inter-cellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1).

Though this study showed that HuR plays a critical role in inducing and mediating an inflammatory response in cells subjected to a stressful environment, the underlying mechanism for this regulation is still not known.

"HuR protein often binds to messenger RNAs to increase their stability and translation, but we found that regulation of other stress-sensitive genes by HuR was not due to changes in mRNA stability by direct protein binding," explained Bao.

To uncover the pathways that lead to HuR's stress sensitivity, the researchers conducted a series of studies to reveal that HuR functions by adding a phosphate group to the transcriptional factor nuclear factor kappa B (NFkB) and its inhibitor IkBa. Additional research is underway to reveal what mRNAs HuR binds to and the mechanisms used to respond to mechanical and chemical stresses. Identifying the triggers for inflammation and unraveling the details of inflammatory pathways may eventually furnish new therapeutic targets.

Hanjoong Jo, the Coulter Department's Ada Lee and Pete Correll Professor in Biomedical Engineering, Kyunghwa Chang, graduate student Chih-Wen Ni and research scientist Zhilan Zheng also contributed to this research.

Under Embargo Till: 19:00 UTC March 15, 2010
Posted: 19:00 UTC 03/15/2010

Scientists Demonstrate Mammalian Regeneration Through a Single Gene Deletion

Monday, March 15, 2010

A quest that began over a decade ago with a chance observation has reached a milestone: the identification of a gene that may regulate regeneration in mammals. The absence of this single gene, called p21, confers a healing potential in mice long thought to have been lost through evolution and reserved for creatures like flatworms, sponges, and some species of salamander. In a report published today in the Proceedings of the National Academy of Sciences, researchers from The Wistar Institute demonstrate that mice that lack the p21 gene gain the ability to regenerate lost or damaged tissue.

Unlike typical mammals, which heal wounds by forming a scar, these mice begin by forming a blastema, a structure associated with rapid cell growth and de-differentiation as seen in amphibians. According to the Wistar researchers, the loss of p21 causes the cells of these mice to behave more like embryonic stem cells than adult mammalian cells, and their findings provide solid evidence to link tissue regeneration to the control of cell division.

"Much like a newt that has lost a limb, these mice will replace missing or damaged tissue with healthy tissue that lacks any sign of scarring," said the project's lead scientist Ellen Heber-Katz, Ph.D., a professor in Wistar's Molecular and Cellular Oncogenesis program. "While we are just beginning to understand the repercussions of these findings, perhaps, one day we'll be able to accelerate healing in humans by temporarily inactivating the p21 gene."

Heber-Katz and her colleagues used a p21 knockout mouse to help solve a mystery first encountered in 1996 regarding another mouse strain in her laboratory. MRL mice, which were being tested in an autoimmunity experiment, had holes pierced in their ears to create a commonly used life-long identification marker. A few weeks later, investigators discovered that the earholes had closed without a trace. While the experiment was ruined, it left the researchers with a new question: Was the MRL mouse a window into mammalian regeneration?

The discovery set the Heber-Katz laboratory off on two parallel paths. Working with geneticists Elizabeth Blankenhorn, Ph.D., at Drexel University, and James Cheverud, Ph.D., at Washington University, the laboratory focused on mapping the critical genes that turn MRL mice into healers.

Meanwhile, cellular studies ongoing at Wistar revealed that MRL cells behaved very differently than cells from "non-healer" mouse strains in culture. Khamilia Bedebaeva, M.D., Ph.D., having studied genetic effects following the Chernobyl reactor radiation accident, noticed immediately that these cells were atypical, showing profound differences in cell cycle characteristics and DNA damage. This led Andrew Snyder, Ph.D., to explore the DNA damage pathway and its effects on cell cycle control.

Snyder found that p21, a cell cycle regulator, was consistently inactive in cells from the MRL mouse ear. P21 expression is tightly controlled by the tumor suppressor p53, another regulator of cell division and a known factor in many forms of cancer. The ultimate experiment was to show that a mouse lacking p21 would demonstrate a regenerative response similar to that seen in the MRL mouse. And this indeed was the case. As it turned out, p21 knockout mice had already been created, were readily available, and widely used in many studies. What had not been noted was that these mice could heal their ears.

"In normal cells, p21 acts like a brake to block cell cycle progression in the event of DNA damage, preventing the cells from dividing and potentially becoming cancerous," Heber-Katz said. "In these mice without p21, we do see the expected increase in DNA damage, but surprisingly no increase in cancer has been reported."

In fact, the researchers saw an increase in apoptosis in MRL mice -- also known as programmed cell death -- the cell's self-destruct mechanism that is often switched on when DNA has been damaged. According to Heber-Katz, this is exactly the sort of behavior seen in naturally regenerative creatures.

"The combined effects of an increase in highly regenerative cells and apoptosis may allow the cells of these organisms to divide rapidly without going out of control and becoming cancerous," Heber-Katz said. "In fact, it is similar to what is seen in mammalian embryos, where p21 also happens to be inactive after DNA damage. The down regulation of p21 promotes the induced pluripotent state in mammalian cells, highlighting a correlation between stem cells, tissue regeneration, and the cell cycle."

The study was supported by grants from the Harold G. and Leila Y. Mathers Foundation, the F.M. Kirby Foundation, the W.W. Smith Foundation, the National Institute for General Medical Sciences and National Cancer Institute.

Study investigators also include Wistar researchers Paul M. Lieberman, Ph.D.; Dmitri Gourevitch M.D.; Lise Clark D.V.M., Ph.D.; Xiang-Ming Zhang; and John Leferovich. Snyder, formerly of the Lieberman laboratory at Wistar, and Bedebaeva are co-first authors on this paper. James Cheverud of Washington University is also a co-author on this paper.

The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the country, Wistar has long held the prestigious Cancer Center designation from the National Cancer Institute. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible.

Developing Weed Resistance in Corn Hybrids

Monday, March 15, 2010

Millions of people in the savannas of west and central Africa rely on maize (corn) as a staple crop, and as an "insurance" food crop at the beginning of the rainy season. A destructive parasitic weed, Striga hermonthica, poses a threat to this valuable crop. Almost 64% of cropland in this area of Africa is affected by the parasite, which causes an average grain yield loss of 68%. Farmers in Striga-infested areas have not yet adopted Striga-resistant hybrids.

Scientists at the International Institute of Tropical Agriculture (IITA) in partnership with scientists in the University of Ibadan in Nigeria and the National Institute of Agricultural Research in Benin Republic investigated the relationship between the genetic diversity of maize inbred lines having different levels of resistance to Striga and the performance of their hybrids under parasite infestation. The results are reported in the March-April 2010 edition of


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