Researchers Discover 'Green' Pesticide Effective Against Citrus Pests
Friday, January 20, 2012

University of Florida researchers have discovered a key amino acid essential for human nutrition is also an effective insecticide against caterpillars that threaten the citrus industry.

The Lime Swallowtail, or Citrus Swallowtail, is a well-known agricultural pest from southern Asia discovered in the Caribbean in 2006, and researchers say its potential impact on the U.S. citrus industry is cause for serious concern.

“Everything that’s in the Caribbean eventually gets to Florida – Florida is an invasive magnet,” said UF lepidopterist Delano Lewis, lead author of the study published in the current issue of the Journal of Economic Entomology. “That’s why we’re trying to make the first strike to see how to stop it.”

Experiments conducted on the UF campus at the Florida Museum of Natural History’s McGuire Center for Lepidoptera and Biodiversity and the College of Medicine show when methionine is sprayed on leaves it is 100 percent effective in killing larvae related to the Lime Swallowtail caterpillars within two to three days. If not controlled, the caterpillars can completely defoliate young wild lime plants.

Because the Lime Swallowtail, Princeps (Papilio) demoleus, is invasive and cannot be legally brought into the U.S., researchers experimented using a genetically related surrogate with a similar life history and appetite for citrus, the Giant Swallowtail, Heraclides (Papilio) cresphontes. Because these pest caterpillars have the same body structure and biology, researchers are confident methionine will also control the Lime Swallowtail, Lewis said.

“Its effectiveness is based on the biochemistry of the insect gut, so although this work was done on a surrogate, the methionine will block the ion channel in the same way,” Lewis said.

Methionine is needed in the human diet for many reasons, including protein-building and metabolism. It is environmentally safe and harmless to citrus plants, mammals and birds.

“It’s a very curious phenomenon to have this nutrient amino acid that humans can’t live without, yet at the concentrations we put on the leaves, it is toxic to crop-destructive caterpillars,” said study co-author Bruce Stevens, professor of physiology and functional genomics in the UF College of Medicine. “It’s a completely different class of pesticides that has not been seen before – most are toxic to not only the pest, but to people and animals, too.”

Stevens first discovered the pesticide properties of methionine while cloning genes that regulate amino acid metabolism in 1998. Working with co-author James Cuda of UF’s department of entomology and nematology, Stevens later found this amino acid to be effective against yellow fever mosquito larvae, tomato hornworm and Colorado potato beetle.

Methionine disrupts an ion channel that controls nutrient absorption in larvae with an alkaline intestine, such as in caterpillars of the Citrus Swallowtail. In 2004 and 2007, Stevens obtained two patents for the use of methionine as a pesticide, through the UF Office of Technology Licensing.

“The methionine is sprayed on the leaves, and when the caterpillars begin to eat the leaves, they ingest the compound – it’s not in the plant itself,” Lewis said. “Once they take those first few bites, they don’t feed again and remain stationary until they die.”

Methionine is low-cost and serves as fertilizer if it reaches the ground because it’s a biodegradable nitrogen source, Stevens said. The amino acid is mass produced and has been used as a nutritional supplement in outdoor livestock feed since the 1960s. The U.S. Department of Agriculture recently approved the use of methionine for organic poultry production.

“This is a neat idea and I’m hoping that more work will be done on this in the future because there’s a lot of potential there,” said John Ruberson, a professor in the entomology department at the University of Georgia, who was not involved in the study. “The one challenge I can see from a grower’s perspective is that it tends to work kind of slowly. Typically, it takes two to three days to kill the insect, but they do show that [insect] feeding is reduced, which is a good thing.”

Patent rights for the use of methionine to control turf and ornamental pests have been licensed to Phoenix Environmental Care LLC, which is developing a pest control product.

While researchers are unsure how the Lime Swallowtail reached the Caribbean, its proximity poses a potential threat to Central and South American citrus industries, as well.

“We suspect someone could have brought them to release the adult butterflies in weddings, or perhaps they arrived with imported citrus stock,” Lewis said. “Regardless, it’s in the Caribbean and it’s a very strong flyer.”

New clue in the battle against Australian Hendra virus
Friday, January 13, 2012

A new study on African bats provides a vital clue for unraveling the mysteries in Australia’s battle with the deadly Hendra virus.

The study focused on an isolated colony of straw-colored fruit bats on islands off the west coast of central Africa. By capturing the bats and collecting blood samples, scientists discovered these animals have antibodies that can neutralize deadly viruses known in Australia and Asia.

The paper is published today, 12 January, in the journal PLoS ONE, and is a collaboration of the Department of Veterinary Medicine at the University of Cambridge, the Zoological Society of London and the CSIRO Australian Animal Health Laboratory.

Hendra virus in Australia and Nipah virus in Asia are carried by fruit bats and sporadically “spill over” into people with tragic consequences. The findings of the new study are significant as they yield valuable insights for our understanding of how these viruses persist in bat populations.

Cambridge PhD student Alison Peel explains, “Hendra and Nipah viruses cause fatal infections in humans, but we currently understand very little about how the viruses are transmitted from bats to other animals or people. To understand what the risk factors for these ‘spill-overs’ are, it is crucial to understand how viruses are maintained in bat populations. The ability to study these viruses within an isolated bat colony has given us new insight into these processes.”

It was previously believed that these viruses were maintained in large interconnected populations of bats, so that if the virus dies out in one colony, it would be reintroduced when bats from different colonies interact. The new study indicates that a closely related virus is able to persist in a very small and isolated population of bats. This is the first time this has been documented in a natural wild population, casting doubt on current theories.

Peel added, “Although Hendra and Nipah viruses are relatively new to science, it appears that bats have lived and evolved with them over a very long time. We hope that by gaining a better understanding of this relationship, we may then be able to understand why it is only within the last 20 years that spill-over to humans has occurred.”

Hereditary Prostate Cancer Risk
Thursday, January 12, 2012

After a 20-year quest to find a genetic driver for prostate cancer that strikes men at younger ages and runs in families, researchers have identified a rare, inherited mutation linked to a significantly higher risk of the disease.

A report on the discovery was published in the January 12, 2012 issue of the New England Journal of Medicine. UNC-Chapel Hill scientist Ethan Lange, PhD, was part of the team of investigators at the Johns Hopkins University School of Medicine, the University of Michigan Health System, Wake Forest University and the Translational Genomics Research Institute.  

Lange is associate professor of genetics and biostatistics and a member of UNC Lineberger Comprehensive Cancer Center. The research team found that men with prostate cancer were 20 times more likely to carry this mutation than screened men without prostate cancer.

Lange explains, “For the first time we have identified an inherited high-risk mutation for prostate cancer. The mutation is significantly more common in men with a family history of prostate cancer that strikes at an earlier age, compared to older patients with no family history. Our findings suggest it could be a valuable early screening tool for men, particularly those with a family history of early-onset disease. The benefit to this population of men could be similar to the benefit of current screening strategies employed for BRCA1 and BRCA2 mutations in women with family history of early-onset breast cancer.

“There is still work to be done regarding understanding the biological function of the mutation and the precise level of absolute risk for carriers of this mutation - a process that took years for the BRCA1 and BRCA2 genes. Still, our results strongly suggest this is the most clinically important mutation identified for prostate cancer to date.”

While accounting for only a small fraction of all prostate cancer cases, the discovery may provide important clues about how this common cancer develops and help to identify a subset of men who might benefit from additional or earlier screening. This year, an estimated 240,000 men in the United States will be diagnosed with prostate cancer.

James P. Evans, MD, PhD, Bryson Distinguished Professor of Genetics in the UNC School of Medicine, leads UNC Lineberger’s clinical genetics program and is an internationally recognized expert in clinical cancer genetics. He was not involved in the study, but observes, “The genetics of prostate cancer have proven surprisingly difficult to unravel and this work represents significant and welcome progress. While fewer than one percent of Caucasian men carry the described mutation in this particular gene, for those men who do carry it, the increased risk for developing prostate cancer is likely greater than for any previous mutation found to date. Larger follow-up studies will be necessary to understand the importance of this finding for prostate cancer, and it remains to be seen whether this mutation is associated with other cancers.”

Lange and Kathleen Cooney, MD, one of two study senior authors, were the first to identify the human chromosome region of interest where the mutation, called HOXB13, was ultimately found. Lange, who has been a collaborator on Dr. Cooney’s University of Michigan Prostate Cancer Genetics Project for 17 years, led the statistical analyses and was actively involved in designing the study and interpreting the findings for the current study.

This particular mutation was found in families of European descent, while two different mutations on the HOXB13 gene were identified in families of African descent. Since only seven of the 94 families studied were of African descent, more research will be required before the significance of those mutations is known. African-American men are more likely to be diagnosed with prostate cancer at younger ages and have a more aggressive form of the disease.

Lange concludes, “Over the past couple years, genetic sequence analysis - the ability to evaluate nearly every base of the DNA code over large genomic regions as opposed to a relatively small number of preselected bases - has become possible for large research studies. The National Institutes of Health and private research companies have invested hundreds of millions of dollars into developing this technology, and our results represent one of the first successes demonstrating its use in identifying a strong but uncommon genetic risk factor for a common disease. This new technology should, in the near future, lead to many exciting discoveries of genes important to a wide range of common, complex human diseases.”

NIH Scientists Find Cause of Rare Immune Disease
Thursday, January 12, 2012

Investigators at the National Institutes of Health have identified a genetic mutation in three unrelated families that causes a rare immune disorder characterized by excessive and impaired immune function. Symptoms of this condition include immune deficiency, autoimmunity, inflammatory skin disorders and cold-induced hives, a condition known as cold urticaria.

The study was led by Joshua Milner, M.D., in the Laboratory of Allergic Diseases at the National Institute of Allergy and Infectious Diseases (NIAID), and Daniel Kastner, M.D., Ph.D., scientific director at the National Human Genome Research Institute (NHGRI). It will appear in the online edition of the New England Journal of Medicine on Jan. 11, 2012.

The mutation discovered occurs in a gene for phospholipase C-gamma2 (PLCG2), an enzyme involved in the activation of immune cells. The investigators have named the condition PLCG2-associated antibody deficiency and immune dysregulation, or PLAID. "Investigating rare diseases gives researchers more clues about how the healthy immune system functions," says NIAID Director Anthony S. Fauci, M.D. "More importantly, identifying the genetic cause of these disorders opens up possibilities for better disease management and potentially a cure for people who may have spent their entire lives debilitated by severe and unexplained symptoms."

The NIH study involved 27 people from three separate families who all suffered from an inherited form of cold urticaria, an allergic disease characterized by the formation of itchy, sometimes painful hives, episodes of fainting and, in certain cases, life-threatening reactions in response to cold temperatures.

Blood sample analysis revealed that many patients produced antibodies to their own cells and tissues (autoantibodies), making them more susceptible to developing autoimmune disease. More than half had a history of recurrent infections, and laboratory tests revealed that most had low levels of infection-fighting antibodies and low numbers and reduced activity of circulating immune B cells — all symptoms of immune deficiency disease. In three cases, patients had common variable immunodeficiency, a disease that requires frequent intravenous infusions of immune globulin to prevent severe infections. Seven patients suffered from granulomas, inflamed masses of tissue, which formed on their fingers, ears, nose and other parts of their skin.

"This is one of few examples in which the allergy symptom directed us to a genetic syndrome," says Dr. Milner. "In trying to understand the link between this group of conditions — autoimmunity, chronic infections and cold urticaria—we not only identified a disease-causing mutation but uncovered a unique and fascinating genetic mechanism at the crux of allergy, immune defense and self-tolerance."

"This study illustrates the power of multidisciplinary teamwork involving clinicians, geneticists and basic immunologists to get to the heart of seemingly insoluble medical mysteries," says Dr. Kastner. "Our team and colleagues working in the field now have much better odds of improving health outcomes for people with PLAID and for understanding this gene's role in other disorders."

The NIAID investigators teamed up with gene hunting experts in Dr. Kastner's laboratory and found the PLCG2 mutation after performing gene analysis and DNA sequencing studies. The mutation caused the PLCG2 enzyme to function without shutting off. Despite the fact that the enzyme was constantly turned on, immune cells ignored its signaling and did not activate normally.

Investigators performed a series of laboratory experiments to understand how the PLCG2 mutation affects B cells and mast cells, immune cells that contain histamine and other chemicals that are released during an allergic response. Patients' B cells containing the mutated gene fail to turn on normally, leading to their inability to produce antibody, but also an inability to sense when they are producing autoantibodies. Laboratory-developed mast cells containing the mutated gene released chemicals on exposure to cool temperatures, which could explain why the patients developed cold-induced hives.

According to the investigators, their findings suggest that inhibiting PLCG2 activity could be a therapeutic strategy to treat cold-induced hives, autoimmunity and immune deficiency in people with PLAID, but more studies are needed. The study findings also suggest that people previously diagnosed with common variable immunodeficiency disease or with granulomatous diseases could have a PLCG2 gene mutation. Further study is needed to understand PLAID and how mutations in PLCG2 could contribute to other allergic and immunologic disorders.

"These findings are gratifying both for researchers and for people with this disorder," says NHGRI Director Eric Green, M.D., Ph.D. "Furthermore, this study illustrates how genome-analysis methods can empower efforts to unravel the molecular basis of rare genetic diseases."

Honeybee Deaths Linked to Seed Insecticide Exposure

Wednesday, January 11, 2012

Honeybee populations have been in serious decline for years, and Purdue University scientists may have identified one of the factors that cause bee deaths around agricultural fields.

Analyses of bees found dead in and around hives from several apiaries over two years in Indiana showed the presence of neonicotinoid insecticides, which are commonly used to coat corn and soybean seeds before planting. The research showed that those insecticides were present at high concentrations in waste talc that is exhausted from farm machinery during planting.

The insecticides clothianidin and thiamethoxam were also consistently found at low levels in soil - up to two years after treated seed was planted - on nearby dandelion flowers and in corn pollen gathered by the bees, according to the findings released in the journal PLoS One this month.

"We know that these insecticides are highly toxic to bees; we found them in each sample of dead and dying bees," said Christian Krupke, associate professor of entomology and a co-author of the findings.

The United States is losing about one-third of its honeybee hives each year, according to Greg Hunt, a Purdue professor of behavioral genetics, honeybee specialist and co-author of the findings. Hunt said no one factor is to blame, though scientists believe that others such as mites and insecticides are all working against the bees, which are important for pollinating food crops and wild plants.

"It’s like death by a thousand cuts for these bees," Hunt said.

Krupke and Hunt received reports that bee deaths in 2010 and 2011 were occurring at planting time in hives near agricultural fields. Toxicological screenings performed by Brian Eitzer, a co-author of the study from the Connecticut Agricultural Experiment Station, for an array of pesticides showed that the neonicotinoids used to treat corn and soybean seed were present in each sample of affected bees. Krupke said other bees at those hives exhibited tremors, uncoordinated movement and convulsions, all signs of insecticide poisoning.

Seeds of most annual crops are coated in neonicotinoid insecticides for protection after planting. All corn seed and about half of all soybean seed is treated. The coatings are sticky, and in order to keep seeds flowing freely in the vacuum systems used in planters, they are mixed with talc. Excess talc used in the process is released during planting and routine planter cleaning procedures.

"Given the rates of corn planting and talc usage, we are blowing large amounts of contaminated talc into the environment. The dust is quite light and appears to be quite mobile," Krupke said.

Krupke said the corn pollen that bees were bringing back to hives later in the year tested positive for neonicotinoids at levels roughly below 100 parts per billion.

"That's enough to kill bees if sufficient amounts are consumed, but it is not acutely toxic," he said.

On the other hand, the exhausted talc showed extremely high levels of the insecticides - up to about 700,000 times the lethal contact dose for a bee.

"Whatever was on the seed was being exhausted into the environment," Krupke said. "This material is so concentrated that even small amounts landing on flowering plants around a field can kill foragers or be transported to the hive in contaminated pollen. This might be why we found these insecticides in pollen that the bees had collected and brought back to their hives."

Krupke suggested that efforts could be made to limit or eliminate talc emissions during planting.

"That's the first target for corrective action," he said. "It stands out as being an enormous source of potential environmental contamination, not just for honeybees, but for any insects living in or near these fields. The fact that these compounds can persist for months or years means that plants growing in these soils can take up these compounds in leaf tissue or pollen."

Although corn and soybean production does not require insect pollinators, that is not the case for most plants that provide food. Krupke said protecting bees benefits agriculture since most fruit, nut and vegetable crop plants depend upon honeybees for pollination. The U.S. Department of Agriculture estimates the value of honeybees to commercial agriculture at $15 billion to $20 billion annually.

Hunt said he would continue to study the sublethal effects of neonicotinoids. He said for bees that do not die from the insecticide there could be other effects, such as loss of homing ability or less resistance to disease or mites.

"I think we need to stop and try to understand the risks associated with these insecticides," Hunt said.

The North American Pollinator Protection Campaign and the USDA's Agriculture and Food Research Initiative funded the research.

President Obama Brings Hope to Future Space Exploration.

Monday, April 19, 2010

President Obama spoke at the Kennedy Space Center on April 15, 2010 about the new direction for NASA and America's Space Program.

Under Embargo Till: 16:00 UTC March 24, 2010
Posted: 16:00 UTC 03/24/2010

Emotions Key To Judging Others

Wednesday, March 24, 2010

A new study from MIT neuroscientists suggests that our ability to respond appropriately to intended harms — that is, with outrage toward the perpetrator — is seated in a brain region associated with regulating emotions.

Patients with damage to this brain area, known as the ventromedial prefrontal cortex (VMPC), are unable to conjure a normal emotional response to hypothetical situations in which a person tries, but fails, to kill another person. Therefore, they judge the situation based only on the outcome, and do not hold the attempted murderer morally responsible.

The finding offers a new piece to the puzzle of how the human brain constructs morality, says Liane Young, a postdoctoral associate in MIT’s Department of Brain and Cognitive Sciences and lead author of a paper describing the findings in the March 25 issue of the journal Neuron.

“We’re slowly chipping away at the structure of morality,” says Young. “We’re not the first to show that emotions matter for morality, but this is a more precise look at how emotions matter.”

Working with researchers at the University of Southern California, led by Antonio Damasio, Young studied a group of nine patients with damage (caused by aneurisms or tumors) to the VMPC, a plum-sized area located a few inches behind the eyes.

Such patients have difficulty processing social emotions such as empathy or embarrassment, but “they have a perfectly intact capacity for reasoning and other cognitive functions,” says Young.

The researchers gave the subjects a series of 24 hypothetical scenarios and asked for their reactions. The scenarios of most interest to the researchers were ones featuring a mismatch between the person’s intention and the outcome — either failed attempts to harm or accidental harms.

When confronted with failed attempts to harm, the patients had no problems understanding the perpetrator’s intentions, but they failed to hold them morally responsible. The patients even judged attempted harms as more permissible than accidental harms (such as accidentally poisoning someone) — a reversal of the pattern seen in normal adults.

“They can process what people are thinking and their intentions, but they just don’t respond emotionally to that information,” says Young. “They can read about a murder attempt and judge it as morally permissible because no harm was done.”

This supports the idea that making moral judgments requires at least two processes — a logical assessment of the intention, and an emotional reaction to it. The study also supports the theory that the emotional component is seated in the VMPC.

Young hopes to study patients who incurred damage to the VMPC when they were younger, to see if they have the same impaired judgment. She also plans to study patient reactions to situations where the harmful attempts may be directed at the patient and therefore are more personal.

Funded by the National Science Foundation, National Institute of Neurological Disorders and Stroke, National Institute on Drug Abuse, gifts from J. Epstein and S. Shuman.

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 Östervåla between Gävle 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 Härd 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.