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Archive - Nov 2012

Date

November 7th

Clots Can Sense Blood Flow

The disease atherosclerosis involves the buildup of fatty tissue within arterial walls, creating unstable structures known as plaques. These plaques grow until they burst, rupturing the wall and causing the formation of a blood clot within the artery. These clots also grow until they block blood flow; in the case of the coronary artery, this can cause a heart attack. New research from the University of Pennsylvania has shown that clots forming under arterial-flow conditions have an unexpected ability to sense the surrounding blood moving over them. If the flow stops, the clot senses the decrease in flow and this triggers a contraction similar to that of a muscle. The contraction squeezes out water, making the clot denser. Better understanding of the clotting dynamics that occur in atherosclerosis, as opposed to the dynamics at play in closing a wound, could lead to more effective drugs for heart attack prevention. The research was conducted by graduate student Ryan Muthard and Dr. Scott Diamond, professor and chair of the Department of Chemical and Biomolecular Engineering in the School of Engineering and Applied Science. Their work was published online on October 18, 2012 in the journal Arteriosclerosis, Thrombosis, and Vascular Biology, which is published by the American Heart Association. “Researchers have known for decades that blood sitting in a test tube will clot and then contract to squeeze out water,” Muthard said. “Yet clots observed inside injured mouse blood vessels don’t display much contractile activity. We never knew how to reconcile these two studies, until an unexpected observation in the lab.” Using a specially designed microfluidic device, the researchers pulsed fluorescent dye across a clot to investigate how well it blocked bleeding.

Soldier Beetle Defense Genes May Be Biotech Opportunity

New antibiotic and anti-cancer chemicals may one day be synthesized using biotechnology, following CSIRO's discovery of the three genes that combine to provide soldier beetles with their potent predator defense system. CSIRO researchers, and a colleague at Sweden's Karolinska Institute, published details of the gene identification breakthrough and potential applications online on October 23, 2012 in the international journal Nature Communications. "For the first time, our team has been able to isolate and replicate the three genes that combine to make the potent fatty acid that soldier beetles secrete to ward off predators and infection," said CSIRO Ecosystem Sciences research leader Dr. Victoria Haritos. "This discovery is important because it opens a new way for the unusual fatty acid to be synthesized for potential antibiotic, anti-cancer, or other industrial purposes," Dr Haritos said. Soldier beetles exude a white viscous fluid from their glands to repel potential attacks from predators, as well as in a wax form to protect against infection. The team found this fluid contains an exotic fatty acid called dihydromatricaria acid, or DHMA, which is one of a group called polyynes that have known anti-microbial and anti-cancer properties. While DHMA and similar polyyne fatty acids are found in a wide variety of plants, fungi, liverworts, mosses, marine sponges, and algae, these compounds have proved very difficult to manufacture using conventional chemical processes. However, Dr. Haritos and her team have developed a way to achieve this. "We have outlined a method for reproducing these polyyne chemicals in living organisms like yeast, using mild conditions," Dr Haritos said. Soldier beetles are the only animals reported to contain DHMA.

Highly Sensitive Sense of Touch Found in Crocodiles and Alligators

Crocodiles and alligators are notorious for their thick skin and well-armored bodies. So it comes as something of a surprise to learn that their sense of touch is one of the most acute in the animal kingdom. The crocodilian sense of touch is concentrated in a series of small, pigmented domes that dot their skin all over their body. In alligators, the spots are concentrated around their face and jaws. A new study, published as the cover story of the December 2012 issue of the Journal of Experimental Biology, has revealed that these spots contain a concentrated collection of touch sensors that make them even more sensitive to pressure and vibration than human fingertips. "We didn't expect these spots to be so sensitive because the animals are so heavily armored," said Duncan Leitch, the graduate student who performed the studies under the supervision of Dr. Ken Catania, Stevenson Professor of Biological Sciences at Vanderbilt. Scientists who have studied crocodiles and alligators have taken note of these spots, which they have labeled "integumentary sensor organs" or ISOs. Over the years they have advanced a variety of different hypotheses about their possible function. These include: source of oily secretions that keep the animals clean; detection of electric fields; detection of magnetic fields; detection of water salinity; and, detection of pressure and vibrations. In 2002, a biologist at the University of Maryland reported that alligators in a darkened aquarium turned to face the location of single droplets of water even when their hearing was disrupted by white noise. She concluded that the sensor spots on their faces allowed them to detect the tiny ripples that the droplets produced. "This intriguing finding inspired us to look further," Dr. Catania said.

November 7th

Stem Cells and Nanofibers Yield Promising Nerve Research

Every week in his clinic at the University of Michigan, neurologist Joseph Corey, M.D., Ph.D., treats patients whose nerves are dying or shrinking due to disease or injury. He sees the pain, the loss of ability, and the other effects that nerve-destroying conditions cause – and wishes he could give patients more effective treatments than what's available, or regenerate their nerves. Then he heads to his research lab at the VA Ann Arbor Healthcare System (VAAAHS), where his team is working toward that exact goal. In new research published in several recent papers, Dr. Corey and his colleagues from the U-M Medical School, VAAAHS, and the University of California, San Francisco (UCSF) report success in developing polymer nanofiber technologies for understanding how nerves form, why they don't reconnect after injury, and what can be done to prevent or slow damage. Using polymer nanofibers thinner than human hairs as scaffolds, researchers coaxed a particular type of brain cell to wrap around nanofibers that mimic the shape and size of nerves found in the body. They've even managed to encourage the process of myelination – the formation of a protective coating that guards larger nerve fibers from damage. They began to see multiple concentric layers of the protective substance called myelin start to form, just as they do in the body. Together with the laboratory team of their collaborator Dr. Jonah Chan at UCSF, the authors reported their findings in Nature Methods online on July 15, 2012. The research involves oligodendrocytes, which are the supporting actors to neurons -- the "stars" of the central nervous system. Without oligodendrocytes, central nervous system neurons can't effectively transmit the electrical signals that control everything from muscle movement to brain function.

New Drug Target Found for Cystic Fibrosis

Vancouver researchers have discovered the cellular pathway that causes lung-damaging inflammation in cystic fibrosis (CF), and determined that reducing the pathway’s activity also decreases inflammation. The finding offers a potential new drug target for treating CF lung disease, which is a major cause of illness and death for people with CF. “Developing new drugs that target lung inflammation would be a big step forward,” says Dr. Stuart Turvey, who led the research. Dr. Turvey is the director of clinical research and senior clinician scientist at the Child & Family Research Institute and a pediatric immunologist at BC Children’s Hospital. He is an associate professor in the Department of Pediatrics at the University of British Columbia. The research was published online on October 26, 2012 in the Journal of Immunology. For the study, researchers compared the immune response of normal lung cells with that of CF lung cells after exposing both types of cells to bacteria in the lab. In healthy cells, exposure to bacteria triggers the cell to secrete special molecules that attract immune cells to fight the infection. In CF lung cells, the researchers discovered that a series of molecular events called the unfolded protein response is more highly activated. It causes the CF lung cells to secrete more molecules that attract an excessive amount of immune cells, which leads to increased inflammation. They also found that treating the CF cells with a special chemical normalized the unfolded protein response and stabilized the cells’ immune response. CF is the most common genetic disease affecting young Canadians. One in every 3,600 children born in Canada has CF. There is no cure.

High SFRP4 Protein Reveals Diabetes Risk Many Years in Advance

When a patient is diagnosed with type 2 diabetes, the disease has usually already progressed over several years and damage to areas such as blood vessels and eyes has already taken place. To find a test that indicates who is at risk at an early stage would be valuable, as it would enable preventive treatment to be put in place. Researchers at Lund University in Sweden, together with colleagues, have now identified a promising candidate for a test of this kind. The findings were published in the November 7, 2012 issue of Cell Metabolism. "We have shown that individuals who have above-average levels of a protein called SFRP4 in the blood are five times more likely to develop diabetes in the next few years than those with below-average levels", says Dr. Anders Rosengren, a researcher at the Lund University Diabetes Centre (LUDC), who has led the work on the risk marker. It is the first time a link has been established between the protein SFRP4, which plays a role in inflammatory processes in the body, and the risk of type 2 diabetes. Studies at the LUDC, in which donated insulin-producing beta cells from diabetic individuals and non-diabetic individuals have been compared, show that cells from diabetics have significantly higher levels of the protein. It is also the first time the link between inflammation in beta cells and diabetes has been proven. "The theory has been that low-grade chronic inflammation weakens the beta cells so that they are no longer able to secrete sufficient insulin. There are no doubt multiple reasons for the weakness, but the SFRP4 protein is one of them", says Dr. Taman Mahdi, main author of the study and one of the researchers in Dr. Rosengren's group. The level of the protein SFRP4 in the blood of non-diabetics was measured three times at intervals of three years.

November 5th

Inhibition of NOX4 Enzyme Prevents Liver Fibrosis

Researchers at the Bellvitge Biomedical Research Institute (IDIBELL) in Barcelona, Spain, have led a study published on September 26, 2012 in the online journal PLoS One showing that the inhibition of a family member of NADPH oxidase enzyme, NOX4, plays an important role in liver fibrosis. The researchers studied the function of a cytokine called transforming growth factor-beta (TGF-beta) in the pathophysiology of the liver, which is one of the main research lines of the Biological Clues of the Invasive and Metastatic Phenotype research group at the IDIBELL, led by Dr. Isabel Fabregat. This paper is related to the processes of liver fibrosis, an illness caused by the overproduction of extracellular matrix proteins in the liver tissue. During fibrosis, levels of TGF-beta are increased, and there is an activation of the extracellular matrix producing the activation of protecting cells of the extracellular matrix and other possible events leading to the death of hepatocytes. The TGF-beta is a complex cytokine. It is a prominent tumor suppressor in early stages of tumor formation, but, in advanced stages, the cells adapt to escape from the growth inhibitory signals and, under these conditions, the TGF-beta is able to potentiate tumor progression, contributing to metastasis. The study published in PLoS One is a collaboration between IDIBELL and the research group of Dr. Wolfgang Mikulits, co-author of the study, at the Cancer Research Institute of the Medical University of Vienna (Austria), that has provided cellular and animal models. The analysis in patient samples has been possible thanks to the collaboration with the University Hospital Alcorcon Foundation and the Complutense University of Madrid.

Second Species of Mole Rat Has Different Anti-Cancer Mechanism

Biologists at the University of Rochester have determined how blind mole rats fight off cancer—and the mechanism differs from what they discovered three years ago in another long-lived and cancer-resistant mole rat species, the naked mole rat. The team of researchers, led by Professor Vera Gorbunova and Assistant Professor Andrei Seluanov, found that abnormally growing cells in blind mole rats secrete the interferon beta protein, which causes those cells to rapidly die. Drs. Seluanov and Gorbunova hope the discovery will eventually help lead to new cancer therapies in humans. Their findings were published November 5, 2012 in PNAS. Blind mole rats and naked mole rats—both subterranean rodents with long life spans—are the only mammals never known to develop cancer. Three years ago, Drs. Seluanov and Gorbunova determined the anti-cancer mechanism in the naked mole rat. Their research found that a specific gene—p16—makes the cancerous cells in naked mole rats hypersensitive to overcrowding, and stops them from proliferating when too many crowd together. "We expected blind mole rats to have a similar mechanism for stopping the spread of cancerous cells," said Dr. Seluanov. "Instead, we discovered they've evolved their own mechanism." Drs. Gorbunova and Seluanov made their discovery by isolating cells from blind mole rats and forcing them to proliferate in culture beyond what occurs in the animal. After dividing approximately 15-20 times, all of the cells in the culture dish died rapidly. The researchers determined that the rapid death occurred because the cells recognized their pre-cancerous state and began secreting a suicidal protein, called interferon beta.

November 4th

Exome Sequencing Identifies Novel Genes That May Drive Rare, Aggressive Form of Uterine Cancer

Researchers have identified several genes that are linked to one of the most lethal forms of uterine cancer, serous endometrial cancer. The researchers describe how three of the genes found in the study are frequently altered in the disease, suggesting that the genes drive the development of tumors. The findings appear in the October 28, 2012 advance online issue of Nature Genetics. The team was led by researchers from the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health. Cancer of the uterine lining, or endometrium, is the most commonly diagnosed gynecological malignancy in the United States. Also called endometrial cancer, it is diagnosed in about 47,000 American women and leads to about 8,000 deaths each year. Each of its three major subtypes — endometrioid, serous, and clear-cell —is caused by a different constellation of genetic alterations and has a different prognosis. Endometrioid tumors make up about 80 percent of diagnosed tumors. Surgery often is a complete cure for women with the endometrioid subtype, because doctors usually diagnose these cases at an early stage. Compared to other subtypes, the 2 to 10 percent of uterine cancers that comprise the serous subtype do not respond well to therapies. The five-year survival rate for serous endometrial cancer is 45 percent, compared to 65 percent for clear-cell and 91 percent for endometrioid subtypes. Serous and clear-cell endometrial tumor subtypes are clinically aggressive and quickly advance beyond the uterus. "Serous endometrial tumors can account for as much as 39 percent of deaths from endometrial cancer," said Daphne W. Bell, Ph.D., an NHGRI investigator and the paper's senior author. Dr. Bell heads the Reproductive Cancer Genetics Section of NHGRI's Cancer Genetics Branch.

November 4th

New Method Empowers Fluorescent Technology

The ability of fluorescence microscopy to study labeled structures like cells has now been empowered to deliver greater spatial and temporal resolutions that were not possible before, thanks to a new method developed by Beckman Institute faculty member Dr. Gabriel Popescu and Dr. Ru Wang from his research group. Using this method, the researchers were able to study the critical process of cell transport dynamics at multiple spatial and temporal scales and reveal, for the first time, properties of diffusive and directed motion transport in living cells. Dr. Popescu leads the Quantitative Light Imaging Laboratory at Beckman, while Dr. Wang of the lab is first author on the paper reporting the method online on November 2, 2012 in Physical Review Letters. The new approach, called dispersion-relation fluorescence spectroscopy (DFS), labels molecules of interest with a fluorophore whose motion, the researchers write, “gives rise to spontaneous fluorescence intensity fluctuations that are analyzed to quantify the governing mass transport dynamics. These data are characterized by the effective dispersion relation.” That ability to study the directed and diffusive transport characteristics of cellular dispersion through a wide range of temporal and spatial scales is more comprehensive than using just fluorescence microscopy. It provides more information than existing methods, such as fluorescence correlation spectroscopy (FCS), which is widely used for studying molecular transport and diffusion coefficients at a fixed spatial scale.