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Comas in Locusts Offer Clues to Human Migraine and Stroke

Neural spreading depression (SD), a phenomenon in which neurons shut down, is associated with important human CNS pathologies, including migraine and stroke. Locusts undergo SD-like events when exposed to extremer conditions such as high temperature or lack of oxygen. The insects essentially go into a coma and emerge from it after the stress is removed. Now, a Queen’s University-Canada research team has shown that the ability of the locusts to resist entering the coma, and the speed of their recovery, can be manipulated using drugs that target one of the cellular signaling pathways in the brain, i.e., the nitric oxide/cyclic guanosine monophosphate/protein kinase G (NO/cGMP/PKG) pathway. "This suggests that similar treatments in humans might be able to modify the thresholds or severity of migraine and stroke," said Gary Armstrong, lead author of the report. "What particularly excites me is that in one of our locust models, inhibition of the targeted pathway completely suppresses the brain disturbance in 70 percent of animals," added Dr. Mel Robertson, senior author of the study. Noting that it is hard to drown an insect, due to its ability to remain safely in a coma under water for several hours, Mr. Armstrong said, "It's intriguing that human neural problems may share their mechanistic roots with the process insects use to survive flash floods." This research was reported in the June issue of the Journal of Neuroscience. [Press release] [Journal of Neuroscience abstract]

Compound Stops Diabetic Retinopathy in Experimental Systems

Researchers at the University of Oklahoma Health Sciences Center and the University of Nebraska Medical Center have found evidence that a natural angiogenic inhibitor known as plasminogen kringle 5 (K5) can be used to stop diabetic retinopathy, one of the leading causes of blindness in the United States. Diabetic retinopathy is caused by changes in blood vessels of the retina, the light-sensitive tissue at the back of the eye. In some people with diabetic retinopathy, blood vessels may swell and leak fluid. In other people, abnormal new blood vessels grow on the surface of the retina. Over time, diabetic retinopathy can worsen and cause some vision loss or blindness. The researchers found that this inflammation and leakage is caused by an imbalance of two systems in the eye. To restore this balance, they delivered K5 to cells using nanoparticle technology. In rat models, the treatment stopped the leakage, blocked inflammation, and kept unwanted blood vessels from growing. “There is no good treatment for retinopathy, which is why we are so excited about this work. This opens an entirely new area for pharmaceutical companies to target,” said Dr. Jay Ma, the senior author of the study. The discovery of K5’s function in inflammation and blood vessel formation related to eye disease means scientists may now possibly be able to develop new therapies, including eye drops, to stop diabetic retinopathy, a disease which affects as many as five million Americans with type 1 or type 2 diabetes. The researchers are now testing K5’s uses for cancer and age-related macular degeneration. The research results were reported online on June 2 in Diabetes. [Press release] [Diabetes abstract]

Interferon-Alpha May Delay Full Onset of Type 1 Diabetes

Results of a phase 2 trial indicate that a low dose of oral interferon-alpha may, for a period, preserve beta cell function in newly diagnosed type 1 diabetes (formerly juvenile diabetes). "It shows a strong trend in preserving insulin-producing beta cell function that is significantly better than placebo," said Dr. Staley Brod, principal investigator of the trial, which includes the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). "It can extend the 'honeymoon phase' of the disease, allowing the body to still produce insulin from beta cells, which correlates with decreased complication rates." A honeymoon phase sometimes occurs just after diagnosis as the body tries to rebound. Many patients experience a period when their need for insulin becomes minimal, control of blood sugar improves and beta cells partially recover. If the pancreas is still able to function, the highs and lows experienced by taking manufactured insulin can be decreased. The results of the phase 2 trial were published in the July issue of Diabetes Care. [Press release] [Diabetes Care abstract]

Desert Rhubarb Is “Self-Irrigating” Plant

Researchers from the University of Haifa-Oranim have discovered that the desert rhubarb in the mountains of Israel’s Negev desert is able to harvest 16 times as much water as other plants in the arid area that receives only 75 mm of rainfall annually. The scientists determined that the rhubarb achieves this feat by having unusually broad leaves that have ridged surfaces much resembling a mountain range. These ridged surfaces funnel water down to the ground surrounding the plant’s single deep root and serve essentially as a “self-watering” system. "We know of no other plant in the deserts of the world that functions in this manner," the researchers concluded. Most desert plants have very small leaves in order to minimize moisture loss and survive on the little rain water that penetrates the ground in their immediate area. In addition to the rhubarb’s harvesting much more water than small-leaved desert plants, experiments showed that water that funneled down the rhubarb’s leaves penetrated as deep as 10 cm into the ground, whereas water that simply fell on the ground penetrated only 1 cm deep. The image shows the desert rhubarb and is credited to Professor Gidi Ne'eman, University of Haifa. [Press release]

Long-Lived Bats Show Less Protein Damage

Bats generally live far longer than would be predicted by their size. Scientists have now shown that the relatively long life spans of some bat species, compared to the much shorter life spans of similarly sized mice, may owe to lower levels of protein oxidation and less misfolding of proteins in the bats. In addition, the researchers found that the bats had low levels of protein ubiquitination and reduced proteasome activity, suggesting diminished protein damage and removal in bats. Based on these results, the scientists concluded that long life span in some bat species may be regulated by very efficient maintenance of protein homeostasis. This work was featured as the cover story in the July issue of the FASEB Journal. [Press release] [FASEB abstract]

New Technique Shatters Barriers of Light Microscopy

In what may prove to be a profound advance, researchers have used a combination of light and ultrasound to visualize fluorescent proteins that are several centimeters below the surface of living tissue. In the past, even modern technologies have failed to produce high-resolution fluorescence images from this depth because of the strong scattering of light. Lead author Dr. Daniel Razansky, who played a pivotal role in developing the new method, said that it "opens the door to a whole new universe of research. For the first time, biologists will be able to optically follow the development of organs, cellular function, and genetic expression through several millimeters to centimeters of tissue.” To achieve its feat, the research team made light “audible.” They illuminated adult zebra fish from multiple angles using flashes of laser light that are absorbed by fluorescent pigments in the tissue of the genetically modified fish. The fluorescent pigments absorb the light, a process that causes slight local increases in temperature, which in turn result in tiny local volume expansions. This happens very quickly and creates small shock waves. In effect, the short laser pulse gives rise to an ultrasound wave that the researchers pick up with an ultrasound microphone. The real power of the technique, however, lies in specially developed mathematical formulas used to analyze the resulting acoustic patterns. An attached computer uses these formulas to evaluate and interpret the specific distortions caused by scales, muscles, bones, and internal organs to generate a three-dimensional image. The researchers performed similar successful experiments with fruit fly pupae. The research team included scientists from the Helmholtz Center Munich, Massachusetts General Hospital, and Harvard Medical School.

Three Toll-Like Receptors Implicated in Lupus

Researchers have shown that three particular Toll-like receptors (TLRs) may play a key role in the development of systemic lupus erythematosus (SLE or lupus), an autoimmune disease affecting over 1.5 million Americans. In mouse strains that spontaneously develop human-similar forms of SLE, the authors showed that TRL 3, TRL 7, and TRL 9 appear to be required for the full autoimmune response to take place. These TLRs may thus provide effective targets for the development of new treatments for lupus, as well as other autoimmune diseases. The researchers did their experiments by first engineering lupus-prone mice to have a non-functioning form of the gene (Unc93b1) that is required for transport of the three TRLs from where they are made to the cell’s endolysosome where they do their work. In the endolysosome, TLRs normally detect foreign DNA and RNA and instruct the body’s immune system to make antibodies against these materials. But the production of antibodies against foreign DNA and RNA seems to be particularly prone to error. The most common types of autoantibodies found in lupus patients are ones to the body's own genetic material—the DNA and RNA that resides inside the cell's nucleus. As a result, doctors often test for the presence of "antinuclear" antibodies to diagnose lupus. In their study, the researchers found that compared to the lupus-prone mice with a functioning Unc93b1 gene, the lupus-prone mice with the Unc93b1 mutation produced fewer antinuclear antibodies and had fewer and less severe symptoms of lupus. "It seems like these three TLRs are absolutely required for optimal autoantibody production," said Dr. Dwight Kono, an author of the study.

BioQuick Editor Wins Medical Writing Award

BioQuick News editor & publisher Michael D. O’Neill has been awarded an APEX 2009 award for publication excellence in the category of health and medical writing. Mr. O’Neill received his award for an article entitled “Surprising Finding Points to Possible Treatment for Huntington Disease.” The article was published in the Huntington Disease (HD) Lighthouse online magazine. The annual APEX awards recognize excellence in graphic design, editorial content, and overall communication effectiveness. Other APEX 2009 winners included individuals/publications from the Walt Disney Company, Sandia National Laboratories, Time Inc., Cleveland Clinic, Lockheed Martin, Multiple Sclerosis Association of America, AARP, WGBH, Toyota, Ford, Bank of America, Mount Sinai Medical Center, ESPN, Elsevier, US DOE, Charles Schwab, Wyeth Pharmaceuticals, Roche, Cisco, Xerox, Weber Shandwick, Sun Microsystems, and Eli Lilly. [APEX Awards] [Winning article]

Protein Targets Tumor Suppressor p53 for Destruction

Researchers at the M.D. Anderson Cancer Center have identified a protein (Trim24) that attaches ubiquitin molecules to p53 and thus targets the tumor suppressor for destruction in the proteasome. Experiments showed that decreased levels of Trim24 led to increased levels of p53 expression in the cell nucleus, and increasing Trim24 expression reduced p53 levels. Loss of Trim24 expression in a breast cancer cell line caused spontaneous programmed cell death (apoptosis). A similar response was confirmed in human lung, colon, and prostate cancer cells. “Targeting Trim24 may offer a therapeutic approach to restoring p53 and killing tumor cells," said Dr. Michelle Barton, senior author of the report, which appeared in the online edition of PNAS on June 25. [Press release] [PNAS abstract]

Tryptophan Deficiency May Underlie Side Effects of Malaria Treatment

Working in a yeast system, researchers have obtained evidence that the anti-malaria drug quinine might cause many of its adverse side effects by blocking a cell’s ability to take up the essential amino acid tryptophan. If confirmed, these findings would suggest that dietary tryptophan supplements could be a simple and inexpensive way to improve the performance of this important drug. Quinine is a very commonly used anti-malaria drug, yet, to this day, the principal mode of quinine action against the malaria parasite is largely unclear, as is the basis for adverse reactions like nausea, headaches, and blurred vision. In a screen of yeast mutants, the researchers found that strains unable to make tryptophan were extremely susceptible to quinine poisoning, which led the scientists to identify a tryptophan transporter as a key quinine target (yeast that cannot make their own tryptophan have to rely exclusively on external sources, and thus die if tryptophan transport is blocked). This discovery fits in well with evidence that, in humans, quinine reactions are more severe in malnourished individuals. Unlike yeast, humans cannot make their own tryptophan and thus require dietary tryptophan, which is abundant in meat but limited in yams, a staple food crop in the tropics where malaria is prevalent. If quinine severely reduces tryptophan uptake, then it follows that people with preexisting tryptophan deficiencies would be especially at risk from this drug. The authors also noted that tryptophan is important as a precursor for the brain chemical serotonin, so the enhanced tryptophan deficiency induced by quinine might explain why many of quinine's side effects are localized to the head region. This work was published online on June 26 in the Journal of Biological Chemistry.

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