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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.

Ebola Virus Infection Blocked in Cell Culture Experiments

Using existing drugs that block activation of either the PI3K pathway or the CAMK2 pathway in cells, researchers have shown that Ebola virus infection can be reduced or entirely blocked in cell culture experiments. This may represent an early first step toward the first successful therapy for this deadly virus. Ebola inflicts severe and often fatal hemorrhagic fever on its victims, producing 90 percent mortality rates in some outbreaks. No vaccine exists for the virus, and it is considered a high-risk agent for bioterrorism. Natural Ebola outbreaks strike periodically, often with devastating effect; recent examples include outbreaks in Uganda in 2008 and the Democratic Republic of the Congo in 2007. "The premise for this work is that the virus is essentially nothing without a cell," said Dr. Robert Davey, lead author of the current report. "It needs to rely on many cell proteins and factors for it to replicate. The idea is that if we can suppress the expression of those cell proteins for just a short time, we can then stop the disease in its tracks." The two key cellular pathways upon which Ebola, in part, depends were identified by a combination of siRNA-based screening and a newly developed algorithm designed especially to prioritize the results of siRNA screens. After initial experiments with artificially created, lab-safe Ebola “pseudotype” viruses (i.e., viruses with the Ebola coat, but with the genetic core from another virus) gave promising results, additional experiments were carried out with real Ebola virus in a maximum containment facility (BSL4). “With the real virus in the BSL4, we found that the PI3K inhibitor dropped virus titers by 65 percent, and if we used drugs which block CAMK2 function, it was just killed — stopped dead," Dr. Davey said.

Serum DNA Analysis May Identify Early Presence of Disease

A new study further confirms the potential diagnostic and prognostic utility of using circulating fragments of DNA to detect early-stage disease, according to researchers from Chronix Biomedical and collaborating institutions who reported their findings online on May 27 in Zoonoses and Public Health. The DNA fragments, referred to as serum DNA, are released into the blood stream in trace amounts during the disease process. Chronix Biomedical has developed proprietary technology that it says can find, isolate, and identify these serum DNA sequences, enabling very early detection of an underlying disease state or of a change in response to treatment. In the current study, the researchers were able to identify specific signature sequences in serum DNA before clinical symptoms appeared in animals experimentally infected with BSE (bovine spongiform encephalopathy or mad cow disease). "These new results add to the growing body of scientific data validating the value of serum DNA as an early indicator of disease, and also advance our unique ability to apply these findings to the development of laboratory tests for routine clinical use," said Dr. Howard Urnovitz, CEO of Chronix, and one of the authors of the study. "Using our proprietary technology and next-generation sequencers, we were able to identify distinctive DNA signatures indicating the presence of BSE in all of the infected animals well before clinical symptoms appeared." These new findings follow three previous published studies demonstrating the utility of using serum DNA to identify human cancers, human infectious disease, and BSE. [Press release] [Zoonoses and Public Health abstract]

Superoxide May Help Birds Navigate

The molecule superoxide, normally thought of as toxic and cell-damaging, may be crucial to a migrating bird’s sense of direction according to researchers from the University of Illinois and Goethe University. The researchers proposed that superoxide interacts with a molecule called cryptochrome to help provide birds with a sense of geomagnetism. Cryptochrome is a blue-light photoreceptor found in plants and in the eyes of birds and other animals, including humans. The senior author of the current research, Dr. Klaus Schulten, was the first to propose (in 2000) that cryptochrome was a key component of birds' geomagnetic sense, a proposal that was later corroborated by experimental evidence. Dr. Schulten made this prediction after he and his colleagues discovered that magnetic fields can influence chemical reactions if the reactions occur quickly enough to be governed by pure quantum mechanics. “Prior to our work, it was thought that this was impossible because magnetic fields interact so weakly with molecules," he said. The rapid chemical reactions involve electron transfers, Dr. Schulten said, "which result in freely tumbling spins of electrons. These spins behave like an axial compass. Changes in the electromagnetic field, such as those experienced by a bird changing direction in flight, appear to alter this biochemical compass in the eye, allowing the bird to see how its direction corresponds to north or south." Dr. Schulten noted that “other researchers had found that cryptochrome, acting through its own molecular spins, recruits a reaction partner that operates at so-called zero spin. They suggested that molecular oxygen is that partner.

Sagebrush Recognizes Self, Warns of Danger

Researchers have shown that sagebrush plants that receive volatile cues from genetically identical cuttings accumulate less natural damage (e.g., from grasshoppers) than do plants receiving cues from non-self cuttings. Based on their results, the authors, Dr. Richard Karban of the University of California-Davis and Dr. Kaori Shiojiri of Kyoto University, concluded that volatile communication is required to coordinate systemic processes such as induced resistance, and that plants respond more effectively to self than non-self cues. They noted that this self/non-self discrimination did not require physical contact and suggested that it is a necessary first step towards possible kin recognition and kin selection. In earlier research, Dr. Karban had found that “volatile cues are required for communication among branches within an individual sagebrush plant. This observation suggests that communication between individuals may be a by-product of a volatile communication system that allows plants to integrate their own systemic physiological processes.” The current research appears in the June issue of Ecology Letters. [UC Davis press release] [Ecologoy Letters abstract]

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