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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]

Scat DNA Testing Permits Accurate Counting of Tigers

A study describing the successful application of fecal DNA testing to the accurate counting of tigers has been published by scientists from the Wildlife Conservation Society (WCS) and collaborating institutions. By testing the DNA in individual samples of tiger scat in a particular area, the scientists were able to obtain unique DNA signatures for particular tigers and use these data in computer models to estimate the tiger population in the area. "This study is a breakthrough in the science of counting tiger numbers, which is a key yardstick for measuring conservation success," said noted tiger scientist Dr. Ullas Karanth of the WCS, and an author of the study. "The technique will allow researchers to establish baseline numbers on tiger populations in places where they have never been able to accurately count them before." The study took place in India's Bandipur Reserve in Karnataka, a long-term WCS research site in the Western Ghats that supports a high abundance of tigers. Researchers collected 58 tiger scats following rigorous protocols, then identified individual animals through their DNA. Tiger populations were then estimated using sophisticated computer models. These results were validated against camera trap data, where individual tigers are photographed automatically and identified by their unique stripe patterns. Camera-trapping is considered the gold standard in tiger population estimation, but is impractical in several areas where tiger densities are low or field conditions too rugged. "We see genetic sampling as a valuable additional tool for estimating tiger abundance in places like the Russian Far East, Sunderban mangrove swamps, and dense rainforests of Southeast Asia where camera trapping might be impractical due to various environmental and logistical constraints," said Dr. Karanth.

New Approach to Anti-Anxiety Medication

Benzodiazepines (e.g., Valium) are fast-acting, effective anti-anxiety agents. However, they have side effects (sedation, tolerance development, and withdrawal symptoms) that can make them problematic for long-term use. Consequently, there is a need for medications that retain the rapid anti-anxiety effects of benzodiazepines, but lack their unfavorable side effects. Researchers have recently shown that a molecule called XBD173 might fill this bill. XBD173 is known to bind to the translocator protein (18 kD), formerly known as peripheral or mitochondrial benzodiazepine receptor. This translocator protein is believed to favor the production of certain neurosteroids that are potent positive modulators of GABA type A receptors that mediate the effects of the inhibitory neurotransmitter GABA in the mammalian nervous system. These neurosteroids produce pronounced anti-anxiety effects in animal models and their levels are reduced during panic attacks in humans with panic disorder. In the current work, the authors showed that XBD173 enhanced GABAergic neurotransmission and counteracted induced panic attacks in rodents, in the absence of sedation and tolerance development. XBD173 also exerted anti-panic activity in humans, and, in contrast to benzodiazepines, did not cause sedation and withdrawal symptoms. Therefore, the authors concluded that ligands of the translocator protein (18 kD) are promising candidates for fast-acting anti-anxiety drugs with less severe side effects than benzodiazepines. This work was published online on June 18 in Science Express. [Science abstract]

Merkel Cells Linked to Light-Touch Sensation

Scientists have demonstrated that the sensation of light touch, such as that which allows one to feel the fine texture of materials or lets the blind read Braille, depends on the activity of the long-mysterious Merkel cells, which are present in high numbers on our fingertips and lips. These cells form complexes with nerve fibers, and while these complexes are known to respond to light touches to the skin, the specific role of the Merkel cells has been controversial. The topic has been debated for more than 100 years, since the cells were first described in 1875 by German scientist Friedrich Merkel, who himself first proposed the link with light-touch sensation. The key to the current conclusive demonstration of the link was work with a transcription factor gene called Atoh1. When this gene was conditionally knocked out in the body skin and foot pads of mice, the resulting knockouts had no Merkel cells in these areas. The skin of these knockout mice did not show the same neurological responses to light touch that normal skin does, suggesting that Merkel cells enable their connecting neurons to resolve fine spatial details, the authors reported. "To our knowledge, Atoh1 is the first gene shown to be necessary for the specification of Merkel cells," the authors noted. "We don't know how any mammalian touch receptor works," added Dr. Ellen Lumpkin, of the Baylor College of Medicine, and a senior author on the report. "What genes allow them to function as light or painful touch receptors? This project gives us the experimental handle with which to start to dissect the genetic basis of touch." Among the other authors on the report were Dr. Huda Zoghbi and Dr. Stephen Maricich. This work was reported in the June 19 issue of Science. [Press release]

Bacteria Can Anticipate Events and Prepare for Them

Through evolution, bacteria and other microorganisms can “learn” to anticipate a future environmental event and prepare for it, according to recent research from the Weizmann Institute, Tel Aviv University, and Harvard Medical School. The research findings showed that certain microorganisms' genetic networks are hard-wired to "foresee" what comes next in a normally predictable sequence of events and to begin responding to the new state of affairs before its onset. This is analogous to classical Pavlovian conditioning. As an example, E. coli bacteria, which normally cruise harmlessly down the human digestive tract, encounter a number of different environments on their way. In particular, they find that one type of sugar, lactose, is invariably followed by a second sugar, maltose, soon afterward. The research team checked the bacterium's genetic response to lactose, and found that, in addition to the genes that enable it to digest lactose, the gene network for utilizing maltose was partially activated. When the researchers switched the order of the sugars, giving the bacteria maltose first, there was no corresponding activation of lactose genes, implying that bacteria have naturally "learned" to get ready for maltose following lactose. In addition, when E. coli were raised in an environment containing the first sugar, lactose, but not the follow-up with maltose, the bacteria evolved, after several months, to stop activating their maltose genes at the taste of lactose, only turning them on when maltose was actually available. Senior author Dr. Yitzhak Pilpel and his team believe that genetic conditioned responses may be a widespread means of evolutionary adaptation that enhances survival in many organisms, and may also take place in the cells of higher organisms, including humans.

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