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Archive - 2009

June 18th

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]

June 17th

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.

Triumphant Return of the Large Blue Butterfly

An upcoming report in Science celebrates the 25-year effort to restore the large blue butterfly (Maculinea arion) in the UK, where it reached extinction in 1979. Meticulous research showed that the extinction was caused by a subtle change in habitat that disrupted the unusual life cycle of this spectacular butterfly. Previously, the extinction had been attributed to the work of overzealous collectors. Adult M. arion females lay their eggs on thyme flowers in the summer. After hatching, the caterpillars stay very small and many eventually fall to the ground. They secrete chemicals that attract red ants and fool them into thinking the caterpillars are ant grubs. The ants then carry the tiny caterpillars into their underground nests. In most cases, only caterpillars that have landed in the nest of one particular ant species, Myrmica sabuleti, will survive to adulthood. The caterpillars' secretions are a sufficiently close match to those of M. sabuleti grubs that the ants never discover that they have been duped, and instead continue to protect the caterpillars for 10 months even though they are feeding on the ants' own brood. In early June, the caterpillars form a chrysalis near the colony entrance and then emerge to crawl aboveground two weeks later as butterflies. Using laboriously collected field data, lead author Dr. Jeremy Thomas and his coauthors explored the possible factors that could be causing the butterflies’ decline. They realized that the grass in the butterflies' habitat had grown too long, as farmers had gradually stopped grazing their livestock on these hillsides and a viral infection had killed many of the wild rabbits in the 1950s. The soil on these overgrown grasslands was therefore too cool to support adequate numbers of M. sabuleti ants.

June 16th

Blood Test Detects Marker for Human Aging

Levels of a well-known tumor suppressor protein, p16INK4a, increase sharply with age in most mammalian tissues, and these increases contribute to an age-induced functional decline of certain self-renewing compartments. Researchers at the University of North Carolina have now shown that p16INK4 can be detected in peripheral blood T-lymphocytes (PBTL) and that its expression levels are strongly correlated with an individual's chronological age and, in fact, increase exponentially with age. In addition, increased expression levels of p16INK4a were independently associated with certain behaviors (tobacco use and physical inactivity) known to accelerate human aging. p16INK4a levels were also associated with a biomarker of human frailty. The authors said that the data suggest that p16INK4 expression in PBTL is an easily measured, peripheral blood biomarker of molecular age. "This is a major step toward a practical tool to clinically determine a person's actual molecular, as opposed to just their chronological, age," said Dr. Norman Sharpless, the senior author of the study. "Although we don't know whether this test is a good reflection of cellular age in all types of human tissues, we believe it is a first step toward a better understanding of issues like the suitability of organs for transplantation, how well patients are likely to recover after surgery, or the future toxicity of chemotherapy for cancer patients," he added. This work was published online ahead of pring in Aging Cell. [Press release] [Aging Cell abstract]

Spectroscopy Technology May Detect Early Alzheimer’s

Researchers have shown that the use of near-infrared (NIR) biospectroscopy to detect indicators of changes in oxidative stress levels in blood plasma may be a useful approach to the early identification of Alzheimer’s disease (AD). The procedure is minimally invasive, rapid, and relatively inexpensive. There is currently no accepted laboratory test for diagnosing AD. Diagnosis is based solely on a patient's medical history and neurological examination, is labor-intensive and expensive, and is often inconclusive in early stages of the illness. The availability of a biologic marker (in this case, a chemical signature of indicators of oxidative stress levels) that reliably differentiates AD from normal aging and other dementing conditions would represent a major achievement in the management of this common neurodegenerative disorder. In differentiating AD patients from the normal elderly control group, the NIR biospectroscopy approach achieved a sensitivity of 80% and specificity of 77%. "These results demonstrate the potential for NIR biospectroscopy to differentiate mild, and possibly pre-clinical, Alzheimer's disease from normal aging with high accuracy," said Dr. Hyman Schipper, senior author of the study. "We are very encouraged by these data and look forward to testing this potential diagnostic tool in larger-scale studies." This work was published in the June issue of the Journal of Alzheimer’s Disease. [Press release 1] [Press release 2] [June issue of JAD]

Targeted Nanoparticles May Improve on Whole-Body Chemotherapy

Researchers using nanoparticles with attached molecules of folic acid and containing the widely-used anti-cancer drug taxol have shown that it may be possible to target cancer cells specifically and thus avoid the multiple side effects that are seen with toxic whole-body chemotherapies such as taxol. The specificity is built upon cancer cells’ high consumption of folic acid. In addition to taxol, the nanoparticles contain a fluorescent dye and an iron oxide magnetic core. Thus, the location of the nanoparticles within cells and the body can be detected with optical imaging and magnetic resonance imaging. This allows the physician to see how the tumor is responding to the treatment. The nanoparticles can also be engineered without the drug and used as imaging (contrast) agents for cancer. If there is no cancer, the biodegradable nanoparticles will not bind to the tissue and will be eliminated by the liver. The iron oxide core will be utilized as regular iron in the body. "What's unique about our work is that the nanoparticle has a dual role, as a diagnostic and therapeutic agent, in a biodegradable and biocompatible vehicle," said Dr. J. Manuel Perez, senior author of the report. This research, by scientists at the University of Central Florida and the Memorial Sloan-Kettering Cancer Center, was published in the journal Small. [Press release] [Small abstract]

June 15th

Electronic Nose May Sniff Out Early Kidney Disease

Scientists may have discovered an ingenious way to detect chronic renal failure (CRF) at its earliest and most treatable stages. The method would involve the electronic detection of volatile molecules found in the breath of those with developing kidney disease, but not in the breath of those without kidney disease. The promise of this approach was supported by experiments in rats where an “electronic nose” was used to detect 27 volatile organic compounds that appear in the breath of rats with no kidney function, but not in the breath of rats with normal kidney function. The “electronic nose” is based on a technology in which a semi-conductive random network of single-walled carbon nanotubes and insulating nonpolymeric organic materials provides arrays of chemically sensitive resistive vapor detectors. The results presented in this study raise expectations for future capabilities for diagnosis, detection, and screening various stages of kidney disease, the researchers said, noting that the tests could detect patients with early disease, when it is possible to control blood pressure and protein intake to slow disease progression. The researchers pointed out that the blood and urine tests now used to diagnose CRF can be inaccurate and may come out "normal" even when patients have lost 75 percent of their kidney function. The most reliable test, a kidney biopsy, is invasive and may result in infections and bleeding. Doctors have long hoped for better tests for early detection of kidney disease. The current research was reported in the May 26 issue of the American Chemical Society journal ACS Nano. [ACS Nano abstract]

Microchannel Device Could Trap Cancer Cells

Scientists at Northwestern University have developed a novel method that can be used to separate metastatic cancer cells from normal cells. They have proposed that the method could be used to create a “cancer trap” using implantable and biodegradable materials. A device they have currently developed illustrates the method. The device takes advantage of a physical principle called ratcheting and is a very tiny system of microfluidic channels for cell locomotion. Each channel is less than a tenth of a millimeter wide. Asymmetric obstacles inside these channels direct cell movement along a preferred direction. To sort metastatic cancer cells from normal cells, the scientists took advantage of the cells' different shapes and mobility characteristics. Migrating cancer cells tend to be rounder and broader, while normal epithelial cells are long and thin with long protrusions on the ends. The researchers designed a channel with "spikes" (rachets) coming out at 45-degree angles from the walls, alternating on opposite sides of the channel. This pattern funnels cancer cells in one direction, while at the same time directing normal cells in the opposite direction. The researchers showed that a device with a number of these channels leading to a central reservoir, like spokes on a wheel, worked just as well at separating cancer and non-cancerous cells. A stack of these radially arranged ratchet channels could be used to create a "cancer trap," the researches suggested. "When implanted next to a tumor, the particles [stack of rachet channels] would guide cancer cells, but not normal cells, inward to the reservoir, where they would be trapped," said Dr. Bartosz Grzybowski, the paper's senior author.

Huntington Disease Clue Discovered

Researchers have demonstrated that mutated huntingtin protein, but not normal huntingtin, activates a neuron-specific protein (JNK3) which inhibits fast axonal transport, a system used to shuttle proteins from the nerve cell body, where they are made, to the synaptic terminals, where they are needed. This discovery might help explain the curious nervous system specificity of Huntington disease, even though the huntingtin protein is expressed in other parts of the body. "Inhibition of neuronal transport is enough to explain what is happening in Huntington's," asserted Dr. Scott Brady, senior author of the report. Loss of delivery of materials to the synaptic terminals results in loss of transmission of signals from the neuron. Loss of signal transmission causes the neurons to begin to die back, leading to reduced transmissions, more dying back, and eventual neuronal cell death. This mechanism might also explain the late onset of the disease, Dr. Brady said. Activation of JNK3 reduces transport, but does not eliminate it. Young neurons have a robust transport system, but transport gradually declines with age. "If you take a hit when you're very young, you still are making more and transporting more proteins in each neuron than you need," Dr. Brady said. "But as you get older and older, the neuron produces and transports less. Each hit diminishes the system further. Eventually, the neuron falls below the threshold needed to maintain cell health." This work was reported online on June 14 in Nature Neuroscience. [Press release] [Nature Neuroscience article]