New Model Of Muscle Function From Toad Research

A toad sits at a pond's edge eyeing a cricket on a blade of grass. In the blink of an eye, the toad snares the insect with its tongue. This deceptively simple, remarkably fast feeding action offers a new look at how muscles work.



This fresh perspective could lead to designing more efficient electric motors, better prostheses and new medical treatments for neuromuscular diseases like Parkinson's.



Science has long held that muscles behave largely like motors. Northern Arizona University researcher Kiisa Nishikawa suggests that muscle acts more like a spring.



"Existing theories don't explain how muscles shorten rapidly," Nishikawa said. "Muscles can only shorten to do work; they can't do work by lengthening." A spring also can only do work by shortening.



By example, Nishikawa explains that the jaw muscles in toads and chameleons shorten in the lower jaw, and the opening of the jaws causes the tongue to stretch by its own momentum.



"When a toad or chameleon captures prey with its tongue, it exerts force over a distance. Figuring out how they do it has immense application to any device that actually moves."



A toad's jaw muscles can produce forces greater than 700 times the animal's weight. "The best electric motor achieves about one-third of that force-to-weight ratio," Nishikawa noted.



Muscles also function as self-stabilizing springs.



"They have built-in self-correcting mechanisms. Before the brain can even react, muscles are changing their elasticity adaptively," she said. Think of walking down a flight of steps and missing a step. Leg muscles instantly become less stiff to afford better shock absorption. "It's an intrinsic property of muscle," Nishikawa said.



Tom Sugar and his colleagues Arizona State University have been inspired by biology in designing a robotic tendon. After meeting with Nishikawa about her work, Sugar said, "We were amazed at the speed, energy storage and power of muscle. We learned how a frog tongue will store energy and release it in a powerful burst."



At ASU's Human Machine Integration Laboratory, Sugar and his team are building "SPARKy" (Spring Ankle with Regenerative Kinetics) that mimics biology by storing and releasing energy during the ankle gait cycle.



"Energy is stored as the leg and body rolls over the ankle, and then this energy is released in a powerful burst to propel the user forward. By mimicking biology, we are able to build a very lightweight and functional device," Sugar said.



"Putting motors and springs together in a smart way is something nature hit on about 600 million years ago (with the earliest vertebrates)," Nishikawa said.



It's a notion that captured the interest of Discovery Channel Canada, which spent a day at NAU and a day at ASU taping for a segment of its Daily Planet show that will air in the fall.



The NAU researcher wants to know more about how the brain controls movement. About decade ago Nishikawa realized that how the brain and body work together to produce coordinated movement means understanding what muscles contribute to the whole process.



"Understanding what the neurological part is and what the muscular part is can help establish cause and effect," she said. Identifying these mechanisms at the molecular level might aid medical research in developing better treatments for sufferers of Parkinson's, whose low force output results in stiff movements.



Nishikawa's studies of the neuromuscular basis for extremely rapid movements in animals, such as the toad snaring prey with its tongue, could leapfrog to a new model of muscle function, changing the standard representation of muscle as a motor.






Source: Lisa Nelson


Northern Arizona University

Animal Study Of Alzheimer's-Associated Plaques Shows New Plaques Develop In 24 Hours, Neuronal Changes Soon After

The amyloid plaques found in the brains of Alzheimer's disease patients may form much more rapidly than previously expected. Using an advanced microscopic imaging technique to examine brain tissue in mouse models of the devastating neurological disorder, researchers from the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND), working with colleagues from Washington University School of Medicine, find that plaques can develop in as little as a day and that Alzheimer's-associated neuronal changes appear soon afterwards. Their report will appear in the Feb. 7 issue of Nature.



"While we've known for a long time what amyloid plaques and other changes seen in the brains of Alzheimer's patients look like, we didn't know in what order and at what speed those changes occur," says Bradley Hyman, MD, PhD, director of the Alzheimer's Unit at MGH-MIND and senior author of the Nature paper. "Understanding the rules that govern plaque formation may lead us to ideas about how to intervene in the process."



To investigate the timing of these brain changes, the researchers used a novel technique for microscopically imaging the brains of living animals. Using several strains of transgenic mice destined to develop amyloid plaques, they imaged initially plaque-free areas of the brain on a regular basis - first weekly and, in subsequent experiments, daily. Although plaques formed rarely, they could appear as little as 24 hours after a previous plaque-free image was taken. The new plaques were similar in appearance to those seen in the brains of Alzheimer's patients and in the mouse models, and subsequent imaging showed little change in the size of plaques once they had formed.



Earlier investigations have shown that levels of microglia - neuronal support cells that react to inflammation and other damage - rise in the vicinity of amyloid plaques. Imaging an Alzheimer's mouse model that expresses a fluorescent marker in microglia showed that the cells were attracted to new plaques within a day of formation. Although there was no evidence that microglia were actively removing the plaques, the investigators hypothesize that they may help restrict further plaque growth. Examining neurons adjacent to plaques showed that the kind of changes associated with Alzheimer's - distortions in the projections through which neuronal signals pass - appear rapidly and approach maximum effect within five days.



"These results confirm the suspicion we've had that plaques are a primary event in the glial and neuronal changes that underlie Alzheimer's dementia," Hyman says. "We hope that what we've learned about the time frame and sequence of events will help us find ways to keep plaques from forming." Hyman is the John Penny Professor of Neurology at Harvard Medical School.







Melanie Meyer-Luehmann, PhD, of MGH-MIND is the first author of the Nature report; Washington University School of Medicine co-authors Jessica Koenigsknecht-Talboo, PhD, and David Holtzman, MD, provided the transgenic mice and collaborated on the microglial experients. Aditional co-authors are Tara Spires-Jones, Claudia Prada, MD, Monica Garcia-Alloza, Alix de Calignon, Anete Rozkalne, and Brian Bacskai, PhD, all of MGH-MIND. The study was supported by grants from the National Institutes of Health and the Alzheimer's Association.



Massachusetts General Hospital (massgeneral/), established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.



Source: Sue McGreevey


Massachusetts General Hospital

Similarities Found In Dog And Human Breast Cancer Pre-Malignant Lesions

Pre-malignant mammary lesions in dogs and humans display many of the same characteristics, a discovery that could lead to better understanding of breast cancer progression and prevention for people and pets, said a Purdue University scientist from the School of Veterinary Medicine.



A group of scientists including Sulma Mohammed have found similarities between benign lesions that are considered to carry risk for developing breast cancer in both canines and humans. Breast cancer is the second leading cause of cancer deaths in women.



"Dogs develop these lesions spontaneously in contrast to other available models and are exposed to the same environmental risk factors as humans," said Mohammed, an associate professor in comparative pathobiology. "These shared features make the dog an ideal model to compare the breast lesions that will progress to cancer and those that will regress. Such a model will facilitate customized treatment and prevention strategies."



Due to the success of mammographic screening and awareness by women, abnormal cell growth within breast tissues is frequently diagnosed, Mohammed said. These intraepithelial lesions are recognized risk factors for invasive cancer, and their presence affects patient management decisions.



"Once a lesion is identified, it can be treated with hormonal therapy if it is estrogen receptor (ER)-positive, but for low-risk and ER-negative lesions, we can't do anything but wait and watch to see if it grows into a tumor," Mohammed said. "With a dog model, we could study these lesions and test different prevention modalities before it becomes a cancer."



The research appears in this month's issue of the Journal of Cancer Epidemiology, Biomarkers, and Prevention. Mohammed's co-authors include Sunil Badve from Indiana University; Margaret (Peg) Miller, Jun Xie and Elisabetta Antuofermo from Purdue; and Salvatore Pirino from the Sassari University School of Veterinary Medicine in Sardinia, Italy.



The scientists studied 212 tissue biopsies from 200 female dogs with tumors that were retrieved from the archives of the Purdue Animal Disease Diagnostic Laboratory and the Veterinary Teaching Hospital as well as from the Institute of General Pathology and Anatomical Pathology at Sassari University.



The canine slides were compared to human specimens collected from the Department of Pathology at the IU School of Medicine. Mohammed said the focus of the study was not on the tumor but on the precancerous, or preneoplasia, lesions in tissue around the tumor.



"We found that preneoplasia lesions are virtually identical, microscopically, in dogs and women," she said. "In fact, many of the slides were so similar it was often difficult to determine if they were from dogs or people without looking at the label."
















In particular, Mohammed said, they wanted to examine each type of mammary intraepithelial lesion for estrogen receptors expression. Recently, scientists have concluded that breast cancer is not a single disease, but a group of malignancies.



"Establishing an animal model is paramount for testing new treatment and prevention modalities, especially for lesions that express none of the targeted receptors, such as triple-negative types, before human clinical trials," Mohammed said.



The team determined that because of the frequency of lesions, their association with spontaneous mammary cancer and the resemblance to human lesions, dogs may be the ideal model to study human breast cancer progression as well as prevention and treatment. Mohammed emphasized that the research results would benefit both dogs and humans.



According to the American Cancer Society, 62,030 cases of precancerous malignant lesions and 178,480 new cases of breast cancer will be diagnosed. There will be 70,880 women who die from breast cancer this year.



Much of the difficulty in research on dogs with breast cancer is that the data is outdated, Mohammed said. According to a 1969 study of female dogs over 4 years old that were not spayed, one out of four were expected to develop mammary neoplasia, or abnormal cell growth that may progress to cancer. Thirty percent to 50 percent of canine mammary tumors were malignant, and 50 percent to 75 percent of these recurred or metastasized within one to two years.



"Women have become more aware and conscientious of conducting their own breast self-exams, and pet owners also are more aware to check their animals," Mohammed said. "With better diagnostic tools and early detection, we are able to give dogs the same treatment that we give humans."



Mohammed said the dogs provide a more realistic comparison to humans than the mice and rat models, in part because the tumors developed spontaneously, just as in humans. Dogs have been evaluated in a few studies, but rodent research is more common, she said.



"This is a very large, untapped resource for comparative oncology research," Mohammed said. "Unlike laboratory rodents, dogs share a common environment with people and, therefore, may be exposed to some of the same carcinogens. Also, because dogs have a shorter life span than people, it is possible to study mammary lesions and invasive tumors that develop after a few years instead of decades."



Miller, a veterinary pathologist in the Animal Disease Diagnostic Laboratory, said that mammary cancer in dogs is one of the most common forms of cancer studied at the Animal Disease Diagnostic Laboratory.



"We already had hundreds of mammary tumor specimens archived in the diagnostic laboratory," Miller said. "It's a wonderful thing when we're able to collaborate with other departments at Purdue and Indiana University with these specimens. There's so much to be learned from these types of studies."



Tissue samples are kept indefinitely at the Animal Disease Diagnostic Laboratory, but most of the samples in this study were less than a year old, she said. The records kept for each sample provide opportunities for follow up if necessary in future studies.



"Diseases such as this are important to a diagnostic laboratory," Miller said. "Through diagnostic pathology, we gain knowledge that's useful for veterinarians and animals, as well as collecting information that's helpful for people."



The main form of treatment of breast cancer tumors has been surgical removal. Both Mohammed and Miller would like to find out if there is a way to identify the lesion early with noninvasive screening, such as ultrasound or magnetic resonance imaging.



As a next step, Mohammed will determine the prevalence of lesions in dogs with no tumors. In addition, she and Miller are looking at cats, which have a 90 percent malignancy rate when they are diagnosed with breast cancer.







This research was funded by the U.S. Department of Defense.



Writer: Maggie Morris



Related Web site:


School of Veterinary Medicine: vet.purdue/



Click here to access abstract on the research in this release.



Source:

Sulma Mohammed

Maggie Morris


Purdue University

Animal Studies In The Land Of The Midnight Sun Illuminate Biological Clocks

The temperature hovers around freezing, but the sun is up for 24 hours each day. How do animals living in the continuous light of the Arctic summer know when to sleep and when to be active? Do they maintain a 24-hour cycle of rest and activity, or does living in continuous light alter their circadian rhythm?



Answering these questions may improve our understanding of biological clocks -- the internal, genetically programmed cycle of rest and activity that affects the behavior, metabolism and physiology of all animals, including humans. A better understanding may also help solve problems -- such as shift-work fatigue, jet lag and even seasonal affective disorder -- that are associated with disruptions of biological clocks.



One scientist who has spent a lifetime pursuing these questions and finding answers that have helped build the field of biological clock research is G. Edgar Folk, Ph.D., emeritus professor of molecular physiology and biophysics at the University of Iowa Roy J. and Lucille A. Carver College of Medicine.



Folk notes that humans have a natural circadian rhythm of close to, but not exactly, 24 hours. Importantly, all biological clocks are adjustable and respond to environmental cues such as sunrise or sunset, which continuously reset the clock and keep us on a regular 24-hour schedule.



However, previous research, including studies in Folk's lab, has shown that lab rats kept in continuous light develop a 26-hour cycle of rest and activity, meaning their peak of activity travels around our usual daily 24-hour clock. This phenomenon is called the "Aschoff Effect" after a German scientist who first recorded it in the 1960s. Folk sometime ago set out to determine if this effect was also seen in wild animals during the continuous light of the Arctic summer.



"In continuous light in the lab, the animal's clock changes depending on the intensity of the light," Folk explained. "We thought that would also happen in the Arctic. "Much to our surprise, the Arctic animals maintained a very crisp 24-hour period of activity."



Working at Folk's permanent Arctic field lab at Barrow, Alaska, the research team studied two types of Arctic rodent: nocturnal porcupines and day-living ground squirrels.



Heart rates -- a good measure of metabolism and activity -- from four porcupines and direct observation of nine squirrels' activity showed that both creatures retained a 24-hour rhythm of behavior, just as they would if they were living under a normal day/night situation. The study results were published in Biological Rhythm Research.



It seemed that although the scientists were very careful not to provide time cues of any sort, the animals had managed to latch onto something that gave them regularity.
















"I have written for years that experimental animals seem to be hungry for cues, or time signals, to keep on a regular cycle," Folk said. "So we tried to figure out what cue the wild animals were using, and we could find only one thing that kept a 24 hour periodicity. At Barrow, the sun travels in a circle overhead for 82 days, but at midnight the circle is tipped to the north.



"We postulate that the animals are conscious of where the sun is in the sky and that the nearness of the sun to the horizon could be a clue to animals, and even plants, to keep on a 24-hour schedule."



Folk found that several other scientific teams have also proposed the same theory.



"Our work shows that clocks are important, and for me it means that you get surprises -- I thought that we would see drift in the times the animals, slept, but we didn't. The broad implication is that, when possible, animals like humans, like to have regularity."



Sixty years of study have not diminished Folk's fascination with biological clocks, and he says the field still produces surprising results and raises new questions.



"There is a lot more to be done," he said. "For example, birds haven't been studied enough - I first got interested in this study when I was listening to birds singing in the Arctic and trying to figure out if they always sang at the same time of day even when the light was continuous. I'm pretty sure that as a species they must learn to resist the Aschoff effect, but no one has studied it."



Although Folk has not visited his Arctic lab in several years, the heart rate data he has collected in Arctic animals, including hibernating bears, continues to provide a goldmine of information. Folk is currently involved in a collaborative project with Eric Dickson, M.D., UI professor and head of emergency medicine, examining the cardiology of hibernating animals and looking at what application that information might have in human emergency medicine.







Folk's UI research colleagues include, Diana Thrift, a research assistant in Folk's lab, Bridget Zimmerman, Ph.D., clinical associate professor in the UI College of Public Health, and Paul Reimann in anatomy and cell biology.



STORY SOURCE: University of Iowa Health Science Relations, 5135 Westlawn, Iowa City, Iowa 52242-1178



Contact: Jennifer Brown


University of Iowa

Steroids In Female Mouse Urine Light Up Nose Nerves Of Male Mice

A group of steroids found in female mouse urine goes straight to the male mouse's head, according to researchers at Washington University School of Medicine in St. Louis. They found the compounds activate nerve cells in the male mouse's nose with unprecedented effectiveness.



"These particular steroids, known as glucocorticoids (GCCs), are involved in energy metabolism, stress and immune function," says senior author Timothy E. Holy, Ph.D., assistant professor of neurobiology and anatomy. "They control many important aspects of the mouse's physiology and theoretically could give any mouse that sniffs them a detailed insider's view of the health of the animal they came from."



Holy plans further research to see if activating the nerves in the male mouse's nose leads to particular behavioral responses. He probes the male mouse's reaction to chemical signals from female mice to advance understanding of pattern recognition and learning in the much more complex human brain. In 2005, he found that female mice or their odors cause male mice to sing. He doesn't know yet if the GCC steroids' effects on the male mouse nose help to trigger this behavior.



Science has long recognized that urine, sweat and other bodily fluids contain chemical communication signals called pheromones that can influence the biology or behavior of others. Most mammals use the information in these signals for social purposes, such as establishing territory or dominance, or in courtship and mating. In many cases, though, the specific chemical identities of the signals are unknown.



The new study, published in The Journal of Neuroscience and led by graduate student Francesco Nodari, identified compounds that are unusually potent stimulators of the mouse nose. The pheromones activate nerve cells 30 times as often as all the other pheromones previously identified in female mouse urine combined. In addition, several of the new signals activate specific nerve cells. This may mean the male mouse's brain can assess different aspects of female mouse health by selectively analyzing individual pheromones.



Stressing female mice led to a threefold increase in the levels of GCCs in their urine, directly linking the female mouse's health and the GCC pheromones.



The GCC pheromones that Nodari identified were sulfated, which means they had a chemical attachment comprised of sulfur and oxygen atoms. This attachment is added to deactivate the steroids prior to excretion in the urine. When Nodari used an enzyme to remove these attachments, the GCCs lost their ability to activate nerves, further suggesting that the link between the sulfated GCCs and the nerve cells is a channel fine-tuned by evolution to carry information from female mice to male mice.



The nerves researchers studied in the male mouse nose are located in an area known as the accessory olfactory system. Humans and many closely related apes don't have an accessory olfactory system, but most other mammals and some reptiles do. The system, found in a structure called the vomeronasal organ, sends its outputs to a different part of the brain than the main olfactory system. Like the main olfactory system, it's dedicated to detecting airborne particles. But researchers believe the accessory olfactory system focuses on compounds from sources that are physically very close to or touching the animal.
















According to Holy, this focus on scents from nearby sources makes the accessory olfactory system "halfway between a taste system and a sense of smell." He believes the GCC pheromones account for approximately 75 percent of the signals detected in female urine by the male accessory olfactory system.



"Because these new pheromones are so good at activating the accessory olfactory system, they will be very helpful in efforts to better understand what this system does," he says. "That high degree of activation likely also means they have much potential for advancing the general study of pheromones."



To follow up, Holy's lab is testing to see how mice change their behavior when they smell these compounds. They are also searching for additional pheromonal cues that the accessory olfactory system can detect in female urine.







Nodari F, Hsu F-F, Fu X, Holekamp TF, Kao L-F, Turk J, Holy TE. Sulfated steroids as natural ligands of mouse pheromone-sensing neurons. The Journal of Neuroscience, June 18, 2008.



Funding from the United States Public Health Service supported this research.



Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.



Source: Michael C. Purdy


Washington University School of Medicine

Discovery Of A New Ally In The Battle Against Cocaine Addiction

A recent study shows that a bacterial protein may help cocaine addicts break the habit.



Cocaine esterase (CocE) is a naturally-occurring bacterial enzyme that breaks down cocaine, thereby reducing its addictive properties. The efficacy of CocE in animals and its suitability for treatment of addiction has been limited by its short half-life in the body.



A recent study, published in the Journal of Pharmacology and Experimental Therapeutics and reviewed by Faculty of 1000 Medicine's Friedbert Weiss, demonstrates that a more stable version of CocE, double mutant or DM CocE, significantly decreased the desire for cocaine and prevented death from cocaine overdose.



In the study, rats were trained to self-administer cocaine by pressing a button in their cage, mimicking the need for regular doses of the drug during addiction. Rats treated with the double mutant form of CocE pressed the button to receive cocaine less often, suggesting that DM-CocE broke down the drug and dampened addiction.



DM-CocE decreased the rats' urge for cocaine but not for an addictive analogue, highlighting the degree of specificity for cocaine. Weiss notes that the DM-CocE enzyme also provides "long-lasting protection" against the toxic effects of a potentially lethal dose.



Though the effects of CocE can be overcome by a sufficiently large dose of cocaine, the present findings suggest that CocE has great promise as a drug abuse treatment.



Weiss says, "These therapeutic approaches may therefore not be "fail-safe" for reducing cocaine intake by determined users" but "long-acting forms of CocE represent potentially valuable treatment approaches not only for the prevention of cocaine-induced toxicity but also for ongoing cocaine abuse in humans."



The full text of this article is available free for 90 days at f1000medicine/article/017fjm0nn9jlk80/id/1167997/evaluation/sections



Source: Steve Pogonowski


Faculty of 1000: Biology and Medicine

Genetic Patterning In Fruit Fly Development Identified By Rutgers-Camden Scholar

No matter the species, from flies to humans, we all start the same: a single-cell fertilized egg that embarks on an incredible journey. The specifics of this journey are being uncovered at Rutgers University-Camden, where a biologist is researching how from one cell a jumble of many are able to organize and communicate, allowing life to spring forth.



According to Nir Yakoby, a recently appointed assistant professor of biology at Rutgers-Camden, his work on cell communication is a lot like genetic play dough. His medium however is fruit flies, thousands and thousands of them from various genetic backgrounds.



Yakoby knows that manipulating certain genes in the fruit fly egg will result in very specific consequences in the development of its shell. He and his colleagues' research has been published this month in the prestigious journal Developmental Cell.



"Most people work on one gene at a time, but we're interested in gene networks," explains Yakoby, who earned his undergraduate and doctoral degrees from Hebrew University in Israel. "While riding on the new wave of biology, systems biology, we are still keeping the fundamentals of developmental biology by asking how many genes are expressed over time and space."



After four years of post-doctoral research at the Lewis-Sigler Institute for Integrative Genomics at Princeton University, the Rutgers-Camden scholar is interested in how Drosophila cells communicate and create genetic patterning during its eggshell formation. To gain this knowledge, Yakoby has studied eggshells from a range of Drosophila species for insight on how variations of patterns could reflect how actual structures have evolved.



Titled "A combinatorial code for pattern formation in Drosophila oogenesis," the Developmental Cell article offers precise outcomes for the tens of genes and hundreds of patterns involved in four developmental stages of the fruit fly's eggs. As part of a research team, Yakoby developed an innovative new coding language to formally follow and manage the dynamics of hundreds of gene-patterns. The team concentrated on the two main patterning pathways of the Drosophila egg development: bone morphogenetic protein and epidermal growth factor receptor. Most developmental and other diseases, such as cancer, are associated with these universal pathways.



Yakoby teaches a course on genetics at Rutgers-Camden, where the newly created Center for Computational and Integrative Biology will offer doctoral and graduate programs in computational and integrative biology. The Rutgers-Camden research center aims to determine the quantitative organizational principles of complex biological systems, using a combination of theoretical and experimental approaches.






The Camden Campus of Rutgers, The State University of New Jersey, offers 34 undergraduate and 16 master's-level programs, as well as the nation's first PhD program in childhood studies. Located in the heart of the vibrant Camden Waterfront, Rutgers-Camden is home to 260 faculty whose research, teaching, and service endeavors are respected worldwide.



Source: Cathy Donovan


Rutgers University