Monday, January 18, 2010

PROTEIN CENTRAL TO BEING MALE PLAYS KEY ROLE IN WOUND HEALING

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A molecular receptor pivotal to the action of male hormones such as testosterone also plays a crucial role in the body’s ability to heal, report scientists in the December issue of the Journal of Clinical Investigation.

In studies in mice, scientists at the University of Rochester Medical Center found that this receptor – the androgen receptor – delays wound healing. When scientists used an experimental compound to block the receptor, wounds healed much more quickly.

Scientists say that while the results in mice offer new insights into a potential new way to help the body heal faster, they stress that more research must be done before considering whether to explore the treatment in people whose wounds are slow to heal.

“This is a very interesting observation,” said Edward Messing, M.D., a urologist and surgeon at the University of Rochester Medical Center who was not involved in the study. “For people at the marginal end of health – the elderly, or people who have impaired healing for other reasons, such as diabetes – maybe blocking the androgen receptor in certain cells could speed up wound healing and help prevent infections.”

The work was led by Chawnshang Chang, Ph.D., director of the George Whipple Laboratory for Cancer Research and a widely recognized expert on the androgen receptor. The first author is former graduate student Jiann-Jyh Lai, Ph.D., who is now a researcher at the University of Massachusetts.

The work thrusts a sex hormone front and center into one of the most important and pervasive processes of the body. Inflammation is crucial for allowing the body to heal from wounds and to fight off invaders. But when our inflammatory response goes beyond what’s necessary, or if it occurs in the wrong time or place, it hurts our health and can be deadly.

By identifying the androgen receptor as a key player in at least one form of inflammation, the work opens a new window for scientists investigating differences between the genders when it comes to autoimmune or inflammatory diseases.

“Many inflammatory diseases, such as atherosclerosis and asthma, manifest themselves differently in the genders, indicating that sexual hormones could be involved. We’ve found that the androgen receptor plays a role regulating the inflammatory response in wound healing. It will be very interesting to see if the receptor plays a similar role in other diseases,” said Lai.

To block the receptor and speed healing, the team used ASC-J9, a synthetic chemical compound loosely based on a compound found in curry that can shut down the receptor selectively. ASC-J9 is being tested in Phase II trials as a treatment for severe acne by San Diego-based AndroScience Corp., a biotech company founded by Chang and colleagues. Both Chang and the University of Rochester own a stake in the company, which has licensed several of Chang’s research findings.

Chang’s current study delves in a detailed way into the molecular underpinnings of wound healing. When the body is injured, myriad cells rush to the scene, a bit like emergency responders hustling to a disaster. Some cells issue cries for help by sending out certain chemical messengers; other cells act as dispatchers to recruit more responders to the scene. It can seem like a great deal of chaos zeroed in on a small patch of skin. Usually, the body gets the job done, drawing upon dozens of molecular actors to heal the wound efficiently and quickly; sometimes, though, the inflammation can be detrimental.

For the current study funded by the National Cancer Institute, Chang and colleagues studied several different types of cells involved in wound healing. The team created different types of mice, turning off the androgen receptor in certain cell types while leaving it functional in other cells. Then scientists applied ASC-J9 to block the activity of the androgen receptor and studied the effects.

The team found that the androgen receptor spurs white blood cells known as macrophages to produce a chemical messenger called TNF-alpha, which in turn stimulates the body’s inflammatory response. The receptor also plays a role recruiting macrophages to the site of injury. When the team blocked the receptor, there were fewer macrophages and less TNF-alpha at the wound site, and the wound healed much more quickly.

“It is a surprise that the androgen receptor is involved in wound healing in so many ways,” said Chang, who is a faculty member in the departments of Pathology and Urology and the James P. Wilmot Cancer Center. “People have suspected that the receptor plays a role in wound healing, but it’s new that it plays a direct role guiding circulating macrophages to the area.”

Shutting off the interaction between the androgen receptor and androgen hormones like testosterone is a goal in several areas of medicine. The action is taken by doctors most commonly to treat patients with advanced prostate cancer. For some patients, doctors prescribe “chemical castration” and shut down the body’s supply of hormones like testosterone. This causes severe, systemic side effects that can include impotence, loss of libido, osteoporosis, and fatigue.

Scientists like Chang are exploring another way to prevent that same interaction, by shutting down the androgen receptor itself in select tissues but keeping the flow of hormones intact.

Messing, a surgeon who regularly treats men with prostate cancer, says that the ability to turn off the effects of androgens in just the tissues necessary is a challenge but holds great promise.

“Currently there is no way of preventing androgens in your body from reaching just one particular wound or one specific part of the body,” said Messing. “To stop them anywhere, you need to turn off androgens throughout the body, which has severe and unpleasant side effects, particularly in men. Turning off the androgen receptor only where you want to, and nowhere else, could lead to new treatments for diseases like prostate cancer and for speeding wound healing.”

(Photo: U. Rochester)

University of Rochester

FOSSIL FOOTPRINTS GIVE LAND VERTEBRATES A MUCH LONGER HISTORY

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The discovery of fossil footprints from early backboned land animals in Poland leads to the sensational conclusion that our ancestors left the water at least 18 million years earlier than previously thought. The results of the Polish-Swedish collaboration are published online in Nature.

These results force us to reconsider our whole picture of the transition from fish to land animals, says Per Ahlberg of Uppsala University, one of the two leaders of the study.

For nearly eighty years, palaeontologists have been scouring the planet for fossil bones and skeletons of the earliest land vertebrates or "tetrapods" – the ultimate progenitors of all later amphibians, reptiles, birds and mammals including ourselves. Their discoveries have suggested that the first tetrapods evolved relatively rapidly from lobe-finned fishes, through a short-lived intermediate stage represented by "elpistostegids" such as Tiktaalik, about 380 million years ago. But there is another potential source of information about the earliest tetrapods: the fossilized footprints they left behind. In the new study a Polish-Swedish team describe a rich and securely dated footprint locality from Zachelmie Quarry in Poland that pushes back the origin of tetrapods a full 18 million years beyond the earliest skeletal evidence and forces a dramatic reassessment of the transition from water to land.

The trackways show that large tetrapods, up to three metres in length, inhabited the marine intertidal zone during the early Middle Devonian some 395 million years ago.

This means not that not only tetrapods but also elpistostegids originated much earlier than we thought, because the position of elpistostegids as evolutionary precursors of tetrapods is not in doubt, and so they must have existed at least as long, says Per Ahlberg.

The elpistostegids, it seems, were not at all a short-lived transitional stage but must have existed alongside their descendants the tetrapods for at least 10 million years. The environment is also a major surprise: almost all previous scenarios for the origin of tetrapods have placed this event in a freshwater setting and have associated it with the development of land vegetation and a terrestrial ecosystem.

Instead, our distant ancestors may first have left the water in order to feed on stranded marine life left behind by the receding tide, says Per Ahlberg.

Uppsala University

30,000-YEAR-OLD TEETH SHED NEW LIGHT ON HUMAN EVOLUTION

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The teeth of a 30,000-year-old child are shedding new light on the evolution of modern humans, thanks to research from the University of Bristol published this week in PNAS.

The teeth are part of the remarkably complete remains of a child found in the Abrigo do Lagar Velho, Portugal and excavated in 1998-9 under the leadership of Professor João Zilhão of the University of Bristol. Classified as a modern human with Neanderthal ancestry, the child raises controversial questions about how extensively Neanderthals and modern human groups of African descent interbred when they came into contact in Europe.

‘Early modern humans’, whose anatomy is basically similar to that of the human race today, emerged over 50,000 years ago and it has long been the common perception that little has changed in human biology since then.

When considering the biology of late archaic humans such as the Neanderthals, it is thus common to compare them with living humans and largely ignore the biology of the early modern humans who were close in time to the Neanderthals.

With this in mind, an international team, including Professor Zilhão, reanalysed the dentition of the Lagar Velho child (all of its deciduous – milk – teeth and almost all of its permanent teeth) to see how they compared to the teeth of Neanderthals, later Pleistocene (12,000-year-old) humans and modern humans.

Employing a technique called micro-tomography which uses x-rays to create cross-sections of 3D-objects, the researchers investigated the relative stages of formation of the developing teeth and the proportions of crown enamel, dentin and pulp in the teeth.

They found that, for a given stage of development of the cheek teeth, the front teeth were relatively delayed in their degree of formation. Moreover, the front teeth had a greater volume of dentin and pulp but proportionally less enamel than the teeth of recent humans.

The teeth of the Lagar Velho child thus fit the pattern evident in the preceding Neanderthals, and contrast with the teeth of later Pleistocene (12,000-year-old) humans and living modern humans.

Professor Zilhão said: “This new analysis of the Lagar Velho child joins a growing body of information from other early modern human fossils found across Europe (in Mladeč in the Czech Republic, Peştera cu Oase and Peştera Muierii in Romania, and Les Rois in France) that shows these ‘early modern humans’ were ‘modern’ without being ‘fully modern’. Human anatomical evolution continued after they lived 30,000 to 40,000 years ago.”

(Photo: Bristol U.)

University of Bristol

MOST EARTHLIKE EXOPLANET STARTED OUT AS A GAS GIANT

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The most earthlike planet yet found around another star may be the rocky remains of a Saturn-sized gas giant, according to research presented at the American Astronomical Society meeting in Washington.

"The first planets detected outside our solar system 15 years ago turned out to be enormous gas-giants in very tight orbits around their stars. We call them 'hot Jupiters,' and they weren't what astronomers expected to find," said Brian Jackson at NASA's Goddard Space Flight Center in Greenbelt, Md. "Now, we're beginning to see Earth-sized objects in similar orbits. Could there be a connection?"

Jackson and his colleagues turned to CoRoT-7b, the smallest planet and the most like Earth that astronomers have found to date. Discovered in February 2009 by the Convection, Rotation and Planetary Transits (CoRoT) satellite, a mission led by the French Space Agency, CoRoT-7b takes just 20.4 hours to circle its sunlike star, located 480 light-years away in the constellation Monoceros. Astronomers believe the star is about 1.5 billion years old, or about one-third the sun's age.

"CoRoT-7b is almost 60 times closer to its star than Earth, so the star appears almost 360 times larger than the sun does in our sky," Jackson said. As a consequence, the planet's surface experiences extreme heating that may reach 3,600 degrees Fahrenheit on the daylight side. CoRoT-7b's size (70 percent larger than Earth) and mass (4.8 times Earth's) indicate that the world is probably made of rocky materials.

"But with such a high dayside temperature, any rocky surface facing the star must be molten, and the planet cannot retain anything more than a tenuous atmosphere, even one of vaporized rock," Jackson said. He estimates that solar heating may have already cooked off several Earth masses of material from CoRoT-7b.

With the help of computer models that track the planet's mass loss and orbital changes, the researchers have turned back the planet's clock.

"There's a complex interplay between the mass the planet loses and its gravitational pull, which raises tides on the star," Jackson explained. Those tides gradually change the planet's orbit, drawing it inward in a process called tidal migration. But closer proximity to the star then increases the mass loss, which in turn slows the rate of orbital change.

After accounting for the give-and-take of mass loss and tidal migration, the team finds that CoRot-7b could have weighed in at 100 Earth masses -- or about the heft of Saturn -- when it first formed. At that time, it orbited 50 percent farther from its star than it does now.

The researchers also show that regardless of whether CoRot-7b started life as a Saturn-like gas giant or as a rocky world, the planet has probably lost many Earth masses of material since its formation.

"You could say that, one way or the other, this planet is disappearing before our eyes," Jackson said.

He suggests that similar processes likely have influenced many other exoplanets that lie close to their stars. In fact, several recent studies suggest that many hot Jupiters have undergone similar mass loss and tidal evolution, perhaps leaving behind remnant cores similar to CoRoT-7b.

"CoRoT-7b may be the first in a new class of planet -- evaporated remnant cores," Jackson said. "Studying the coupled processes of mass loss and migration may be crucial to unraveling the origins of the hundreds of hot, earthlike planets space missions like CoRoT and NASA's Kepler will soon uncover."

(Photo: ESO/L. Calçada)

NASA

SILENCING BRAIN CELLS WITH YELLOW AND BLUE LIGHT

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Neuroscientists at the Massachusetts Institute of Technology have developed a powerful new class of tools to reversibly shut down brain activity using different colors of light. When targeted to specific neurons, they could potentially lead to new treatments for abnormal brain activity associated with disorders including chronic pain, epilepsy, brain injury and Parkinson's disease.

Such disorders could best be treated by silencing, rather than stimulating abnormal brain activity. These new tools, or 'super silencers,' exert exquisite control over the timing in which overactive neural circuits are shut down --an effect that is not possible with existing drugs or other conventional therapies.

The National Science Foundation's division of mathematical sciences supports the research through a grant to the Cognitive Rhythms Collaborative, which is comprised of four research groups in the Boston area focused on questions in neuroscience. The collaborative brings together researchers with expertise ranging from experimental design to mathematical modeling. The research paper, "High-Performance Genetically-Targetable Optical Neural Silencing by Light-Driven Proton Pumps," appeared in the Jan. 7 issue of the journal Nature.

"Silencing different sets of neurons with different colors of light allows us to understand how they work together to implement brain functions," explains Ed Boyden, senior author of the study. "Using these new tools, we can look at two neural pathways and study how they compute together," he says.

The tools promise to help researchers understand how to control neural circuits, leading to new understandings and treatments for brain disorders. Boyden, the Benesse Career Development Professor in the MIT Media Lab and an associate member of the McGovern Institute for Brain Research at MIT, calls brain disorders "some of the biggest unmet medical needs in the world."

Boyden's 'super silencers' derive from two genes found in different natural organisms such as bacteria and fungi. These genes, referred to as Arch and Mac, are light-activated proteins that help the organisms make energy. When Arch and Mac are placed within neurons, researchers can inhibit their activity by shining light on them. Light activates the proteins, which lowers the voltage in the neurons and safely and effectively prevents them from firing. Arch is specifically sensitive to yellow light, while Mac is activated with blue light.

"In this way the brain can be programmed with different colors of light to study and possibly correct the corrupted neural computations that lead to disease," explains co-author Brian Chow, postdoctoral associate in Boyden's lab.

"Multicolor silencing dramatically increases the complexity with which you can study neural circuits," says co-author Xue Han, another postdoctoral researcher in Boyden's lab. "We will use these tools to parse out the neural mechanisms of cognition."

Determining whether Arch and Mac are safe and effective in monkeys will be a critical next step towards the potential use of these optical silencing tools in humans. Boyden plans to use these 'super silencers' to examine the neural circuits of cognition and emotion and to find targets in the brain that, when shut down, could relieve pain and treat epilepsy.

His group continues to mine the natural world for new and even more powerful tools to manipulate brain cell activity--tools that he hopes will empower scientists to explore neural circuits in ways never before possible.

(Photo: Arthur Toga, Laboratory of Neuro Imaging, Department of Neurology, UCLA School of Medicine)

National Science Foundation

SEEING WITH YOUR HANDS? HAND AMPUTATION MAY RESULT IN ALTERED PERCEPTION AROUND THE HANDS

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The space within reach of our hands — where actions such as grasping and touching occur — is known as the “action space.” Research has shown that visual information in this area is organized in hand-centered coordinates — in other words, the representation of objects in the human brain depends on their physical location with respect to the hand. According to new research in Psychological Science, a journal of the Association for Psychological Science, amputation of the hand results in distorted visuospatial perception (i.e., figuring out where in space objects are located) of the action space.

Scientists Tamar R. Makin, Meytal Wilf, and Ehud Zohary from the Hebrew University of Jerusalem along with Isabella Schwartz from Hadassah Mount Scopus Hospital in Jerusalem wanted to investigate how hand amputations affect visuospatial perception in near space. Volunteers with either left- or right-hand amputations participated in this experiment. Volunteers were instructed to look at a central cross on a screen as two white squares were briefly shown to the left and right side of the cross. The volunteers had to indicate which of the squares was further away from the cross.

The results reveal that hand amputations affect visuospatial perception. When the right square was slightly further away from the center, participants with right-hand amputations tended to perceive it as being at the same distance from the center as the left square; this suggests that these volunteers underestimated the distance of the right square relative to the left. Conversely, when the left square was further away, participants with left-hand amputations perceived both squares as being equally far away from the center — these participants underestimated the left side of near space. Interestingly, when the volunteers were seated farther away from the screen, they were more accurate in judging the distances, indicating that hand amputations may only affect perception of the space close to the body.

The findings suggest that losing a hand may shrink the action space on the amputated side, leading to permanent distortions in spatial perception. According to the researchers, “This shows that the possibility for action in near space shapes our perception — the space near our hands is really special, and our ability to move in that space affects how we perceive it.”

The researchers note that these results have implications for spatial hemineglect — a condition (often following brain injury) in which the patient cannot perceive objects on one side of space. This condition is very often associated with paralysis of the hand in the neglected side, which, according to the current study, might intensify the perceptual neglect. The authors suggest that, based on their findings, “current rehabilitation approaches that emphasize action on the affected side may reverse this process.” For example, encouraging the use of the affected hand or by providing visual feedback (through prism adaptation or mirrors) may help overcome hemineglect by increasing the size of the action space on the affected side.

Association for Psychological Science

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