Research led by Manu Platt, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, has shown for the first time that members of the cathepsin family of proteases can attack one another – instead of the protein substrates they normally degrade. (Credit: Georgia Tech Photo by Gary Meek)
Researchers for the first time have shown that members of a family of enzymes known as cathepsins – which are implicated in many disease processes – may attack one another instead of the bodily proteins they normally degrade. Dubbed “cathepsin cannibalism,” the phenomenon may help explain problems with drugs that have been developed to inhibit the effects of these powerful proteases.
Cathepsins are involved in disease processes as varied as cancer metastasis, atherosclerosis, cardiovascular disease, osteoporosis and arthritis. Because cathepsins have harmful effects on critical proteins such as collagen and elastin, pharmaceutical companies have been developing drugs to inhibit activity of the enzymes, but so far these compounds have had too many side effects to be useful and have failed clinical trials.
Using a combination of modeling and experiments, researchers from the Georgia Institute of Technology and Emory University have shown that one type of cathepsin preferentially attacks another, reducing the enzyme’s degradation of collagen. The work could affect not only the development of drugs to inhibit cathepsin activity, but could also lead to a better understanding of how the enzymes work together.
“These findings provide a new way of thinking about how these proteases are working with and against each other to remodel tissue – or fight against each other,” said Manu Platt, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “There has been an assumption that these cathepsins have been inert in relationship to one another, when in actuality they have been attacking one another. We think this may have broader implications for other classes of proteases.”
The research was supported by the National Institutes of Health, the National Science Foundation and the Georgia Cancer Coalition. Details of the study were reported August 10 in the Journal of Biological Chemistry.
Platt and student Zachary Barry made their discovery accidentally while investigating the effects of cathepsin K and cathepsin S – two of the 11-member cathepsin family. Cathepsin K degrades both collagen and elastin, and is one of the most powerful proteases. Cathepsin S degrades elastin, and does not strongly attack collagen.
When the researchers combined the two cathepsins and allowed them to attack samples of elastin, they expected to see increased degradation of the protein. What they saw, however, was not much more damage than cathepsin K did by itself.
Platt at first believed the experiment was flawed, and asked Barry – an undergraduate student in his lab who specializes in modeling – to examine what possible conditions could account for the experimental result. Barry’s modeling suggested that effects observed could occur if cathepsin S were degrading cathepsin K instead of attacking the elastin – a protein essential in arteries and the cardiovascular system.
That theoretical result led to additional experiments in which the researchers measured a direct correlation between an increase in the amount of cathepsin S added to the experiment and a reduction in the degradation of collagen. By increasing the amount of cathepsin S ten-fold over the amount used in the original experiment, Platt and Barry were able to completely block the activity of cathepsin K, preventing damage to the collagen sample.
“We saw that the cathepsin K was going away much faster when there was cathepsin S present than when it was by itself,” said Platt, who is also a Georgia Cancer Coalition Distinguished Scholar and a Fellow of the Keystone Symposia on Molecular and Cellular Biology. “We kept increasing the amount of cathepsin S until the collagen was not affected at all because all of the cathepsin K was eaten by the cathepsin S.”
The researchers used a variety of tests to determine the amount of each enzyme, including fluorogenic substrate analysis, Western blotting and multiplex cathepsin zymography – a sensitive technique developed in the Platt laboratory.
Beyond demonstrating for the first time that cathepsins can attack one another, the research also shows the complexity of the body’s enzyme system – and may suggest why drugs designed to inhibit cathepsins haven’t worked as intended.
“The effect of the cathepsins on one another complicates the system,” said Platt. “If you are targeting this system pharmaceutically, you may not have the types or quantities of cathepsins that you expect, which could cause off-target binding and side effects that were not anticipated.”
Platt’s long-term research has focused on cathepsins, including the development of sensitive tools and assays to quantify their activity in cells and tissue, as well as potential diagnostic applications for breast, lung and cervical cancer. Cathepsins normally operate within cells to carry out housekeeping tasks such as breaking down proteins that are no longer needed.
“These enzymes are very powerful, but they have been overlooked because they are difficult to study,” said Platt. “We are changing the way that people view them.”
For the future, Platt plans to study interactions of additional cathepsins – as many as three or four are released during certain disease processes – and to develop a comprehensive model of how these proteases interact while they degrade collagen and elastin. That model could be useful to the designers of future drugs.
“As we build toward a comprehensive model of how these enzymes work, we can begin to understand how they behave in the extracellular matrix around these cells,” said Platt. “That will help us be smarter about how we go about treating diseases and designing new drugs.”
Last spring private industry successfully sent a spacecraft carrying cargo to the International Space Station. Now the race is on to see which company will be the first to make commercial human spaceflight a reality.
Sierra Nevada Corporation (SNC) is one of three companies that will receive hundreds of millions of dollars to further develop its commercial human spacecraft system, NASA announced earlier this month.
SNC has turned to Georgia Tech for expertise on how to ensure the smoothest possible re-entry for its spacecraft, the Dream Chaser, which is reminiscent of NASA’s space shuttle.
Robert Braun, Georgia Tech professor of space technology, and his research team – Research Engineer Jenny Kelly and engineering graduate students Zach Putnam and Mike Grant – are working with SNC on the design of an advanced guidance algorithm that will make the most of the Dream Chaser’s superior aerodynamic performance during re-entry and landing.
Of the three companies selected by NASA to develop spaceships to taxi astronauts to and from the International Space Station, Sierra Nevada Corporation is the only one with a winged vehicle. It is designed to launch vertically and land on a runway, similar to the Space Shuttle. Boeing and SpaceX are developing capsules that would land in a body of water.
Because the Dream Chaser is similar to the Space Shuttle, it could land using the same guidance algorithm the shuttle used. However, that algorithm, like the shuttle, is based on technology that is more than 40 years old; it does not take advantage of the onboard computing available for today’s space systems.
“The shuttle was built in the 1970s, and its designers didn’t have the onboard computing capabilities we have today,” Braun said. “The Dream Chaser can capitalize on an advanced entry guidance algorithm matched to its aerodynamic and onboard computing capability.”
Braun and his team took the Dream Chaser’s aerodynamic configuration, control surfaces and mass properties into account when developing the algorithm. To date, the algorithm runs a computer simulation that allows SNC engineers to tweak aspects of the spacecraft design based on scenarios such as variable atmospheric conditions to perfect the landing process.
The result is an algorithm that “allows the vehicle to fly how it was meant to fly,” Putnam said.
Georgia Tech engineers delivered an early prototype of the software to the SNC team this month for detailed evaluation and testing.
Zachary Krevor, a Georgia Tech graduate who is SNC’s principal systems engineer with the flight dynamic and performance group, was eager to see the results.
“This is important for us because we feel the algorithm could have performance benefits for our vehicle and make it robust to atmospheric disturbances while ensuring we have a ‘low g’ re-entry,” he said. “Capsules do not have the ‘low g’ re-entry that is so important for both astronauts and sensitive science payloads.”
For the students, the project provides real-world experience in the nascent commercial space industry.
“To be able to participate in the new era of commercial flight is very exciting,” Grant said. “It has been a great learning experience to see how commercial space companies work and a real thrill to contribute in a meaningful way to the potential flight of this new space flight system.”
Sierra Nevada Corporation’s Dream Chaser received an award of $212.5 million from NASA’s Commercial Crew Integrated Capability Program on August 3 that will allow the company to complete development of the system and transport crews to space as early as 2016. An approach and landing test for the Dream Chaser is scheduled for later this year.
If you’ve ever bathed a dog, you know firsthand how quickly a drenched pup can shake water off.
Now researchers at the Georgia Institute of Technology have found that furry mammals can shake themselves 70 percent dry in just a fraction of a second.
David Hu, assistant professor of mechanical engineering and biology at Georgia Tech, and mechanical engineering graduate student Andrew Dickerson, who led the project, used high-speed videography and fur particle tracking to characterize the shakes of 33 different animals – 16 species and five dog breeds – at Zoo Atlanta. The research was published in the Journal of Royal Society Interface.
Understanding the physics of the wet dog shake could help engineers recreate the optimal oscillation frequency and use it to improve the efficiency of washing machines, dryers, painting devices, spin coaters and other machines.
“We hope the findings from our research will contribute to technology that can harness these efficient and quick capabilities of drying seen in nature,” Dickerson said.
It may even lead to improved functioning for robotics, such as the Mars Rover, which suffered reduced power from the accumulation of dust on its solar panels.
“In the future, self-cleaning and self-drying may arise as an important capability for cameras and other equipment subject to wet or dusty conditions,” Hu said.
Over millions of years, animals have perfected the mechanism to dry quickly to avoid hypothermia. Wet fur, being a poor insulator, causes the animal to lose heat quickly and the evaporation of the entrapped water may zap an animal’s energy reserves, making it a matter of life or death to remain dry in cold weather, Hu said.
Small animals may trap substantial volumes of water in their fur for their size. For example, when emerging for a bath, a person carries one pound of water. A rat, however, carries five percent of its mass and an ant three times its mass.
Georgia Tech researchers found that animals oscillate at frequencies sufficient to lose water droplets and that shaking frequency is a function of animal size.
The larger the animal, the more slowly it shakes dry, Hu and Dickerson said. For example, a mouse moves its body back and forth 27 times per second, but a grizzly bear shakes four times per second. The tinier mammals can experience more than 20 g’s of acceleration.
Mammals with fur, unlike humans, tend to have loose skin that whips around as the animal changes direction, increasing the acceleration. This is crucial to shaking success, and subsequently, body heat regulation, Dickerson said.
“What would you do on a cold day if you were wet and could not towel off or change clothes? Every warm-blooded furry creature faces this dilemma often,” Dickerson said. “It turns out that oscillatory shaking exhibited by mammals is a quite efficient way to dry.”
In addition to observing live animals, the engineers also built a robotic wet-dog-shake simulator to further study how drops were ejected.
Hu and Dickerson will continue to look at how animals interact with water in the natural world. Specifically, the researchers want to investigate how animals such as beavers and otters have adapted to life in the water and how water droplets interact with hair.
Model synapses revealed that, when a GABA-A receptor had Alpha 2 subunits, the receptor tended to move toward and form at the synaptic region. However, when a GABA-A receptor had Alpha 6 subunits, the receptor tended to move toward the extrasynaptic region. (Credi: Gong Chen lab. Penn State)
A new way to study the role of a critical neurotransmitter in disorders such as epilepsy, anxiety, insomnia, depression, schizophrenia, and alcohol addiction has been developed by a group of scientists led by Gong Chen, an associate professor of biology at Penn State University. The new method involves molecularly engineering a model synapse — a structure through which a nerve cell send signals to another cell. This model synapse can precisely control a variety of receptors for the neurotransmitter called GABA, which is important in brain chemistry. The research, which will be published in the Journal of Biological Chemistry on Aug. 10 opens the door to the possibility of creating safer and more-efficient drugs that target GABA receptors and that cause fewer side effects.
Neurotransmitters — chemicals sent by nerves to trigger other cells to change their electrical responses — interact with special receptors located on the cell’s outer membrane. These receptors form inside the cell, and then are transported to different locations on the membrane to await the arrival of neurotransmitters. Chen explained that understanding how these receptors work and how they move to various locations on a cell’s membrane is a critical step toward the development of new drugs targeting diseases that affect brain chemistry.
In their study, Chen and his team focused on a particular receptor — called the GABA-A receptor– that responds to the neurotransmitter GABA. “The GABA-A receptors are associated with various disorders in which nerve-cell excitability is altered, such as epilepsy and anxiety, and these receptors mediate major inhibition in the brain,” Chen explained. “Each GABA-A receptor protein is made up of five subunits and there are 19 possible subunits that can combine in various ways to form any single receptor. We focused on a particular group of subunits called Alpha, and how changing these tiny subunits might affect the GABA-A receptor’s location on the cell membrane.”
First, Chen and his team used molecular engineering techniques to develop a model synapse between a nerve cell and a special kind of kidney cell used widely in cell-biology research — called an HEK cell — in order to study how specific receptors behaved. They then altered the Alpha subunits in the GABA-A receptors expressed in the kidney cell in order to test how a single variation might affect the behavior of the receptor. They found that the receptors behaved very differently in response to the GABA neurotransmitter, depending on whether they had an Alpha 2 or an Alpha 6 subunit. “Not only do the Alpha subunits play an important role in determining how the GABA-A receptor responds to the neurotransmitter, but the Alpha 2 and Alpha 6 subunits also guide the receptors to very different regions on the cell membrane,” Chen said.
Specifically, Chen and his collaborators found that when a GABA-A receptor had an Alpha 2 subunit, the receptor tended to cluster at the synaptic region on the cell membrane. However, when a GABA-A receptor had an Alpha 6 subunit, the receptor tended to migrate to a different area on the cell membrane called the extrasynaptic region.
Chen explained that understanding such a difference in receptor behavior can be especially important in predicting what side effects a drug might cause. For example, many GABA-receptor-targeting drugs such as Valium and Xanax, which are used to treat anxiety, appear to directly change the GABA neurotransmitter’s synaptic transmission, significantly altering nerve-cell activity and causing side effects such as confusion, agitation, and memory loss.
“If we imagine that a cell represents a big city, then the synaptic regions are major highways leading to the city,” Chen said. “There are serious side effects of disrupting those ‘major highways’ because brain function relies upon a delicate excitation-inhibition balance and breaking that balance will affect the output of neural circuits.” Chen added that, in the same analogy, the extrasynaptic regions could be thought of as the less-trafficked, but numerous smaller roads. “The idea is that if drugs could be developed that manipulate only the extrasynaptic receptors rather than the synaptic receptors, the ‘major highways’ would remain undisturbed and the heavy traffic could continue with less interruption. That is, targeting extrasynaptic receptors by modulating the Alpha 6 subunit represents a step toward creating new drugs with fewer side effects.”
In addition to Chen, other researchers who contributed to this study include Xia Wu, Zheng Wu, Gang Ning, Yao Guo, and Bernhard Luscher from Penn State; Rashid Ali and Angel L. De Blas from the University of Connecticut; and Robert L. Macdonald from Vanderbilt University.
The research is supported by two organizations of the U.S. National Institutes of Health: the National Institute of Neurological Disorders and Stroke and the National Institute of Mental Health.
It’s one thing for consumers to know intellectually that our gas-guzzling, polluting ways are taking their toll on the planet. It’s another thing to connect all the dots in terms of actions and consequences. Yet, even as we continue to drive SUVs and convert wilderness areas into housing developments, we hold out hope that the environment will rebound.
Unfortunately, for coral reefs, it’s going to take a lot more than hope, says Todd LaJeunesse, assistant professor of biology at Penn State.
Coral reefs are suffering from overfishing and other types of resource exploitation, LaJeunesse explains. In addition, they are being degraded by pollution from sewage and agricultural runoff, and by increasing sea-surface temperatures and acidification as a result of global warming.
“Coral reefs are important not only for the beauty they provide to snorkeling tourists, but for the ecosystem services they provide to us all,” says LaJeunesse. “They protect coastal areas by buffering the effects of hurricanes; they serve as habitat for food fish and other edible animals; and they are sources of medicines.”
According to the National Oceanic and Atmospheric Administration, reef-supported tourism alone generates an estimated $30 billion annually, with additional environmental and economic benefits valued at ten times that amount.
LaJeunesse’s own research focuses on the relationship between corals — which are animals — and the symbiotic algae, known as zooxanthellae, that live inside their cells. The photosynthetic algae provide food and energy to the corals, while the corals, in turn, provide a safe home for the algae.
“Heat disrupts the association between corals and their symbionts,” explains LaJeunesse, “and this causes the algae to be expelled from the corals, leaving behind a dead, bleached skeleton.”
Because of the barrage of human-induced pressures on corals, most places in the world have seen significant declines in coral cover over the last couple of decades, he adds. “Our own Florida Keys has been among the hardest hit. The area used to be covered with corals of all shapes, sizes, and colors; now there is just a whole lot of dead coral.”
Many of the reefs in the Caribbean Ocean have taken a turn for the worse, adds LaJeunesse. “Elsewhere on the planet, they seem to be doing a little better — in the Indo-Pacific, for example — but scientists think those reefs are just a couple decades behind the Caribbean in their decline.”
“Not only is coral cover declining, but coral species diversity also is dropping,” says LaJeunesse.
He uses genetic techniques to identify the species of zooxanthellae that associate with certain species of coral. Knowing exactly what species you’re working with is the first step in really understanding the organisms, he says.
“No doubt in the future, some species of coral that are better adapted to heat and pollution and that associate with thermally tolerant species of zooxanthellae will survive,” says LaJeunesse. But, he cautions, these species likely won’t be robust enough to withstand the constant wave action and animal predation that, over time, breaks reefs down. And species-poor reefs won’t, in any way, resemble the healthy reefs that we have seen historically and still see in a few places today.
“We don’t want to underestimate life’s ability to persist, but life needs a chance,” he adds. “Whether you view it from a spiritual or an analytical perspective, life is remarkable and it should be cherished. It seems people are looking to scientists to tell them that everything is going to be okay, that technology will save our beloved ecosystems. But that’s not going to happen.
“What I can tell people,” concludes LaJeunesse, “is that, as a functioning ecosystem, coral reefs are in critical danger. “They likely won’t exist in the future in any state resembling what they do now, and if we want to save even some of them, it is going to take major socio-political action that changes the way we exploit nature and use energy.”
“To save what is left of the reefs,” he says with conviction, “we need to drastically change the way we consume — that’s the bottom line.”
Patterns in nature are in everything from ocean currents to a flower’s petal.
Scientists are taking a new look at Earth patterns, studying the biodiversity of yard plants in the U.S. and that of desert mammals in Israel, studying where flowers and bees live on the Tibetan plateau and how willow trees in America’s Midwest make use of water.
They’re finding that ecology, the study of relationships between living organisms and their environment, and phylogenetics, research on evolutionary relationships among groups of organisms, are inextricably intertwined.
Results of this tale of two fields are highlighted in a special, August 2012 issue of the journal Ecology, published by the Ecological Society of America (ESA). Most of the results reported are funded by the National Science Foundation (NSF).
The issue will be released at the annual ESA meeting, held this year from August 5-10 in Portland, Ore.
Melding information from ecology and phylogenetics allows scientists to understand why plants and animals are distributed in certain patterns across landscapes, how these species adapt to changing environments across evolutionary time–and where their populations may be faltering.
“To understand the here and now, ecologists need more knowledge of the past,” says Saran Twombly, program director in NSF’s Division of Environmental Biology. “Incorporating evolutionary history and phylogenies into studies of community ecology is revealing complex feedbacks between ecological and evolutionary processes.”
Maureen Kearney, also a program director in NSF’s Division of Environmental Biology adds, “Recent studies have demonstrated that species’ evolutionary histories can have profound effects on the contemporary structure and composition of ecological communities.”
In the face of rapid changes in Earth’s biota, understanding the evolutionary processes that drive patterns of species diversity and coexistence in ecosystems has never been more pressing, write co-editors Jeannine Cavender-Bares of the University of Minnesota, David Ackerly of the University of California at Berkeley and Kenneth Kozak of the University of Minnesota.
“As human domination of our planet accelerates,” says Cavender-Bares, “our best hope for restoring and sustaining the ‘environmental services’ of the biological world is to understand how organisms assemble, persist and coexist in ecosystems across the globe.”
Papers in the volume address subjects such as the vanishingly rare oak savanna ecosystem of U.S. northern tier states, revealing an ancient footprint of history on the savanna as well as how it has fared in a 40-year fire experiment.
Other results cover the influence of ecological and evolutionary factors on hummingbird populations; habitat specialization in willow tree communities; growth strategies in tropical tree lineages and their implications for biodiversity in the Amazon region; and the characteristics of common urban plants.
“The studies in this issue show that knowledge of how organisms evolve reveals new insights into the ecology and persistence of species,” says Cavender-Bares.
Plants in urban yards, for example, are more closely related to each other–and live shorter lives–than do plants in rural areas, found Cavender-Bares and colleagues.
Their study compared plant diversity in private urban yards in the U.S. Midwest with that in the rural NSF Cedar Creek Long-Term Ecological Research site in Minnesota.
Cities are growing faster and faster, with unexpected effects, says Sonja Knapp of the Hemholtz Center for Environmental Research in Germany, lead author of the paper reporting the results.
“Understanding how urban gardening affects biodiversity is increasingly important,” says Cavender-Bares. “Urbanites should consider maintaining yards with a higher number of species.”
In the special issue, researchers also look at topics such as what determines the number of coexisting species in local and regional communities of salamanders. Kenneth Kozak of the University of Minnesota and John Wiens of Stony Brook University report that variation in the amount of time salamanders occupy different climate zones is the primary factor.
Evolution of an herbaceous flower called goldfields, and how that led to the plant’s affinity for certain habitats, is the subject of a paper by David Ackerly, Nancy Emery of Purdue University and colleagues. Emery is the paper’s lead author.
In all, 17 papers combine ecology and phylogenetics to offer new answers to long-standing questions about the patterns and processes of biodiversity on Planet Earth.
Alvin extends its mechanical arm to a high-temperature black smoker at Endeavor Segment.
(Photo Credit: Bruce Strickrott/WHOI)
By some estimates, a third of Earth’s organisms live in our planet’s rocks and sediments, yet their lives are almost a complete mystery.
This week, the work of microbiologist James Holden of the University of Massachusetts-Amherst and colleagues shines a light into this dark world.
In the journal Proceedings of the National Academy of Sciences (PNAS), they report the first detailed data on methane-exhaling microbes that live deep in the cracks of hot undersea volcanoes.
“Evidence has built that there’s an incredible amount of biomass in the Earth’s subsurface, in the crust and marine sediments, perhaps as much as all the plants and animals on the surface,” says Holden.
“We’re interested in the microbes in the deep rock, and the best place to study them is at hydrothermal vents at undersea volcanoes. Warm water there brings the nutrient and energy sources these microbes need.”
Just as biologists studied the habitats and life requirements of giraffes and penguins when they were new to science, Holden says, “for the first time we’re studying these subsurface microorganisms, defining their habitat requirements and determining how they differ among species.”
The result will advance scientists’ comprehension of biogeochemical cycles in the deep ocean, he and co-authors believe.
“Studies such as this add greatly to our understanding of microbial processes in the still poorly-known deep biosphere,” says David Garrison, program director in the National Science Foundation’s Division of Ocean Sciences, which funded the research.
The project also addresses such questions as what metabolic processes may have looked like on Earth three billion years ago, and what alien microbial life might look like on other planets.
Because the study involves methanogens–microbes that inhale hydrogen and carbon dioxide to produce methane as waste–it may also shed light on natural gas formation on Earth.
One major goal was to test results of predictive computer models and to establish the first environmental hydrogen threshold for hyperthermophilic (super-heat-loving), methanogenic (methane-producing) microbes in hydrothermal vent fluids.
“Models have predicted the ‘habitability’ of the rocky environments we’re most interested in, but we wanted to ground-truth these models and refine them,” Holden says.
In a two-liter bioreactor at UMass Amherst where the scientists could control hydrogen levels, they grew pure cultures of hyperthermophilic methanogens from their study site alongside a commercially available hyperthermophilic methanogen species.
The researchers found that growth measurements for the organisms were about the same. All grew at the same rate when given equal amounts of hydrogen and had the same minimum growth requirements.
Holden and Helene Ver Eecke at UMass Amherst used culturing techniques to look for organisms in nature and then study their growth in the lab.
Co-investigators Julie Huber at the Marine Biological Laboratory on Cape Cod provided molecular analyses of the microbes, while David Butterfield and Marvin Lilley at the University of Washington contributed geochemical fluid analyses.
Using the research submarine Alvin, they collected samples of hydrothermal fluids flowing from black smokers up to 350 degrees C (662 degrees F), and from ocean floor cracks with lower temperatures.
Samples were taken from Axial Volcano and the Endeavour Segment, both long-term observatory sites along an undersea mountain range about 200 miles off the coast of Washington and Oregon and more than a mile below the ocean’s surface.
“We used specialized sampling instruments to measure both the chemical and microbial composition of hydrothermal fluids,” says Butterfield.
“This was an effort to understand the biological and chemical factors that determine microbial community structure and growth rates.”
A happy twist awaited the researchers as they pieced together a picture of how the methanogens live and work.
At the low-hydrogen Endeavour site, they found that a few hyperthermophilic methanogens eke out a living by feeding on the hydrogen waste produced by other hyperthermophiles.
“This was extremely exciting,” says Holden. “We’ve described a methanogen ecosystem that includes a symbiotic relationship between microbes.”
The greatest risk factor for Alzheimer’s disease (AD) is advancing age. By age 85, the likelihood of developing the dreaded neurological disorder is roughly 50 percent. But researchers at the University of California, San Diego School of Medicine say AD hits hardest among the “younger elderly” – people in their 60s and 70s – who show faster rates of brain tissue loss and cognitive decline than AD patients 80 years and older.
The findings, reported online in the August 2, 2012 issue of the journal PLOS One, have profound implications for both diagnosing AD – which currently afflicts an estimated 5.6 million Americans, a number projected to triple by 2050 – and efforts to find new treatments. There is no cure for AD and existing therapies do not slow or stop disease progression.
“One of the key features for the clinical determination of AD is its relentless progressive course,” said Dominic Holland, PhD, a researcher at the Department of Neurosciences at UC San Diego and the study’s first author. “Patients typically show marked deterioration year after year. If older patients are not showing the same deterioration from one year to the next, doctors may be hesitant to diagnose AD, and thus these patients may not receive appropriate care, which can be very important for their quality of life.”
Holland and colleagues used imaging and biomarker data from participants in the Alzheimer’s Disease Neuroimaging Initiative, a multi-institution effort coordinated at UC San Diego. They examined 723 people, ages 65 to 90 years, who were categorized as either cognitively normal, with mild cognitive impairment (an intermediate stage between normal, age-related cognitive decline and dementia) or suffering from full-blown AD.
“We found that younger elderly show higher rates of cognitive decline and faster rates of tissue loss in brain regions that are vulnerable during the early stages of AD,” said Holland. “Additionally cerebrospinal fluid biomarker levels indicate a greater disease burden in younger than in older individuals.”
Holland said it’s not clear why AD is more aggressive among younger elderly.
“It may be that patients who show onset of dementia at an older age, and are declining slowly, have been declining at that rate for a long time,” said co-author Linda McEvoy, PhD, associate professor of radiology. “But because of cognitive reserve or other still-unknown factors that provide ‘resistance’ against brain damage, clinical symptoms do not manifest till later age.”
Another possibility, according to Holland, is that older patients may be suffering from mixed dementia – a combination of AD pathology and other neurological conditions. These patients might withstand the effects of AD until other adverse factors, such as brain lesions caused by cerebrovascular disease, take hold. At the moment, AD can only be diagnosed definitively by an autopsy. “So we do not yet know the underlying neuropathology of participants in this study,” Holland said.
Clinical trials to find new treatments for AD may be impacted by the differing rates, researchers said. “Our results show that if clinical trials of candidate therapies predominately enroll older elderly, who show slower rates of change over time, the ability of a therapy to successfully slow disease progression may not be recognized, leading to failure of the clinical trial,” said Holland. “Thus, it’s critical to take into account age as a factor when enrolling subjects for AD clinical trials.”
The obvious downside of the findings is that younger patients with AD lose more of their productive years to the disease, Holland noted. “The good news in all of this is that our results indicate those who survive into the later years before showing symptoms of AD will experience a less aggressive form of the disease.”
Researchers at the University of California, San Diego School of Medicine have identified a link between patients who undergo total nephrectomy – complete kidney removal – and erectile dysfunction. Results from the multi-center study were recently published online in the British Journal of Urology International.
“This is the first study in medical literature to suggest that surgery for kidney removal can negatively impact erectile function while partial kidney removal can protect sexual function,” said Ithaar Derweesh, MD, senior author, associate professor of surgery, UC San Diego School of Medicine and urologic surgeon at UC San Diego Health System.
The retrospective study evaluated two cohorts of men, totaling 432 patients, who underwent surgery for renal cell carcinoma. One group underwent complete removal of the kidney while the other had kidney-sparing surgery. Sexual function was accessed pre- and post-operatively with a sexual health questionnaire known as the International Index of Erectile Function.
“What we are seeing is a dramatic yet delayed effect. Approximately six years after surgery, patients who had a total nephrectomy were 3.5 times more likely to develop erectile dysfunction compared to those who had kidney reconstruction,” said Derweesh.
“The primary argument for kidney-sparing surgery over total kidney removal has been to preserve the kidney filtration function. However, we are also beginning to understand that total kidney removal may also increase the risk of metabolic diseases and significantly decrease quality of life,” said lead author Ryan Kopp, MD, chief resident, Division of Urology, UC San Diego School of Medicine.
Derweesh added that this is the latest in a series of studies that point to the wisdom of saving the kidney in appropriate patients. Prior research led by Derweesh also shows that partial nephrectomy can reduce the risk of osteoporosis and chronic kidney insufficiency, which can lead to cardiac events and metabolic disturbances. Further investigation is needed to prevent erectile dysfunction in patients and to predict its potential occurrence.
Funding for this study was provided by the Sexual Medicine Society of North America Scholars in Sexuality Research Grant.
Contributors to this paper included Ryan P. Kopp, Jonathan L. Silberstein, Caroline J. Colangelo, Wassim M. Bazzi and Christopher J. Kane of UCSD; Brian M. Dicks and Irwin Goldstein of UCSD and Alvarado Hospital; Reza Mehrazin, Aditya Bagrodia, Robert W. Wake, Anthony L. Patterson, and Jim Y. Wan of University of Tennessee.
Plastic electronics hold the promise of cheap, mass-produced devices. But plastic semiconductors have an important flaw: the electronic current is influenced by “charge traps” in the material. These traps, which have a negative impact on plastic light-emitting diodes and solar cells, are poorly understood.
However, a new study by a team of researchers from the University of Groningen and the Georgia Institute of Technology reveals a common mechanism underlying these traps and provides a theoretical framework to design trap-free plastic electronics. The results are presented in an advance online publication of the journal Nature Materials.
Plastic semiconductors are made from organic, carbon-based polymers, comprising a tunable forbidden energy gap. In a plastic light-emitting diode (LED), an electron current is injected into a higher molecular orbital, situated just above the energy gap. After injection, the electrons move toward the middle of the LED and fall down in energy across the forbidden energy gap, converting the energy loss into photons. As a result, an electrical current is converted into visible light.
However, during their passage through the semiconductor, a lot of electrons get stuck in traps in the material and can no longer be converted into light. In addition, this trapping process greatly reduces the electron current and moves the location where electrons are converted into photons away from the center of the device.
“This reduces the amount of light the diode can produce,” explained Herman Nicolai, first author of the Nature Materials paper.
The traps are poorly understood, and it has been suggested that they are caused by kinks in the polymer chains or impurities in the material.
“We’ve set out to solve this puzzle by comparing the properties of these traps in nine different polymers,” Nicolai explained. “The comparison revealed that the traps in all materials had a very similar energy level.”
The Georgia Tech group, led by Professor Jean-Luc Bredas in the School of Chemistry & Biochemistry, investigated computationally the electronic structure of a wide range of possible traps. “What we found out from the calculations is that the energy level of the traps measured experimentally matches that produced by a water-oxygen complex,” said Bredas.
Nicolai explains that “such a complex could easily be introduced during the manufacturing of the semiconductor material, even if this is done under controlled conditions.” The devices Nicolai studied were fabricated in a nitrogen atmosphere, “but this cannot prevent contamination with minute quantities of oxygen and water,” he noted.
The fact that the traps have a similar energy level means that it is now possible to estimate the expected electron current in different plastic materials. And it also points the way to trap-free materials. “The trap energy lies in the forbidden energy gap,” Nicolai explained.
This energy gap represents the difference in energy of the outer shell in which the electrons circle in their ground state and the higher orbital to which they can be moved to become mobile charge carriers. When such a mobile electron runs into a trap that is within the energy gap it will fall in, because the trap has a lower energy level.
“But if chemists could design semiconducting polymers in which the trap energy is above that of the higher orbital in which the electrons move through the material, they couldn’t fall in,” he suggested. “In this case, the energy level of the trap would be higher than that of the electron.”
The results of this study are therefore important for both plastic LEDs and plastic solar cells. “In both cases, the electron current should not be hindered by charge trapping. With our results, more efficient designs can be made,” Nicolai concluded.
The experimental work for this study was done in the Zernike Institute of Advanced Materials (ZIAM) at the faculty of Mathematics and Natural Sciences, University of Groningen, the Netherlands. The theoretical work to identify the nature of the trap was carried out at the School of Chemistry and Biochemistry and Center for Organic Photonics and Electronics at the Georgia Institute of Technology, Atlanta, USA.
The work at the University of Groningen was supported by the European Commission under contract FP7-13708 (AEVIOM). The work at Georgia Tech was supported by the MRSEC program of the National Science Foundation under award number DMR-0819885.