Unique skull find rebuts theories on species diversity in early humans

Oct. 17, 2013 — This is the best-preserved fossil find yet from the early era of our genus. The particularly interesting aspect is that it displays a combination of features that were unknown to us before the find. The skull, found in Dmanisi by anthropologists from the University of Zurich as part of a collaboration with colleagues in Georgia funded by the Swiss National Science Foundation, has the largest face, the most massively built jaw and teeth and the smallest brain within the Dmanisi group.find yet from the early era of our genus. The particularly interesting aspect is that it displays a combination of features that were unknown to us before the find. The skull, found in Dmanisi by anthropologists from the University of Zurich as part of a collaboration with colleagues in Georgia funded by the Swiss National Science Foundation, has the largest face, the most massively built jaw and teeth and the smallest brain within the Dmanisi group. It is the fifth skull to be discovered in Dmanisi. Previously, four equally well-preserved hominid skulls as well as some skeletal parts had been found there. Taken as a whole, the finds show that the first representatives of the genus Homo began to expand from Africa through Eurasia as far back as 1.85 million years ago.Diversity within a species instead of species diversityBecause the skull is completely intact, it can provide answers to various questions which up until now had offered broad scope for speculation. These relate to none less than the evolutionary beginning of the genus Homo in Africa around two million years ago at the beginning of the Ice Age, also referred to as the Pleistocene. …

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Most distant gravitational lens helps weigh galaxies

Oct. 17, 2013 — An international team of astronomers has found the most distant gravitational lens yet — a galaxy that, as predicted by Albert Einstein’s general theory of relativity, deflects and intensifies the light of an even more distant object. The discovery provides a rare opportunity to directly measure the mass of a distant galaxy. But it also poses a mystery: lenses of this kind should be exceedingly rare. Given this and other recent finds, astronomers either have been phenomenally lucky — or, more likely, they have underestimated substantially the number of small, very young galaxies in the early Universe.Light is affected by gravity, and light passing a distant galaxy will be deflected as a result. Since the first find in 1979, numerous such gravitational lenses have been discovered. In addition to providing tests of Einstein’s theory of general relativity, gravitational lenses have proved to be valuable tools. Notably, one can determine the mass of the matter that is bending the light — including the mass of the still-enigmatic dark matter, which does not emit or absorb light and can only be detected via its gravitational effects. The lens also magnifies the background light source, acting as a “natural telescope” that allows astronomers a more detailed look at distant galaxies than is normally possible.Gravitational lenses consist of two objects: one is further away and supplies the light, and the other, the lensing mass or gravitational lens, which sits between us and the distant light source, and whose gravity deflects the light. When the observer, the lens, and the distant light source are precisely aligned, the observer sees an Einstein ring: a perfect circle of light that is the projected and greatly magnified image of the distant light source.Now, astronomers have found the most distant gravitational lens yet. …

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Physical activity in parks can been boosted by modest marketing

Oct. 17, 2013 — Modest increases in marketing and outreach to local communities can increase the amount of physical activity that occurs in parks, providing a cost-effective way to potentially improve a community’s health, according to a new RAND Corporation study.The project, which examined 50 parks across Los Angeles, found that simple interventions such as increased signage boosted physical activity by 7 to 12 percent over the study period in relation to parks that did not make changes. The findings are published online by the American Journal of Preventive Medicine.”The study shows that environmental cues influence and change individual behavior, including physical behavior,” said Dr. Deborah A. Cohen, the study’s lead author and a senior natural scientist at RAND, a nonprofit research organization. “When physical activity opportunities and reminders become more obvious, whether they are overt signs or notices for classes or new walking paths, they may lead people to becoming more active, especially if they are already in a park.”Although most Americans live in a community with a network of parks and recreation facilities suited to exercise, most do not meet the national guidelines for physical activity. Those recommendations suggest adults engage in physical activity for 150 minutes per week, while children should do so for 60 minutes per day.An increase in physical activity among people in Finland over the past few decades has been attributed, in part, to an increased focus on local parks and sports facilities. In contrast, many U.S. municipalities — including Los Angeles — have trimmed support for public physical activity programs and parks.RAND researchers wanted to examine whether, given limited resources, parks could adjust their programming and outreach efforts to increase activity if they had better information about local use and activity preferences. The second question was whether the involvement of park advisory boards composed of community members would help improve the decisions made by park directors.To conduct the project, 50 parks in the City of Los Angeles that included a recreation center and full-time staff were randomized into three groups. …

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Face transplantation calls for ‘reverse craniofacial planning’

Dec. 10, 2012 — As surgical teams gain experience with facial transplantation, a careful approach to planning based on the principles of craniofacial surgery can help to maximize patient outcomes in terms of facial form and function, according to an article in The Journal of Craniofacial Surgery.

In patients with extensive facial defects including loss of the normal bone and soft tissue landmarks, a “reverse craniofacial planning” approach can restore normal facial relationships, the report suggests. The lead author was Dr. Edward J. Caterson, a member of the facial transplant team at Brigham and Women’s Hospital/Harvard Medical School, Boston.

Craniofacial Principles Applied to Facial Transplantation

Dr. Caterson and colleagues apply some basic principles of craniofacial surgery to the planning and performance of facial transplants. Although still a rare and relatively new procedure, facial transplantation now offers a reconstructive option for patients with severe facial deficits. Most patients who are candidates for facial transplant have loss of soft tissues only (such as skin, muscle, blood vessels, and nerves).

However, some patients also have defects of the underlying facial bones. In these cases, the challenge for the facial transplant team is nothing less than “the complete restoration of the structural anatomy of the craniofacial skeleton,” the authors write.

Through their experience with reconstructive surgery in patients with severe congenital deformities, craniofacial surgeons have developed an understanding of the “intimate functional relationship” between the facial soft tissue and supporting bone. In the traditional craniofacial procedure, the surgeon carefully plans and designs “bone movements that will translate into a desired change of the attached soft tissues.”

But in facial transplantation, the situation is essentially reversed: the degree of injury and the subsequent transplantation of facial soft tissues dictate the “osteosynthesis” of the craniofacial skeleton. Dr. Caterson and colleagues describe a simple but practical technique for surgical planning to promote proper positioning of the facial transplant. The technique applies “normative” data on facial landmarks and relationships and then transposes them onto the recipient.

Understanding the relationships of facial structure allows surgeons to compensate for missing bony or soft tissue landmarks. The authors provide a straightforward approach to establishing a plane of reference, allowing the facial transplant to be positioned in a proper relationship with the skull base and occlusal plane (teeth and lower face).

Optimal positioning of the facial transplant is essential not only to achieve the most normal-appearing result, but also to maximize function — particularly in eating and breathing. Dr. Caterson and colleagues emphasize that “proper positioning of the hard tissues of the allograft is the fundamental starting point for functional and aesthetic restoration.” As long as the bony structure is right, any cosmetic soft tissue problems that remain after surgery are relatively easy to correct.

The authors believe that such craniofacial principles are likely to become an increasingly important consideration — “especially with the trend toward full face transplantation.” In early experience, donor selection for face transplantation has focused mainly on immunological factors — similar to those used in organ transplantation.

In the future, transplant teams may become more sophisticated in donor selection — including assessment of the degree of “craniofacial match” between donors and recipients. In the meantime, Dr. Caterson and coauthors conclude, “[C]areful attention to the soft tissue relationships with the skeletal anatomy requires that face transplantation include ‘reverse craniofacial planning’ to optimize the form and function of the recipient’s new face.”

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Series of studies first to examine acupuncture’s mechanisms of action

Mar. 14, 2013 — While acupuncture is used widely to treat chronic stress, the mechanism of action leading to reported health benefits are not understood. In a series of studies at Georgetown University Medical Center (GUMC), researchers are demonstrating how acupuncture can significantly reduce the stress hormone response in an animal model of chronic stress.

The latest study was published today in the April issue of Journal of Endocrinology.

“Many practitioners of acupuncture have observed that this ancient practice can reduce stress in their patients, but there is a lack of biological proof of how or why this happens,” says the study’s lead author, Ladan Eshkevari, PhD, an associate professor of nursing at Georgetown University School of Nursing & Health Studies, a part of GUMC. “We’re starting to understand what’s going on at the molecular level that helps explain acupuncture’s benefit.”

Eshkevari, a physiologist, nurse anesthetist and certified acupuncturist, designed a series of studies in rats to test the effect of electronic acupuncture on levels of proteins and hormones secreted by biologic pathways involved in stress response.

Eshkevari used rats because these animals are often used to research the biological determinants of stress. They mount a stress response when exposed to winter-like temperatures for an hour a day.

“I used electroacupuncture because I could make sure that each animal was getting the same treatment dose,” she explains.

The spot used for the acupuncture needle is called “Zusanli,” which is reported to help relieve a variety of conditions including stress. As with rats, that acupuncture point for humans is on the leg below the knee.

The study utilized four groups of rats for a 10-day experiment: a control group that was not stressed and received no acupuncture; a group that was stressed for an hour a day and did not receive acupuncture; a group that was stressed and received “sham” acupuncture near the tail; and the experimental group that were stressed and received acupuncture to the Zusanli spot on the leg.

The researchers then measured blood hormone levels secreted by the hypothalamus pituitary adrenal (HPA) axis, which includes the hypothalamus, the pituitary gland and the adrenal gland. The interactions among these organs control reactions to stress and regulate digestion, the immune system, mood and emotions, sexuality and energy storage and expenditure.

They also measured levels of NPY, a peptide secreted by the sympathetic nervous system in rodents and humans. This system is involved in the “flight or fight” response to acute stress, resulting in constriction of blood flow to all parts of the body except the heart, lungs and brain (the organs most needed to react to danger). Chronic stress, however, can cause elevated blood pressure and cardiac disease.

“We found that electronic acupuncture blocks the chronic, stress-induced elevations of the HPA axis hormones and the sympathetic NPY pathway,” Eshkevari says. She adds that the rats receiving the sham electronic acupuncture had elevation of the hormones similar to that of the stress-only animals.

Eshkevari says this research complements her earlier reported work that focused only on NPY. In that study, Eshkevari and her team found that NPY levels were reduced in the experimental group almost to the level of the control group, while the rats that were stressed and not treated with Zusanli acupuncture had high levels of NPY (Experimental Biology and Medicine Dec. 2011).

“Our growing body of evidence points to acupuncture’s protective effect against the stress response,” she continues. Eshkevari says additional research is needed to examine if acupuncture would be effective in reducing hormone levels after the animals are exposed to the stress of cold temperatures, and whether a similar observation can be made in humans.

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Coffee, green tea, may help lower stroke risk, research shows

Mar. 14, 2013 — Green tea and coffee may help lower your risk of having a stroke, especially when both are a regular part of your diet, according to research published in Stroke: Journal of the American Heart Association.

“This is the first large-scale study to examine the combined effects of both green tea and coffee on stroke risks,” said Yoshihiro Kokubo, M.D., Ph.D., F.A.H.A., F.A.C.C., F.E.S.C., lead author of the study at Japan’s National Cerebral and Cardiovascular Center. “You may make a small but positive lifestyle change to help lower the risk of stroke by adding daily green tea to your diet.”

Researchers asked 83,269 Japanese adults about their green tea and coffee drinking habits, following them for an average 13 years. They found that the more green tea or coffee people drink, the lower their stroke risks.

People who drank at least one cup of coffee daily had about a 20 percent lower risk of stroke compared to those who rarely drank it.
People who drank two to three cups of green tea daily had a 14 percent lower risk of stroke and those who had at least four cups had a 20 percent lower risk, compared to those who rarely drank it.
People who drank at least one cup of coffee or two cups of green tea daily had a 32 percent lower risk of intracerebral hemorrhage, compared to those who rarely drank either beverage. (Intracerebral hemorrhage happens when a blood vessel bursts and bleeds inside the brain. About 13 percent of strokes are hemorrhagic.)

Participants in the study were 45 to 74 years old, almost evenly divided in gender, and were free from cancer and cardiovascular disease.

During the 13-years of follow-up, researchers reviewed participants’ hospital medical records and death certificates, collecting data about heart disease, strokes and causes of death. They adjusted their findings to account for age, sex and lifestyle factors like smoking, alcohol, weight, diet and exercise.

Green tea drinkers in the study were more likely to exercise compared to non-drinkers.

Previous limited research has shown green tea’s link to lower death risks from heart disease, but has only touched on its association with lower stroke risks. Other studies have shown inconsistent connections between coffee and stroke risks.

Initial study results showed that drinking more than two cups of coffee daily was linked to increasing coronary heart disease rates in age- and sex-adjusted analysis. But researchers didn’t find the association after factoring in the effects of cigarette smoking — underscoring smoking’s negative health impact on heart and stroke health.

A typical cup of coffee or tea in Japan was approximately six ounces. “However, our self-reported data may be reasonably accurate, because nationwide annual health screenings produced similar results, and our validation study showed relatively high validity.” Kokubo said. “The regular action of drinking tea, coffee, largely benefits cardiovascular health because it partly keeps blood clots from forming.”

Tea and coffee are the most popular drinks in the world after water, suggesting that these results may apply in America and other countries.

It’s unclear how green tea affects stroke risks. A compound group known as catechins may provide some protection. Catechins have an antioxidant anti-inflammatory effect, increasing plasma antioxidant capacity and anti-thrombogenic effects.

Some chemicals in coffee include chlorogenic acid, thus cutting stroke risks by lowering the chances of developing type 2 diabetes.

Further research could clarify how the interaction between coffee and green tea might help further lower stroke risks, Kokubo said.

Co-authors are: Isao Saito, M.D., Ph.D.; Kazumasa Yamagishi, M.D., Ph.D.; Hiroshi Yatsuya, M.D., Ph.D.; Junko Ishihara, Ph.D.; Manami Inoue, M.D., Ph.D.; and Shoichiro Tsugane, M.D., Ph.D.

The study was supported by Grants-in-Aid for Cancer Research and the Third-Term Comprehensive Ten-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare of Japan.

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People lie about their health related behaviors: Truth in barcodes

May 29, 2013 — People lie about their health related behaviors. It’s a problem that has long bedeviled health research on issues ranging from diet to exercise to smoking. And it’s not just that we have faulty memories. Many of us stretch the truth to make ourselves seem more virtuous in the eyes of the person in the white coat. That makes drawing conclusions about behaviors that affect health from self-reported records tricky.

Kusum Ailawadi, the Charles Jordan 1911 TU’12 Professor of Marketing at Tuck, has found a way around this problem — at least with regard to diet. Ailawadi and her colleagues examined data on several years of household food purchases from a marketing database that tracks what people buy at the store by having them scan their groceries with a device at home.

Paired with information on the same consumers’ health status and other demographics and data on the nutritional content of groceries, the researchers were able to track the link between factors such as income, food price, self-control, and health knowledge and the nutritional quality of their food purchases. “We know that recall is not accurate and we know people, especially obese people, are hesitant to admit to unhealthy eating,” says Ailawadi. “We were interested in actual purchasing behavior.”

The researchers were also able to study how food-buying patterns changed in the household following one member’s diagnosis of Type 2 diabetes, a chronic disease strongly linked with obesity. The latter point is of particular interest to Ailawadi given the expanding obesity epidemic and the ensuing scrutiny of processed food companies’ marketing practices.

According to the Centers for Disease Control and Prevention, the number of Americans with diabetes has more than tripled in the last 30 years to 20.9 million. As many as 95 percent of the cases are Type 2 diabetes and tens of millions more Americans are considered pre-diabetic, a situation that has helped lead to bans on trans fats and large servings of sugary drinks in New York City.

Some of the researchers’ findings were expected. In families where the head of household is highly educated and interested in nutrition, purchases of fatty and sugary foods were lower than in others. But price had the greatest effect by far on the healthfulness of peoples’ food purchases. In families where there was a Type 2 diabetes diagnosis, total purchases of sugary foods declined. Other results were more surprising. The study examined the performance of people with “high self-control,” as defined by healthy practices such as regular exercise and infrequent consumption of fast food or late-night snacks. As expected, the self-controllers bought less junk food like sugary cola and potato chips. Yet they offset this benefit with greater quantity of “healthy foods” like yogurt and cereal, leading to greater overall consumption of calories and sugar. This paradox of consuming more because of a perception of healthy attributes is known as a “health halo bias.”

“They’re putting more of the healthy foods in their mouths,” says Ailawadi. “They focus on quality and not on quantity: Is a food healthy or unhealthy? Once they categorize it as healthy they don’t focus on how much of it they’re eating.”

The study also finds that households with high levels of education, nutrition interest, and self-control were no better at responding to a diabetes diagnosis than others, although high income spurred improved responses. Also, households where a woman was diagnosed with diabetes or where the patient was younger made healthier changes than households where a man or an older person was diagnosed.

In addition, consumption of fatty foods like processed meats and salty snacks increased in households following a Type 2 diabetes diagnosis — even though doctors advise diabetics to cut both sugar and fat in their diets. As for sugar reduction, it came mainly from high-sugar colas and juices where low-sugar alternatives are easily available. Consumption of treats like cookies and ice cream did not decline following a diabetes diagnosis. “They taste good, they make you feel good,” says Ailawadi. “The human palate loves the combination of fat and sugar so they are hard to resist. And it doesn’t help that less unhealthy versions of these products are sold at a substantial price premium over the high fat/high sugar versions.”

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New flu strains prompt review of current research, call to redouble flu fight

May 29, 2013 — Despite numerous medical advances over the past century, the flu — a seasonal rite of passage for many around the world — still remains deadly and dangerous. An estimated 150,000 to 200,000 are hospitalized from influenza annually just in the United States, and between 30,000 to 50,000 die from this infection. The flu takes a heavy financial toll as well, leading countries to lose billions in direct medical costs, loss of productivity, and loss of life. In April of this year, a new flu strain known as H7N9, thought to have the potential to cause a pandemic, emerged in China. This novel strain’s high mortality rate, more than 20 percent, has led the Centers for Disease Control and Prevention to issue predictions of hospitalizations, deaths, and economic impacts several times higher than those caused by the typical seasonal flu.

In light of this new information, researchers have published a comprehensive overview of current flu research and efforts to combat this potentially lethal disease, including global surveillance to track the flu and vaccines and antiviral drugs currently in use. They also issue a call to improve efforts to fight the flu, including improving surveillance, developing new types of vaccines and drugs, and — most importantly — improving efforts to educate the public about the flu. This review article, entitled “Adapting global influenza management strategies to address emerging viruses” is published online by the American Journal of Physiology-Lung Cellular and Molecular Physiology.

The new article is written by Diana L. Noah and James W. Noah, both of the Southern Research Institute.

Fighting Flu Now In their review, the researchers explain that various strains of the flu circulate annually, with new strains arising through small mutations in current strains and others arising spontaneously. Of these, several H7 strains — so named for a portion of the virus called hemagglutinin — have caused flu outbreaks in various parts of the world. For the most part, these infectious have caused mild upper respiratory symptoms. However, as the authors’ review was completed, the130 known H7N9 infections had caused 31 fatalities — a morality rate of more than 20 percent.

Though the transmission mode of the strain is not yet known, some research suggests that H7N9 is being passed between humans, rather than from animals to humans, a dangerous sign that this outbreak has the potential to escalate into a deadly pandemic.

The authors point out that the best way to curb flu deaths is by preventing the disease altogether through vaccination. However, many countries, including the United States, have suboptimal flu vaccination rates. Even if more people got the flu shot, they write, the vaccine itself isn’t perfect — although each year’s flu vaccine has been crafted to inspire an immune response to several different flu strains, it’s not always a match to currently circulating strains.

Because the flu mutates each year, researchers must develop a new vaccine annually. But when surveillance efforts identify dangerous strains, the authors say, current manufacturing efforts may not be able to produce new vaccines quickly enough to protect a large population.

For those who have the bad luck of contracting the flu, antivirals are currently available to limit disease severity and shorten its duration. However, the review authors say, the antiviral drugs currently in use are increasingly becoming less effective due to the flu’s ability to constantly mutate.

Flu in the Future To better combat the flu, Noah and Noah review a number of current efforts. For example, they say, a universal vaccine that could fight any flu strain and still be useful year after year is in development. Also, several companies are now working on new ways to manufacture current flu vaccines more quickly to avoid the problem of a vaccine shortage in the face of a rapidly arising pandemic. Other companies are focusing on developing new antivirals to gain the upper hand on flu strains that are immune to current drugs, as well as other drugs that modulate the human host’s immune response to the flu, which researchers now know can cause as much or more damage as the virus itself.

With a call to support each of these efforts, the authors point out that educating the public about the flu is equally important. Outreach efforts to increase public awareness, hygiene practices, and vaccination rates could significantly stem flu deaths, they say.

“Key innovations that result in new antivirals and new, broadly effective vaccines will contribute to increased public health, but aggressive education programs may be the most important factor in immediately leveraging current vaccines and antivirals,” they write.

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Wit, grit and a supercomputer yield chemical structure of HIV capsid

May 29, 2013 — A team led by researchers at the University of Pittsburgh School of Medicine has described for the first time the 4-million-atom structure of the HIV’s capsid, or protein shell. The findings, highlighted on the cover of the May 30 issue of Nature, could lead to new ways of fending off an often-changing virus that has been very hard to conquer.

Scientists have long struggled to decipher how the HIV capsid shell is chemically put together, said senior author Peijun Zhang, Ph.D., associate professor, Department of Structural Biology, University of Pittsburgh School of Medicine.

“The capsid is critically important for HIV replication, so knowing its structure in detail could lead us to new drugs that can treat or prevent the infection,” she said. “This approach has the potential to be a powerful alternative to our current HIV therapies, which work by targeting certain enzymes, but drug resistance is an enormous challenge due to the virus’ high mutation rate.”

Previous research has shown that the cone-shaped shell is composed of identical capsid proteins linked together in a complex lattice of about 200 hexamers and 12 pentamers, Dr. Zhang said. But the shell is non-uniform and asymmetrical; uncertainty remained about the exact number of proteins involved and how the hexagons of six protein subunits and pentagons of five subunits are joined. Standard structural biology methods to decipher the molecular architecture were insufficient because they rely on averaged data, collected on samples of pieces of the highly variable capsid to identify how these pieces tend to go together.

Instead, the team used a hybrid approach, taking data from cryo-electron microscopy at an 8-angstrom resolution (a hydrogen atom measures 0.25 angstrom) to uncover how the hexamers are connected, and cryo-electron tomography of native HIV-1 cores, isolated from virions, to join the pieces of the puzzle. Collaborators at the University of Illinois then used their new Blue Waters supercomputer to run simulations at the petascale, involving 1 quadrillion operations per second, that positioned 1,300 proteins into a whole that reflected the capsid’s known physical and structural characteristics.

The process revealed a three-helix bundle with critical molecular interactions at the seams of the capsid, areas that are necessary for the shell’s assembly and stability, which represent vulnerabilities in the protective coat of the viral genome.

“The capsid is very sensitive to mutation, so if we can disrupt those interfaces, we could interfere with capsid function,” Dr. Zhang said. “The capsid has to remain intact to protect the HIV genome and get it into the human cell, but once inside it has to come apart to release its content so that the virus can replicate. Developing drugs that cause capsid dysfunction by preventing its assembly or disassembly might stop the virus from reproducing.”

The project was funded by National Institutes of Health grants GM082251, GM085043 and GM104601 and the National Science Foundation.

“By using a combination of experimental and computational approaches, this team of investigators has produced a clearer picture of the structure of HIV’s protective covering,” said the National Institutes of Health’s Michael Sakalian, Ph.D., who oversees this and other grants funded through an AIDS-related structural biology program. “The new structural details may reveal vulnerabilities that could be exploited by future therapeutics.”

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Gene therapy gives mice broad protection to pandemic flu strains, including 1918 flu

May 29, 2013 — Researchers at the Perelman School of Medicine, University of Pennsylvania have developed a new gene therapy to thwart a potential influenza pandemic. Specifically, investigators in the Gene Therapy Program, Department of Pathology and Laboratory Medicine, directed by James M. Wilson, MD, PhD, demonstrated that a single dose of an adeno-associated virus (AAV) expressing a broadly neutralizing flu antibody into the nasal passages of mice and ferrets gives them complete protection and substantial reductions in flu replication when exposed to lethal strains of H5N1 and H1N1 flu virus. These strains were isolated from samples associated from historic human pandemics — one from the infamous 1918 flu pandemic and another from 2009.

Wilson, Anna Tretiakova, PhD, Senior Research Scientist, Maria P. Limberis, PhD, Research Assistant Professor, all from the Penn Gene Therapy Program, and colleagues published their findings online this week in Science Translational Medicine ahead of print. In addition to the Penn scientists, the international effort included colleagues from the Public Health Agency of Canada, Winnipeg; the University of Manitoba, Winnipeg; and the University of Pittsburgh. Tretiakova is also the director of translational research, and Limberis is the director of animal models core, both with the Gene Therapy Program.

“The experiments described in our paper provide critical proof-of-concept in animals about a technology platform that can be deployed in the setting of virtually any pandemic or biological attack for which a neutralizing antibody exists or can be easily isolated,” says Wilson. “Further development of this approach for pandemic flu has taken on more urgency in light of the spreading infection in China of the lethal bird strain of H7N9 virus in humans.”

At the Ready Influenza infections are the seventh leading cause of death in the United States and result in almost 500,000 deaths worldwide per year, according to the Centers for Disease Control. The emergence of a new influenza pandemic remains a threat that could result in a much loss of life and worldwide economic disruption.

There is also interest by the military in developing an off-the-shelf prophylactic vaccine should soldiers be exposed to weaponized strains of infectious agents in biologic warfare.

Human antibodies with broad neutralizing activity against various influenza strains exist but their direct use as a prophylactic treatment is impractical. Now, yearly flu vaccines are made by growing the flu virus in eggs. The viral envelope proteins on the exterior, namely hemagglutinin, are cleaved off and used as the vaccine, but vary from year to year, depending on what flu strains are prevalent. However, high mutation rates in the proteins result in the emergence of new viral types each year, which elude neutralization by preexisting antibodies in the body (specifically specific receptor binding sites on the virus that are the targets of neutralizing antibodies).

This approach has led to annual vaccinations against seasonal strains of flu viruses that are predicted to emerge during the upcoming season. Strains that arise outside of the human population, for example in domestic livestock, are distinct from those that normally circulate in humans, and can lead to deadly pandemics.

These strains are also not effectively controlled by vaccines developed to human strains, as with the 2009 H1N1 pandemic. The vaccine development time for that strain, and in general, was not fast enough to support vaccination in response to an emerging pandemic.

Knowing this, the Penn team proposed a novel approach that does not require the elicitation of an immune response, which does not provide sufficient breadth to be useful against any strain of flu other than the one for which it was designed, as with conventional approaches.

The Penn approach is to clone into a vector a gene that encodes an antibody that is effective against many strains of flu and to engineer cells that line the nasal passages to express this broadly neutralizing antibody, effectively establishing broad-based efficacy against a wide range of flu strains.

A Broad Approach The rational for targeting nasal epithelial cells for antibody expression was to focus this expression to the site of the body where the virus usually enters the body and replicates which is the nasal and oral mucosa. Antibodies are normally expressed from B lymphocytes so one challenge was to design vectors that could deliver antibody genes to the non- lymphoid respiratory cells of the nasal and lung passages and could express functional antibody protein.

Targeting the respiratory cells was achieved through the use of a vector based on a primate virus — AAV9 — which was discovered in the Wilson laboratory and evaluated previously by Limberis for possibly treating patients with cystic fibrosis. The team constructed a genetic payload for AAV9 that expressed an antibody that was showed by other investigators to have broad activity against flu.

Efficacy of the treatment was tested in mice that were exposed to lethal quantities of three strains of H5N1 and two strains of H1N1, all of which have been associated with historic human pandemics (including the infamous H1N1 1918).

Flu virus rapidly replicated in untreated animals all of which needed to be euthanized. However, pretreatment with the AAV9 vector virtually shut down virus replication and provided complete protection against all strains of flu in the treated animals. The efficacy of this approach was also demonstrated in ferrets, which provide a more authentic model of human pandemic flu infection.

“The novelty of this approach is that we’re using AAV and we’re delivering the prophylactic vaccine to the nose in a non-invasive manner, not a shot like conventional vaccines that passively transfer antibodies to the general circulation,” says Limberis.

“There’s a long history of using antibodies for cancer and autoimmune disease, but only two have been approved for infectious diseases,” notes Tretikova. “This novel technique has allowed for the development of a prophylactic passive vaccine that is cost effective, easily administered, and quickly manufactured.”

The team is working with various stakeholders to accelerate the development of this product for pandemic flu and to explore the potential of AAV vectors as generic delivery vehicles for countermeasures of biological and chemical weapons.

The research was supported in part by ReGenX, the Public Health Agency of Canada (#531252), the Canadian Institutes of Health Research (#246355) and the National Institutes of Health (GM083602).

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Neuroscientists discover new phase of synaptic development

May 29, 2013 — Students preparing for final exams might want to wait before pulling an all-night cram session — at least as far as their neurons are concerned. Carnegie Mellon University neuroscientists have discovered a new intermediate phase in neuronal development during which repeated exposure to a stimulus shrinks synapses. The findings are published in the May 8 issue of the Journal of Neuroscience.

It’s well known that synapses in the brain, the connections between neurons and other cells that allow for the transmission of information, grow when they’re exposed to a stimulus. New research from the lab of Carnegie Mellon Associate Professor of Biological Sciences Alison L. Barth has shown that in the short term, synapses get even stronger than previously thought, but then quickly go through a transitional phase where they weaken.

“When you think of learning, you think that it’s cumulative. We thought that synapses started small and then got bigger and bigger. This isn’t the case,” said Barth, who also is a member of the joint Carnegie Mellon/University of Pittsburgh Center for the Neural Basis of Cognition. “Based on our data, it seems like synapses that have recently been strengthened are peculiarly vulnerable — more stimulation can actually wipe out the effects of learning.

“Psychologists know that for long-lasting memory, spaced training — like studying for your classes after very lecture, all semester long — is superior to cramming all night before the exam,” Barth said. “This study shows why. Right after plasticity, synapses are almost fragile — more training during this labile phases is actually counterproductive.”

Previous research from Barth’s lab established the biochemical mechanisms responsible for the strengthening of synapses in the neocortex, the part of the brain responsible for thought and language, but only measured the synapses after 24 hours. In the current study, post-doctoral student Jing A. Wen investigated how the synapses developed throughout the first 24 hours of exposure to a stimulus using a specialized transgenic mouse model created by Barth. The model senses its surroundings using only one whisker, which alters its ability to sense its environment and creates a sensory imbalance that increases plasticity in the brain. Since each whisker is linked to a specific area of the cortex, researchers can easily track neuronal changes.

Wen found that during this first day of learning, synapses go through three distinct phases. In the initiation phase, synaptic plasticity is spurred on by NMDA receptors. Over the next 12 hours or so, the synapses get stronger and stronger. As the stimulus is repeated, the NDMA receptors change their function and start to weaken the synapses in what the researchers have called the labile phase. After a few hours of weakening, another receptor, mGluR5, initiates a stabilization phase during which the synapses maintain their residual strength.

Furthermore, the researchers found that they could maintain the super-activated state found at the beginning of the labile phase by stopping the stimulus altogether or by injecting a glutamate receptor antagonist drug at an optimal time point. The findings are analogous to those seen in many psychological studies that use space training to improve memory.

“While synaptic changes can be long lasting, we’ve found that in this initial period there are a number of different things we could play with,” Barth said. “The discovery of this labile phase suggests there are ways to control learning through the manipulation of the biochemical pathways that maintain memory.”

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Charred micro-bunny sculpture shows promise of new material for 3-D shaping

May 29, 2013 — Though its surface has been turned to carbon, the bunny-like features can still be easily observed with a microscope. This rabbit sculpture, the size of a typical bacterium, is one of several whimsical shapes created by a team of Japanese scientists using a new material that can be molded into complex, highly conductive 3-D structures with features just a few micrometers across. Combined with state-of-the-art micro-sculpting techniques, the new resin holds promise for making customized electrodes for fuel cells or batteries, as well as biosensor interfaces for medical uses. The research team, which includes physicists and chemists from Yokohama National University, Tokyo Institute of Technology, and the company C-MET, Inc., presents its results in a paper published today in the Optical Society’s (OSA) open-access journal Optical Materials Express.

The work opens a door for researchers trying to create conductive materials in almost any complex shape at the microscopic or cellular level. “One of the most promising applications is 3-D microelectrodes that could interface with the brain,” says Yuya Daicho, graduate student at Yokohama National University and lead author of the paper. These brain interfaces, rows of needle-shaped electrodes pointing in the same direction like teeth on combs, can send or receive electrical signals from neurons and can be used for deep brain stimulation and other therapeutic interventions to treat disorders such as epilepsy, depression, and Parkinson’s disease. “Although current microelectrodes are simple 2-D needle arrays,” Daicho says, “our method can provide complex 3-D electrode arrays” in which the needles of a single device have different lengths and tip shapes, giving researchers more flexibility in designing electrodes for specialized purposes. The authors also envision making microscopic 3-D coils for heating applications.

Currently, researchers have access to materials that can be used to make complex 3-D structures. But the commercially available resins that work best with modern 3-D shaping techniques do not respond to carbonization, a necessary part of the electrode preparation process. In this stage, a structure is baked at a temperature high enough to turn its surface to carbon. The process of “carbonizing,” or charring, increases the conductivity of the resin and also increases its surface area, both of which make it a good electrode. Unfortunately, this process also destroys the resin’s shape; a sphere becomes an unrecognizable charred blob. What researchers needed were new materials that could be crafted using 3-D shaping techniques but that would also survive the charring process.

The Japanese team, led by Daicho and his advisor Shoji Maruo, sought to develop materials that would fit these needs. Trained as a chemist, Daicho developed a light-sensitive resin that included a material called Resorcinol Diglycidyl Ether (RDGE), typically used to dilute other resins but never before used in 3-D sculpting. The new mixture had a unique advantage over other compounds — it was a liquid, and therefore potentially suitable for manipulation using the preferred 3-D sculpting methods.

Daicho, Maruo, and colleagues tested three different concentrations of RDGE in their new compounds. Though there was shrinkage, the materials held their shapes during the charring process (controlled shrinkage of a microstructure can be a good thing in cases where miniaturization of a structure is desired). The resin with the lowest concentration of RDGE shrank 30 percent, while that with the highest concentration shrank 20 percent.

The researchers also tested their new resin’s ability to be manipulated using techniques specifically suited for 3-D shaping. In one technique, called microtransfer molding, the light-sensitive liquid was molded into a desired shape and then hardened by exposure to ultraviolet (UV) light. The other technique, preferred because of its versatility, made use of the liquid resin’s property of solidifying when exposed to a laser beam. In this process, called two-photon polymerization, researchers used the laser to “draw” a shape onto the liquid resin and build it up layer by layer. Once the objects were shaped, they were carbonized and viewed with a scanning electron microscope (SEM).

In addition to crafting pyramids and discs, the researchers reproduced the well-known “Stanford bunny,” a shape commonly used in 3-D modeling and computer graphics. Maruo says that when he first saw a picture of the rabbit structure taken with the SEM, he was delighted at how well it had held up during the charring process.

“When we got the carbon bunny structure, we were very surprised,” Maruo says. It was exciting, he continues, to see that “even with a very simple experimental structure, we could get this complicated 3-D carbon microstructure.” The rabbit’s shape would be much more difficult, expensive, and time-consuming to create using any of the existing processes compatible with carbonization, he adds.

Next steps for the team include fabricating usable carbon microstructures, as well as charring the resins at temperatures above the 800 degrees Celsius tested in this study. Moving to higher temperatures may destroy the microstructures, Maruo says, but there is a chance they will turn the surfaces into graphite, a higher-quality conductor than the carbonized surfaces they have created so far.

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Mind-body course has positive impact on well-being of medical students

May 1, 2013 — A Boston University School of Medicine (BUSM) study shows a mind-body class elective for medical students helps increase their self-compassion and ability to manage thoughts and tasks more effectively. The study, published in Medical Education Online, also discusses how this innovative course may help medical students better manage stress and feel more empowered to use mind-body skills with their patients.

Allison Bond, MA, a third-year medical student at BUSM, served as the paper’s first author. The course was designed and taught by co-author Heather Mason, MA, founder and director of the Minded Institute.

“An effective career in medicine requires technical competence and expertise, but just as important is the ability to empathize and connect with others, including patients,” said Robert Saper, MD, MPH, director of integrative medicine at Boston Medical Center and associate professor of family medicine at BUSM. However, medical students experience tremendous demands from workload, stress and competition from other students to succeed, resulting in burnout and a decreased ability to connect with patients, according to studies.

“Research has shown that mindfulness meditation and yoga may increase psychological well-being, which is why we looked at how a course based on these principles could impact medical students,” said Bond.

The 11-week course, Embodied Health: Mind-Body Approaches to Well-Being, was open to first and second year medical students in good academic standing. It was developed to teach students about mind-body approaches, and the neuroscience behind the activities, that they might not otherwise learn in medical school but could use to help their patients achieve better overall health. Offered for the first time in Spring 2012, it met once weekly and included a 30 minute lecture about the neuroscience of yoga, relaxation and breathing exercises followed by a 60 minute yoga, deep breathing and mediation session. Each student was asked to practice the techniques (breathing, yoga, etc.) at least three times a week.

Participants filled out surveys before the course began and after it ended, and were asked about perceived empathy, perceived stress, self-regulation (ability to develop, implement and flexibly maintain planned behavior to achieve goals) and self-compassion. They also were asked to compose a one-page essay at the completion of the course to discuss if what they learned helped them personally and whether it influenced their ability to cope with stress or enhanced their sense of well-being.

Overall, responses indicate a statistically significant increase in self-regulation and self-compassion. There also was a decrease in perceived stress and an increase in empathy, although not statistically significant. The essays also indicate that the course helped many students:

feel more aware of their bodies,
feel a sense of community among their peers despite the competitive environment,
build confidence in using mind-body skills with patients and
better manage stress.

“Our study provides compelling evidence that mind-body approaches have benefits for medical students and could have a positive impact on their interaction with peers and patients,” said Bond.

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