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New insights into how the mind influences the body

Neuroscientists at the University of Pittsburgh have identified the neural networks that connect the cerebral cortex to the adrenal medulla, which is responsible for the body’s rapid response in stressful situations. These findings, reported in the online Early Edition of the journal Proceedings of the National Academy of Sciences (PNAS), provide evidence for the neural basis of a mind-body connection.

Specifically, the findings shed new light on how stress, depression and other mental states can alter organ function, and show that there is a real anatomical basis for psychosomatic illness. The research also provides a concrete neural substrate that may help explain why meditation and certain exercises such as yoga and Pilates can be so helpful in modulating the body’s responses to physical, mental and emotional stress.

“Our results turned out to be much more complex and interesting than we imagined before we began this study,” said senior author Peter L. Strick, Ph.D., Thomas Detre Chair of the Department of Neurobiology and scientific director of the University of Pittsburgh Brain Institute.

In their experiments, the scientists traced the neural circuitry that links areas of the cerebral cortex to the adrenal medulla (the inner part of the adrenal gland, which is located above each kidney). The scientific team included lead author Richard P. Dum, Ph.D., research associate professor in the Department of Neurobiology; David J. Levinthal, M.D., Ph.D., assistant professor in the Department of Medicine; and Dr. Strick.

The scientists were surprised by the sheer number of neural networks they uncovered. Other investigators had suspected that one or, perhaps, two cortical areas might be responsible for the control of the adrenal medulla. The actual number and location of the cortical areas were uncertain. In the PNAS study, the Strick laboratory used a unique tracing method that involves rabies virus. This approach is capable of revealing long chains of interconnected neurons. Using this approach, Dr. Strick and his colleagues demonstrated that the control of the adrenal medulla originates from multiple cortical areas. According to the new findings, the biggest influences arise from motor areas of the cerebral cortex and from other cortical areas involved in cognition and affect.

Why does it matter which cortical areas influence the adrenal medulla? Acute responses to stress include a wide variety of changes such as a pounding heart, sweating and dilated pupils. These responses help prepare the body for action and often are characterized as “fight or flight responses.” Many situations in modern life call for a more thought-out reaction than simple “fight or flight,” and it is clear that we have some cognitive control (or what neuroscientists call “top-down” control) over our responses to stress.

“Because we have a cortex, we have options,” said Dr. Strick. “If someone insults you, you don’t have to punch them or flee. You might have a more nuanced response and ignore the insult or make a witty comeback. These options are part of what the cerebral cortex provides.”

Another surprising result was that motor areas in the cerebral cortex, involved in the planning and performance of movement, provide a substantial input to the adrenal medulla. One of these areas is a portion of the primary motor cortex that is concerned with the control of axial body movement and posture. This input to the adrenal medulla may explain why core body exercises are so helpful in modulating responses to stress. Calming practices such as Pilates, yoga, tai chi and even dancing in a small space all require proper skeletal alignment, coordination and flexibility.

The PNAS study also revealed that the areas of the cortex that are active when we sense conflict, or are aware that we have made an error, are a source of influence over the adrenal medulla. “This observation,” said Dr. Strick, “raises the possibility that activity in these cortical areas when you re-imagine an error, or beat yourself up over a mistake, or think about a traumatic event, results in descending signals that influence the adrenal medulla in just the same way as the actual event.” These anatomical findings have relevance for therapies that deal with post-traumatic stress.

Additional links with the adrenal medulla were discovered in cortical areas that are active during mindful mediation and areas that show changes in bipolar familial depression. “One way of summarizing our results is that we may have uncovered the stress and depression connectome,” says Dr. Strick.

Overall, these results indicate that circuits exist to link movement, cognition and affect to the function of the adrenal medulla and the control of stress. This circuitry may mediate the effects of internal states like chronic stress and depression on organ function and, thus, provide a concrete neural substrate for psychosomatic illness.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/08/160815185555.htm  Original web page at Science Daily

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Cognitive offloading: How the Internet is increasingly taking over human memory

Our increasing reliance on the Internet and the ease of access to the vast resource available online is affecting our thought processes for problem solving, recall and learning. In a new article published in the journal Memory, researchers at the University of California, Santa Cruz and University of Illinois, Urbana Champaign have found that ‘cognitive offloading’, or the tendency to rely on things like the Internet as an aide-mémoire, increases after each use. We might think that memory is something that happens in the head but increasingly it is becoming something that happens with the help of agents outside the head. Benjamin Storm, Sean Stone & Aaron Benjamin conducted experiments to determine our likelihood to reach for a computer or smartphone to answer questions. Participants were first divided into two groups to answer some challenging trivia questions — one group used just their memory, the other used Google. Participants were then given the option of answering subsequent easier questions by the method of their choice.

The results revealed that participants who previously used the Internet to gain information were significantly more likely to revert to Google for subsequent questions than those who relied on memory. Participants also spent less time consulting their own memory before reaching for the Internet; they were not only more likely to do it again, they were likely to do it much more quickly. Remarkably 30% of participants who previously consulted the Internet failed to even attempt to answer a single simple question from memory.

Lead author Dr Benjamin Storm commented, “Memory is changing. Our research shows that as we use the Internet to support and extend our memory we become more reliant on it. Whereas before we might have tried to recall something on our own, now we don’t bother. As more information becomes available via smartphones and other devices, we become progressively more reliant on it in our daily lives.”

This research suggests that using a certain method for fact finding has a marked influence on the probability of future repeat behaviour. Time will tell if this pattern will have any further reaching impacts on human memory than has our reliance on other information sources. Certainly the Internet is more comprehensive, dependable and on the whole faster than the imperfections of human memory, borne out by the more accurate answers from participants in the internet condition during this research. With a world of information a Google search away on a smartphone, the need to remember trivial facts, figures, and numbers is inevitably becoming less necessary to function in everyday life.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/08/160816085029.htm  Original web page at Science Daily

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* Pre-Hispanic Mexican civilization may have bred and managed rabbits and hares

Humans living in the pre-Hispanic Mexican city of Teotihuacan may have bred rabbits and hares for food, fur and bone tools, according to a study published August 17, 2016 in the open-access journal PLOS ONE by Andrew Somerville from the University of California San Diego, US, and colleagues.

Human-animal relationships often involve herbivore husbandry and have been key in the development of complex human societies across the globe. However, fewer large mammals suitable for husbandry were available in Mesoamerica. The authors of the present study looked for evidence of small animal husbandry in the pre-Hispanic city of Teotihuacan, which existed northeast of what is now Mexico City from A.D. 1-600. The authors performed stable carbon and oxygen isotope analysis of 134 rabbit and hare bone specimens from the ancient city and 13 modern wild specimens from central Mexico to compare their potential diets and ecology.

Compared to modern wild specimens, the authors found that Teotihuacan rabbit and hare specimens had carbon isotope values indicating higher levels of human-farmed crops, such as maize, in their diet. The specimens with the greatest difference in isotope values came from a Teotihuacan complex that contained traces of animal butchering and a rabbit sculpture.

While the ancient rabbits and hares included in this study could have consumed at least some farmed crops through raiding of fields or wild plants, the authors suggest their findings indicate that Teotihuacan residents may have provisioned, managed, or bred rabbits and hares for food, fur, and bone tools, which could be new evidence of small mammal husbandry in Mesoamerica.

“Because no large mammals such as goats, cows, or horses were available for domestication in pre-Hispanic Mexico, many assume that Native Americans did not have as intensive human-animal relationships as did societies of the Old World,” said Andrew Somerville. “Our results suggest that citizens of the ancient city of Teotihuacan engaged in relationships with smaller and more diverse fauna, such as rabbits and jackrabbits, and that these may have been just as important as relationships with larger animals.”

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/08/160817142539.htm  Original web page at Science Daily

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Zika infection may affect adult brain cells

Concerns over the Zika virus have focused on pregnant women due to mounting evidence that it causes brain abnormalities in developing fetuses. However, new research in mice from scientists at The Rockefeller University and La Jolla Institute for Allergy and Immunology suggests that certain adult brain cells may be vulnerable to infection as well. Among these are populations of cells that serve to replace lost or damaged neurons throughout adulthood, and are also thought to be critical to learning and memory.

“This is the first study looking at the effect of Zika infection on the adult brain,” says Joseph Gleeson, adjunct professor at Rockefeller, head of the Laboratory of Pediatric Brain Disease, and Howard Hughes Medical Institute investigator. “Based on our findings, getting infected with Zika as an adult may not be as innocuous as people think.”

Although more research is needed to determine if this damage has long-term biological implications or the potential to affect behavior, the findings suggest the possibility that the Zika virus, which has become widespread in Central and South America over the past eight months, may be more harmful than previously believed. The new findings were published in Cell Stem Cell on August 18.

“Zika can clearly enter the brain of adults and can wreak havoc,” says Sujan Shresta, a professor at the La Jolla Institute of Allergy and Immunology. “But it’s a complex disease — it’s catastrophic for early brain development, yet the majority of adults who are infected with Zika rarely show detectable symptoms. Its effect on the adult brain may be more subtle, and now we know what to look for.”

Early in gestation, before our brains have developed into a complex organ with specialized zones, they are comprised entirely of neural progenitor cells. With the capability to replenish the brain’s neurons throughout its lifetime, these are the stem cells of the brain. In healthy individuals, neural progenitor cells eventually become fully formed neurons, and it is thought that at some point along this progression they become resistant to Zika, explaining why adults appear less susceptible to the disease.

But current evidence suggests that Zika targets neural progenitor cells, leading to loss of these cells and to reduced brain volume. This closely mirrors what is seen in microcephaly, a developmental condition linked to Zika infection in developing fetuses that results in a smaller-than-normal head and a wide variety of developmental disabilities.

The mature brain retains niches of these neural progenitor cells that appear to be especially impacted by Zika. These niches — in mice they exist primarily in two regions, the subventricular zone of the anterior forebrain and the subgranular zone of the hippocampus — are vital for learning and memory.

Gleeson and his colleagues suspected that if Zika can infect fetal neural progenitor cells, it wouldn’t be a far stretch for them to also be able to infect these cells in adults. In a mouse model engineered by Shresta and her team to mimic Zika infection in humans, fluorescent biomarkers illuminated to reveal that adult neural progenitor cells could indeed be hijacked by the virus.

“Our results are pretty dramatic — in the parts of the brain that lit up, it was like a Christmas tree,” says Gleeson. “It was very clear that the virus wasn’t affecting the whole brain evenly, like people are seeing in the fetus. In the adult, it’s only these two populations that are very specific to the stem cells that are affected by virus. These cells are special, and somehow very susceptible to the infection.”

The researchers found that infection correlated with evidence of cell death and reduced generation of new neurons in these regions. Integration of new neurons into learning and memory circuits is crucial for neuroplasticity, which allows the brain to change over time. Deficits in this process are associated with cognitive decline and neuropathological conditions, such as depression and Alzheimer’s disease.

Gleeson and colleagues recognize that healthy humans may be able to mount an effective immune response and prevent the virus from attacking. However, they suggest that some people, such as those weakened immune systems, may be vulnerable to the virus is a way that has not yet been recognized.

“In more subtle cases, the virus could theoretically impact long-term memory or risk of depression,” says Gleeson, “but tools do not exist to test the long-term effects of Zika on adult stem cell populations.”

In addition to microcephaly, Zika has been linked to Guillain-Barré syndrome, a rare condition in which the immune system attacks parts of the nervous system, leading to muscle weakness or even paralysis. “The connection has been hard to trace since Guillain-Barré usually develops after the infection has cleared,” says Shresta. “We propose that infection of adult neural progenitor cells could be the mechanism behind this.”

There are still many unanswered questions, including exactly how translatable findings in this mouse model are to humans. Gleeson’s findings in particular raise questions such as: Does the damage inflicted on progenitor cells by the virus have lasting biological consequences, and can this in turn affect learning and memory? Or, do these cells have the capability to recover? Nonetheless, these findings raise the possibility that Zika is not simply a transient infection in adult humans, and that exposure in the adult brain could have long-term effects.

“The virus seems to be traveling quite a bit as people move around the world,” says Gleeson. “Given this study, I think the public health enterprise should consider monitoring for Zika infections in all groups, not just pregnant women.”

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/08/160818131134.htm Original web page at Science Daily

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Burnout is caused by mismatch between unconscious needs and job demands

New research shows that burnout is caused by a mismatch between a person’s unconscious needs and the opportunities and demands at the workplace. These results have implications for the prevention of jobburnout.

Imagine an accountant who is outgoing and seeks closeness in her social relationships, but whose job offers little scope for contact with colleagues or clients. Now imagine a manager, required to take responsibility for a team, but who does not enjoy taking center-stage or being in a leadership role. For both, there is a mismatch between their individual needs and the opportunities and demands at the workplace. A new study in the open-access journal Frontiers in Psychology shows that such mismatches put employees at risk of burnout.

Burnout is a state of physical, emotional, and mental exhaustion from work, which results in a lack of motivation, low efficiency, and a helpless feeling. Its health effects include anxiety, cardiovascular disease, immune disorders, insomnia, and depression. The financial burden from absenteeism, employee turnover, reduced productivity, and medical, legal, and insurance expenses due to burnout and general work-related stress is staggering: for example, the American Institute of Stress estimates the total cost to American enterprises at 300 billion US$ per year, while a 2012 study commissioned by the Health Programme of the European Union estimates the annual cost to EU enterprises at 272 billion €.

In the new study, researchers from the Universities of Zurich and Leipzig show that the unconscious needs of employees — their so-called “implicit motives” — play an important role in the development of burnout. The researchers focus on two important motives: the power motive, that is, the need to take responsibility for others, maintain discipline, and engage in arguments or negotiation, in order to feel strong and self-efficacious; and the affiliation motive, the need for positive personal relations, in order to feel trust, warmth, and belonging. A mismatch between job characteristics and either implicit motive can cause burnout, the results show. Moreover, a mismatch in either direction is risky: employees can get burned out when they have too much or not enough scope for power or affiliation compared to their individual needs.

“We found that the frustration of unconscious affective needs, caused by a lack of opportunities for motive-driven behavior, is detrimental to psychological and physical well-being. The same is true for goal-striving that doesn’t match a well-developed implicit motive for power or affiliation, because then excessive effort is necessary to achieve that goal. Both forms of mismatch act as ‘hidden stressors’ and can cause burnout,” says the leading author, Veronika Brandstätter, Professor of Psychology at the University of Zurich, Switzerland.

Brandstätter and colleagues recruited 97 women and men between 22 and 62 through the Swiss Burnout website, an information resource and forum for Swiss people suffering from burnout. Participants completed questionnaires about their physical well-being, degree of burnout, and the characteristics of their job, including its opportunities and demands.

To assess implicit motives — whose strength varies from person to person, but which can’t be measured directly through self-reports since they are mostly unconscious — Brandstätter et al. used an inventive method: they asked the participants to write imaginative short stories to describe five pictures, which showed an architect, trapeze artists, women in a laboratory, a boxer, and a nightclub scene. Each story was analyzed by trained coders, who looked for sentences about positive personal relations between persons (thus expressing the affiliation motive) or about persons having impact or influence on others (expressing the power motive). Participants who used many such sentences in their story received a higher score for the corresponding implicit motive.

The greater the mismatch between someone’s affiliation motive and the scope for personal relations at the job, the higher the risk of burnout, show the researchers. Likewise, adverse physical symptoms, such as headache, chest pain, faintness, and shortness of breath, became more common with increasing mismatch between an employee’s power motive and the scope for power in his or her job.

Importantly, these results immediately suggest that interventions that prevent or repair such mismatches could increase well-being at work and reduce the risk of burnout.

“A starting point could be to select job applicants in such a way that their implicit motives match the characteristics of the open position. Another strategy could be so-called “job crafting,” where employees proactively try to enrich their job in order to meet their individual needs. For example, an employee with a strong affiliation motive might handle her duties in a more collaborative way and try to find ways to do more teamwork,” says Brandstätter.

“A motivated workforce it the key to success in today’s globalized economy. Here, we need innovative approaches that go beyond providing attractive working conditions. Matching employees’ motivational needs to their daily activities at work might be the way forward. This may also help to address growing concerns about employee mental health, since burnout is essentially an erosion of motivation. To do so, we must increasingly take account of motivational patterns in the context of occupational stress research, and study person-environment-fit across entire organizations and industries,” says Beate Schulze, a Senior Researcher at the Department of Social and Occupational Medicine of the University of Leipzig and Vice-President of the Swiss Expert Network on Burnout.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/08/160811171643.htm  Original web page at Science Daily

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More evidence that ‘healthy obesity’ may be a myth

The term “healthy obesity” has gained traction over the past 15 years, but scientists have recently questioned its very existence. A study published August 18 in Cell Reports provides further evidence against the notion of a healthy obese state, revealing that white fat tissue samples from obese individuals classified as either metabolically healthy or unhealthy actually show nearly identical, abnormal changes in gene expression in response to insulin stimulation.

“The findings suggest that vigorous health interventions may be necessary for all obese individuals, even those previously considered to be metabolically healthy,” says first author Mikael Rydén of the Karolinska Institutet. “Since obesity is the major driver altering gene expression in fat tissue, we should continue to focus on preventing obesity.”

Obesity has reached epidemic proportions globally, affecting approximately 600 million people worldwide and significantly increasing the risk of heart disease, stroke, cancer, and type 2 diabetes. Since the 1940s, evidence supporting the link between obesity and metabolic and cardiovascular diseases has been steadily growing. But in the 1970s and 80s, experts began to question the extent to which obesity increases the risk for these disorders. Subsequent studies in the late 90s and early 2000s showed that some obese individuals display a relatively healthy metabolic and cardiovascular profile.

Recent estimates suggest that up to 30% of obese individuals are metabolically healthy and therefore may need less vigorous interventions to prevent obesity-related complications. A hallmark of metabolically healthy obesity is high sensitivity to the hormone insulin, which promotes the uptake of blood glucose into cells to be used for energy. However, there are currently no accepted criteria for identifying metabolically healthy obesity, and whether or not such a thing exists is now up for debate.

To address this controversy, Rydén, Carsten Daub, and Peter Arner of the Karolinska Institutet assessed responses to insulin in 15 healthy, never-obese participants and 50 obese subjects enrolled in a clinical study of gastric bypass surgery. The researchers took biopsies of abdominal white fat tissue before and at the end of a two-hour period of intravenous infusion of insulin and glucose. Based on the glucose uptake rate, the researchers classified 21 obese subjects as insulin sensitive and 29 as insulin resistant.

Surprisingly, mRNA sequencing of white fat tissue samples revealed a clear distinction between never-obese participants and both groups of obese individuals. White fat tissue from insulin-sensitive and insulin-resistant obese individuals showed nearly identical patterns of gene expression in response to insulin stimulation. These abnormal gene expression patterns were not influenced by cardiovascular or metabolic risk factors such as waist-to-hip ratio, heart rate, or blood pressure. The findings show that obesity rather than other common risk factors is likely the primary factor determining metabolic health.

“Our study suggests that the notion of metabolically healthy obesity may be more complicated than previously thought, at least in subcutaneous adipose tissue,” Rydén says. “There doesn’t appear to be a clear transcriptomic fingerprint that differentiates obese subjects with high or low insulin sensitivity, indicating that obesity per se is the major driver explaining the changes in gene expression.”

One limitation of the study is that it examined gene expression profiles only in subcutaneous white fat tissue, not other types of fat tissue or other organs. Moreover, all of the obese subjects were scheduled to undergo bariatric surgery, so the findings may only apply to individuals with severe obesity.

In future research, Rydén and his collaborators will track the study participants after bariatric surgery to determine whether weight loss normalizes gene expression responses to insulin. They will also look for specific genes linked to improved metabolic health in these individuals.

In the meantime, the study has an important take-home message. “Insulin-sensitive obese individuals may not be as metabolically healthy as previously believed,” Rydén says. “Therefore, more vigorous interventions may be necessary in these individuals to prevent cardiovascular and metabolic complications.”

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/08/160818131127.htm  Original web page web page at Science Daily

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Heart muscle made from stem cells aid precision cardiovascular medicine, study shows

Heart muscle cells made from induced pluripotent stem cells faithfully mirror the expression patterns of key genes in the donor’s native heart tissue, according to researchers at the Stanford University School of Medicine. As a result, the cells can be used as a proxy to predict whether a patient is likely to experience drug-related heart damage.

The discovery validates the use of such cells to test the potential cardiotoxicity of certain drugs and to devise new therapies for conditions like cardiomyopathy. Pinpointing people who are likely to suffer heart damage before these people undergo treatment could increase the safety profile of many medications, the researchers believe.

“Thirty percent of drugs in clinical trials are eventually withdrawn due to safety concerns, which often involve adverse cardiac effects,” said Joseph Wu, MD, PhD, director of Stanford’s Cardiovascular Institute and professor of cardiovascular medicine and of radiology. “This study shows that these cells serve as a functional readout to predict how a patient’s heart might respond to particular drug treatments and identify those who should avoid certain treatments.”

Wu is the senior author of the study, which will be published online Aug. 18 in Cell Stem Cell. Cardiovascular medicine instructor Elena Matsa, PhD, is the lead author of the research.

The ability to create stem cells from easily obtained skin or blood samples has revolutionized the concept of personalized medicine and made it possible to create many types of human tissue for use in the clinic. Researchers have wondered, however, whether the process of creating stem cells, and subsequently coaxing those stem cells to become other tissues, might affect the patterns of gene expression and even the ways the specialized cells function. If so, these changes could limit their clinical usefulness.

Matsa, Wu and their colleagues created heart muscle cells, or cardiomyocytes, from iPS cells from seven people not known to have genetic predisposition to cardiac problems. They sequenced the RNA molecules made by the heart muscle cells to learn which proteins the cells were making, and how much. They then compared the results within individuals — looking at the gene expression patterns of cardiomyocytes derived from several batches of iPS cells from each person — as well as among all seven study subjects.

They also investigated how the cardiomyocytes from each person responded to increasing amounts of two drugs, one called rosiglitazone that is sometimes used to treat Type 2 diabetes and another called tacrolimus that serves as an immunosuppressant to inhibit the rejection of transplanted organs. Each of the two drugs has been associated with adverse cardiac effects in some people, but it has not been possible to predict which patients will experience heart damage.

“We found that the gene expression patterns of the iPS cell-derived cardiomyocytes from each individual patient correlated very well,” said Matsa. “But there was marked variability among the seven people, particularly in genes involved in metabolism and stress responses. In fact, one of our subjects exhibited a very abnormal expression of genes in a key metabolic pathway.”

Heart muscle cells from this person, the researchers found, responded differently than the others to exposure to rosiglitazone. Concerns about its effect on cardiac function have caused the drug to be withdrawn from the market in Europe and have strictly limited its use in the United States.

“This person’s cells produced abnormal amounts of reactive oxygen species, were unable to regenerate their mitochondria and contracted much more weakly when exposed to rosiglitazone than cells derived from the other subjects,” said Matsa.

Although the researchers were unable to identify a specific genetic mutation likely to cause such an outcome, they were able to pinpoint an important metabolic pathway involved in the response to the drug by comparing the subject’s gene expression profile with that of the others whose cells were unaffected. They were also able to correct the defect by using a genome editing technique to boost the expression of a gene in the pathway and restore normal function.

Finally, although the researchers showed that meaningful variability exists in the gene expression patterns of the seven individuals, they couldn’t yet be certain that the iPS-derived cardiomyocytes faithfully replicated each person’s native heart tissue. To investigate, they created iPS cells from another three people who had undergone either heart biopsies or transplants. They then compared the iPS-derived cardiomyocytes with the matching native heart tissue and confirmed that the gene expression patterns correlated in many significant ways — particularly for genes involved in metabolic pathways critical to cardiac function.

“Many people talk about precision medicine or precision health, but there are only few examples of how to carry it out in a clinically meaningful way,” said Wu. “I think the patient-derived iPS cell platform gives us a surrogate window into the body and allows us to not only predict the body’s function but also to learn more about key disease-associated pathways.”

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https://www.sciencedaily.com/releases/2016/08/160818131132.htm  Original web page at Science Daily

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Citrus fruits could help prevent obesity-related heart disease, liver disease, diabetes

Oranges and other citrus fruits are good for you — they contain plenty of vitamins and substances, such as antioxidants, that can help keep you healthy. Now a group of researchers reports that these fruits also help prevent harmful effects of obesity in mice fed a Western-style, high-fat diet.

The researchers are presenting their work today at the 252nd National Meeting & Exposition of the American Chemical Society (ACS).

“Our results indicate that in the future we can use citrus flavanones, a class of antioxidants, to prevent or delay chronic diseases caused by obesity in humans,” says Paula S. Ferreira, a graduate student with the research team.

More than one-third of all adults in the U.S. are obese, according to the U.S. Centers for Disease Control and Prevention. Being obese increases the risk of developing heart disease, liver disease and diabetes, most likely because of oxidative stress and inflammation, Ferreira says. When humans consume a high-fat diet, they accumulate fat in their bodies. Fat cells produce excessive reactive oxygen species, which can damage cells in a process called oxidative stress. The body can usually fight off the molecules with antioxidants. But obese patients have very enlarged fat cells, which can lead to even higher levels of reactive oxygen species that overwhelm the body’s ability to counteract them.

Citrus fruits contain large amounts of antioxidants, a class of which are called flavanones. Previous studies linked citrus flavanones to lowering oxidative stress in vitro and in animal models. These researchers wanted to observe the effects of citrus flavanones for the first time on mice with no genetic modifications and that were fed a high-fat diet.

The team, at Universidade Estadual Paulista (UNESP) in Brazil, conducted an experiment with 50 mice, treating them with flavanones found in oranges, limes and lemons. The flavanones they focused on were hesperidin, eriocitrin and eriodictyol. For one month, researchers gave groups either a standard diet, a high-fat diet, a high-fat diet plus hesperidin, a high-fat diet plus eriocitrin or a high-fat diet plus eriodictyol.

The high-fat diet without the flavanones increased the levels of cell-damage markers called thiobarbituric acid reactive substances (TBARS) by 80 percent in the blood and 57 percent in the liver compared to mice on a standard diet. But hesperidin, eriocitrin and eriodictyol decreased the TBARS levels in the liver by 50 percent, 57 percent and 64 percent, respectively, compared with mice fed a high-fat diet but not given flavanones. Eriocitrin and eriodictyol also reduced TBARS levels in the blood by 48 percent and 47 percent, respectively, in these mice. In addition, mice treated with hesperidin and eriodictyol had reduced fat accumulation and damage in the liver.

“Our studies did not show any weight loss due to the citrus flavanones,” says Thais B. Cesar, Ph.D., who leads the team. “However, even without helping the mice lose weight, they made them healthier with lower oxidative stress, less liver damage, lower blood lipids and lower blood glucose.”

Ferreira adds, “This study also suggests that consuming citrus fruits probably could have beneficial effects for people who are not obese, but have diets rich in fats, putting them at risk of developing cardiovascular disease, insulin resistance and abdominal obesity.”

Next, the team will explore how best to administer these flavanones, whether in citrus juice, by consuming the fruit or developing a pill with these antioxidants. In addition, the team plans to conduct studies involving humans, Cesar says.

Cesar acknowledges funding from the Support Program for Scientific Development of the School of Pharmaceutical Sciences at UNESP and by Citrosuco, an orange juice production company in Matão, Sao Paulo, Brazil.

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/08/160821093054.htm  Original web page at Science Daily

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Human ‘super predator’ more terrifying than bears, wolves and Human ‘super predator’ more terrifying than bears, wolves and dogs

Bears, wolves and other large carnivores are frightening beasts but the fear they inspire in their prey pales in comparison to that caused by the human ‘super predator.’

A new study by Western University demonstrates that smaller carnivores, like European badgers, that may be prey to large carnivores, actually perceive humans as far more frightening. Globally, humans now kill smaller carnivores at much higher rates than large carnivores do, and these results indicate that smaller carnivores have learned to fear the human ‘super predator’ far more than they fear their traditional enemies.

These findings by Liana Zanette and Michael Clinchy from Western’s Faculty of Science, in collaboration with celebrated British biologist David Macdonald from University of Oxford’s Wildlife Conservation Research Unit (WildCRU) and others, were published this week in Behavioral Ecology.

Zanette, a professor in Western’s Department of Biology, and her colleagues experimentally demonstrated that smaller carnivores, like badgers, foxes and raccoons, that may appear to be habituated to humans because they live among us, are actually experiencing elevated levels of fear — living in fear of the human ‘super predator’ in human-dominated landscapes.

“Our previous research has shown that the fear large carnivores inspire can itself shape ecosystems. These new results indicate that the fear of humans, being greater, likely has even greater impacts on the environment, meaning humans may be distorting ecosystem processes even more than previously imagined,” explains Zanette, a wildlife ecologist. “These results have important implications for conservation, wildlife management and public policy.”

By frightening their prey, large carnivores help maintain healthy ecosystems by preventing smaller carnivores from eating everything in sight, and the loss of this ‘landscape of fear’ adds to conservation concerns regarding the worldwide loss of large carnivores. Fear of humans has been proposed to act as a substitute, but these new results demonstrate that the fear of humans is qualitatively different and cannot be expected to fulfill the same ecosystem function.

The team conducted the study on Europeans badgers in Wytham Woods, just outside of Oxford (UK). To experimentally compare their relative fearfulness, the team played badgers the sounds of bears, wolves, dogs and humans in their natural habitat and filmed their responses, using hidden automated speakers and cameras. Whereas hearing bears and dogs had some effect, simply hearing the sound of people speaking, in conversation, or reading passages from books, prevented most badgers from feeding entirely, and dramatically reduced the time spent feeding by those few badgers that were brave enough to venture forth — while hearing the sound of the human ‘super predator.’

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/07/160725135357.htm Original web page at Science Daily

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Scientists grow mini human brains

Scientists in Singapore have made a big leap on research on the ‘mini-brain’. These advanced mini versions of the human midbrain will help researchers develop treatments and conduct other studies into Parkinson’s Disease (PD) and aging-related brain diseases.

These mini midbrain versions are three-dimensional miniature tissues that are grown in the laboratory and they have certain properties of specific parts of the human brains. This is the first time that the black pigment neuromelanin has been detected in an organoid model. The study also revealed functionally active dopaminergic neurons.

The human midbrain, which is the information superhighway, controls auditory, eye movements, vision and body movements. It contains special dopaminergic neurons that produce dopamine — which carries out significant roles in executive functions, motor control, motivation, reinforcement, and reward. High levels of dopamine elevate motor activity and impulsive behaviour, whereas low levels of dopamine lead to slowed reactions and disorders like PD, which is characterised by stiffness and difficulties in initiating movements.

Also causing PD is the dramatic reduction in neuromelanin production, leading to the degenerative condition of patients, which includes tremors and impaired motor skills. This creation is a key breakthrough for studies in PD, which affects an estimated seven to 10 million people worldwide. Furthermore, there are people who are affected by other causes of parkinsonism. Researchers now have access to the material that is affected in the disease itself, and different types of studies can be conducted in the laboratory instead of through simulations or on animals. Using stem cells, scientists have grown pieces of tissue, known as brain organoids, measuring about 2 to 3 mm long. These organoids contain the necessary hallmarks of the human midbrain, which are dopaminergic neurons and neuromelanin.

Jointly led by Prof Ng Huck Hui from A*STAR’s Genome Institute of Singapore (GIS) and Assistant Prof Shawn Je from Duke-NUS Medical School, this collaborative research between GIS, Duke-NUS, and the National Neuroscience Institute (NNI) is funded by the National Medical Research Council’s Translational Clinical Research (TCR) Programme In Parkinson’s disease (PD) and A*STAR. Other collaborators are from the Lieber Institute for Brain Development, the Johns Hopkins University School of Medicine, and the Nanyang Technological University.

Assistant Prof Shawn Je from Duke-NUS Medical School’s Neuroscience & Behavioural Disorders Programme said, “It is remarkable that our midbrain organoids mimic human midbrain development. The cells divide, cluster together in layers, and become electrically and chemically active in three-dimensional environment like our brain. Now we can really test how these mini brains react to existing or newly developed drugs before treating patients, which will be a game changer for drug development.”

Prof Tan Eng King, Research Director and Senior Consultant, Department of Neurology at NNI and Lead PI of the TCR Programme in PD, remarked, “The human brain is arguably the most complex organ and chronic brain diseases pose considerable challenges to doctors and patients. This achievement by our Singapore team represents an initial but momentous scientific landmark as we continue to strive for better therapies for our patients.”

GIS Executive Director Prof Ng Huck Hui said, “Considering one of the biggest challenges we face in PD research is the lack of accessibility to the human brains, we have achieved a significant step forward. The midbrain organoids display great potential in replacing animals’ brains which are currently used in research; we can now use these midbrains in culture instead to advance our understanding and future studies for the disease, and perhaps even other related diseases.”

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https://www.sciencedaily.com/releases/2016/07/160730154504.htm Original web page at Science Daily

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Scientists identify immunological profiles of people who make powerful HIV antibodies

People living with HIV who naturally produce broadly neutralizing antibodies (bNAbs) that may help suppress the virus have different immunological profiles than people who do not, researchers report. While bNAbs cannot completely clear HIV infections in people who have already acquired the virus, many scientists believe a successful preventive HIV vaccine must induce bNAbs. The new findings indicate that bNAb production may be associated with specific variations in individual immune functions that may be triggered by unchecked HIV infection. Defining how to safely replicate these attributes in HIV-uninfected vaccine recipients may lead to better designed experimental vaccines to protect against HIV. The study was supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

Researchers led by a team at Duke University identified these immunologic variations by studying blood samples collected from people living with HIV by the NIAID-supported Center for HIV/AIDS Vaccine Immunology (CHAVI). The team compared blood samples from the 51 individuals with the highest level of bNAbs with samples taken from 51 individuals with few or no bNAbs present. The analysis performed revealed that many variations in immune cell function triggered by chronic HIV infection are associated with high levels of bNAbs. The specific changes included a higher frequency of antibodies that attack one’s own cells, called autoantibodies; fewer immune regulatory T cells, which were also less active in these individuals; and a higher frequency of memory T follicular helper immune cells.

With this immune system configuration, the activity of antibody-producing immune cells called B cells may be less restricted because they are supported by T follicular helper cells and may be hindered by regulatory T cells. This, in turn, could lead to more efficient production of protective bNAbs against HIV. These findings support approaches to developing an HIV vaccine that involve modifying an individual’s immune system to mimic these conditions through the addition of vaccine boosters called adjuvants or other means.

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https://www.sciencedaily.com/releases/2016/07/160729143030.htm Original web page at Science Daily

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Financial cycles of acquisition and ‘buybacks’ threaten public access to breakthrough drugs

New research on the financial practices surrounding a ‘wonder drug’ with a more than 90% cure rate for hepatitis C — a blood-borne infection that damages the liver over many years — shows how this medical breakthrough, developed with the help of public funding, was acquired by a major pharmaceutical company following a late-stage bidding war.

The research shows how that company more than doubled the drug’s price over original pricing estimates, calculating “how much health systems could bear” according to researchers, and channelled billions of dollars in profits into buying its own shares rather than funding further research.

In this way, the company, Gilead Sciences, passed significant rewards on to shareholders while charging public health services in the US up to $86k per patient, and NHS England almost £35k per patient, for a three month course of the drug.

The high prices have contributed to a rationing effect: many public systems across the US and Europe treat only the sickest patients with the new drug, despite its extraordinary cure rate, and the fact that earlier treatment of an infectious disease gives it less opportunity to spread.

Gilead’s strategy of acquisitions and buybacks is an example of an industry-wide pattern, say the researchers. Many big pharmaceutical companies now rely on innovation emerging from public institutes, universities, and venture-capital supported start-ups — acquiring the most promising drug compounds once there is a level of “certainty,” rather than investing in their own internal research and development.

The researchers, from Cambridge University’s Department of Sociology, say this effectively leaves the public “paying twice”: firstly for the initial research, and then for patent-protected high priced medications. A summary of their research has been commissioned by the British Medical Journal (BMJ) and is published today.

“Large pharmaceutical companies rarely take a drug from early stage research all the way to patients. They often operate as regulatory and acquisition specialists, returning most of the subsequent profits to shareholders and keeping some to make further acquisitions,” said lead researcher Victor Roy, a Cambridge Gates Scholar.

The study’s senior author, Prof Lawrence King, said: “Drug research involves trial and error, and can take years to bear fruit — too long for companies that need to show the promise of annual growth to investors, so acquisitions are often the best way to generate this growth.”

There are an estimated 150 million people worldwide chronically infected with hepatitis C. It disproportionately affects vulnerable groups such as drug users and HIV sufferers, and can ultimately lead to liver failure through cirrhosis if left untreated.

Roy and King’s article tells the story of the curative drug Sofosbuvir. The compound was developed by a start-up that emerged from an Emory-based laboratory that received funding from the US National Institutes of Health and the US Veterans Administration.

The start-up, Pharmasset, eventually raised private funding to develop sofosbuvir. When Phase II trials proved more promising than Gilead’s in-house hepatitis C prospects, it acquired Pharmasset for $11bn following a bidding war — the final weeks of which saw Pharmasset’s valuation rocket by nearly 40%.

“The cost of this late stage arms race for revenues has become part of the industry justification for high drug prices,” write Roy and King.

Once Sofosbuvir was market-ready in 2013, Gilead set a price of $84k. A US Senate investigation later revealed that Pharmasset had initially considered a price of $36k.

By the first quarter of 2016, Gilead had accumulated over $35bn in revenue from hepatitis C medicines in a little over two years — nearly 40 times Gilead and Pharmasset’s combined reported costs for developing the medicines.

Last year, Gilead announced that a lion’s share of those profits — some $27bn — will go towards ‘share buybacks’: purchasing its own shares to increase the value of the remaining ones for shareholders. By contrast, between 2013 and 2015 Gilead increased research investment by $0.9bn to $3bn total.

“Share buybacks are a financial manoeuvre that emerged during the early 1980s due to a change in rules for corporations by the Reagan administration. The financial community now expects companies to reward shareholders with buybacks, but directing profit into buybacks can mean cannibalising innovation,” said Roy.

A further example they cite is that of Merck, who spent $8.4bn in 2014 to acquire a drug developer specialising in staph infections. The next year they closed the developer’s early stage research unit, laying off 120 staff. Three weeks after that, Merck announced an extra $10bn in share buybacks.

In the BMJ article, the researchers set out a number of suggestions to counter the consequences of the current financial model. These include giving health systems greater bargaining power to negotiate deals for breakthrough treatments, and limiting share buybacks.

Roy and King also highlight a possible future model that uses a mix of grants and major milestone prizes to “push” and “pull” promising therapies into wider application, and, crucially, uncouples drug prices from supposed development costs, including those added by shareholder expectations. They write that this approach may be attempted for areas of major public health concern.

“The treatments for Hepatitis C may portend a future of expensive therapies for Alzheimer’s to many cancers to HIV/AIDS. Health systems and patients could face growing financial challenges,” said King.

“We need to recognise what current business models around drug development might mean for this future.”

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https://www.sciencedaily.com/releases/2016/07/160727194358.htm  Original web page at Science Daily

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Hybrid treatment hunts down and kills leukemia cells

Researchers at UC Davis and Ionis Pharmaceuticals have developed a hybrid treatment that harnesses a monoclonal antibody to deliver antisense DNA to acute lymphoblastic leukemia (ALL) cells and that may lead to less toxic treatments for the disease.

The study, published in the journal Molecular Medicine, demonstrated that once delivered, the therapeutic DNA reduced levels of MXD3, a protein that helps cancer cells survive. This novel conjugate therapy showed great promise in animal models, destroying ALL cells while limiting other damage.

“We’ve shown, for the first time, that anti-CD22 antibody-antisense conjugates are a potential therapeutic agent for ALL,” said Noriko Satake, associate professor in the Department of Pediatrics at UC Davis. “This could be a new type of treatment that kills leukemia cells with few side effects.”

ALL is the most common type of childhood cancer. It is a disease in which the bone marrow makes too many immature lymphocytes, a type of white blood cell. While most children survive ALL, many patients suffer late or long-term side effects from treatment, which may include heart problems, growth and development delays, secondary cancers and infertility.

Antisense oligonucleotides are single strands of DNA that can bind to messenger RNA, preventing it from making a protein. While antisense technology has long shown therapeutic potential, getting the genetic material inside target cells has been a problem.

In the study, researchers attached antisense DNA that inhibits the MXD3 protein to an antibody that binds to CD22, a protein receptor expressed almost exclusively in ALL cells and normal B cells.

Once the antibody binds to CD22, the conjugate is drawn inside the leukemia cell, allowing the antisense molecule to prevent MXD3 production. Without this anti-apoptotic protein, ALL cells are more prone to cell death.

The hybrid treatment was effective against ALL cell lines in vitro and primary (patient-derived) ALL cells in a xenograft mouse model. Animals that received the hybrid therapy survived significantly longer than those in the control group.

Designed to be selective, the treatment only targets cells that express CD22. While it does attack healthy B cells, the therapy is expected to leave blood stem cells and other tissues unscathed.

“You really don’t want to destroy hematopoietic stem cells because then you have to do a stem cell transplant, which is an extremely intensive therapy,” noted Satake. “Our novel conjugate is designed so that it does not harm hair, eyes, heart, kidneys or other types of cells.”

While the study shows the conjugate knocked down MXD3, researchers still have to figure out how this was accomplished. In addition, they will investigate combining this treatment with other therapies. Because it hastens cell death, the conjugate could make traditional chemotherapy drugs more effective. In addition, the approach might work against other cancers.

“You can see this as proof of principle,” Satake said. “You could switch the target and substitute the antibody, which could be used to treat other cancers or even other diseases.”

Access the full report at: http://static.smallworldlabs.com/molmedcommunity/content/pdfstore/15_210_Satake.pdf

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https://www.sciencedaily.com/releases/2016/07/160728155631.htm  Original web page at Science Daily

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* Human nose holds novel antibiotic effective against multiresistant pathogens

A potential lifesaver lies unrecognized in the human body: Scientists at the University of Tübingen and the German Center for Infection Research (DZIF) have discovered that Staphylococcus lugdunensis which colonizes in the human nose produces a previously unknown antibiotic. As tests on mice have shown, the substance which has been named Lugdunin is able to combat multiresistant pathogens, where many classic antibiotics have become ineffective. The research results will be published on 27 July in the scientific journal Nature.

Infections caused by antibiotic-resistant bacteria — like the pathogen Staphylococcus aureus (MRSA) which colonizes on human skin — are among the leading causes of death worldwide. The natural habitat of harmful Staphylococcus bacteria is the human nasal cavity. In their experiments, Dr. Bernhard Krismer, Alexander Zipperer and Professor Andreas Peschel from the Interfaculty Institute for Microbiology and Infection Medicine Tübingen (IMIT) observed that Staphylococcus aureus is rarely found when Staphylococcus lugdunensis is present in the nose.

“Normally antibiotics are formed only by soil bacteria and fungi,” says Professor Andreas Peschel. “The notion that human microflora may also be a source of antimicrobial agents is a new discovery.” In future studies, scientists will examine whether Lugdunin could actually be used in therapy. One potential use is introducing harmless Lugdunin-forming bacteria to patients at risk from MRSA as a preventative measure.

Researchers from the Institute of Organic Chemistry at the University of Tübingen closely examined the structure of Lugdunin and discovered that it consists of a previously unknown ring structure of protein blocks and thus establishes a new class of materials.

Antibiotic resistance is a growing problem for physicians. “There are estimates which suggests that more people will die from resistant bacteria in the coming decades than cancer,” says Dr. Bernhard Krismer. “The improper use of antibiotics strengthens this alarming development” he continues. As many of the pathogens are part of human microflora on skin and mucous membranes, they cannot be avoided. Particularly for patients with serious underlying illnesses and weakened immune systems they represent a high risk — these patients are easy prey for the pathogens. Now the findings made by scientists at the University of Tübingen open up new ways to develop sustainable strategies for infection prevention and to find new antibiotics — also in the human body.

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https://www.sciencedaily.com/releases/2016/07/160729093039.htm  Original web page at  Science Daily

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An hour of moderate exercise a day enough to counter health risks from prolonged sitting

The health risks associated with sitting for eight or more hours a day — whether at work, home or commuting — can be eliminated with an hour or more of physical activity a day, according to a study from an international team of researchers.

Ever since a study back in 1953 discovered that London bus drivers were at greater risk of heart disease compared to bus conductors, scientists have found increasing evidence that lack of physical activity is a major risk factor for several diseases and for risk of early death. Recent estimates suggest that more than 5 million people die globally each year as a result of failing to meet recommended daily activity levels.

Studies in high-income countries have suggested that adults spend the majority of their waking hours sitting down. A typical day for many people is driving to work, sitting in an office, driving home and watching TV. Current physical activity guidelines recommend that adults do at least 150 minutes of moderate intensity exercise per week.

In an analysis published today in The Lancet that draws together a number of existing studies, an international team of researchers asked the question: if an individual is active enough, can this reduce, or even eliminate, the increased risk of early death associated with sitting down?

In total the researchers analysed 16 studies, which included data from more than one million men and women. The team grouped individuals into four quartiles depending on their level of moderate intensity physical activity, ranging from less than 5 minutes per day in the bottom group to over 60 minutes in the top. Moderate intensity exercise was defined as equating to walking at 3.5 miles/hour or cycling at 10 miles/hour, for example.

The researchers found that 60 to 75 minutes of moderate intensity exercise per day were sufficient to eliminate the increased risk of early death associated with sitting for over eight hours per day. However, as many as three out of four people in the study failed to reach this level of daily activity.

The greatest risk of early death was for those individuals who were physically inactive, regardless of the amount of time sitting — they were between 28% and 59% more likely to die early compared with those who were in the most active quartile — a similar risk to that associated with smoking and obesity. In other words, lack of physical activity is a greater health risk than prolonged sitting.

“There has been a lot of concern about the health risks associated with today’s more sedentary lifestyles,” says Professor Ulf Ekelund from the Medical Research Council Epidemiology Unit at the University of Cambridge. “Our message is a positive one: it is possible to reduce — or even eliminate — these risks if we are active enough, even without having to take up sports or go to the gym.

“For many people who commute to work and have office-based jobs, there is no way to escape sitting for prolonged periods of time. For these people in particular, we cannot stress enough the importance of getting exercise, whether it’s getting out for a walk at lunchtime, going for a run in the morning or cycling to work. An hour of physical activity per day is the ideal, but if this is unmanageable, then at least doing some exercise each day can help reduce the risk.”

The researchers acknowledge that there are limitations to the data analysed, which mainly came from participants aged 45 years and older and living in western Europe, the US and Australia. However, they believe that the strengths of the analysis outweigh these limitations. Most importantly, the researchers asked all included studies to reanalyse their data in a harmonized manner, an approach that has never before been adopted for a study of this size and therefore also provides much more robust effect estimates compared with previous studies.

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Scientists move closer to developing therapeutic window to the brain

Researchers at the University of California, Riverside are bringing their idea for a ‘Window to the Brain’ transparent skull implant closer to reality through the findings of two studies that are forthcoming in the journals Lasers in Surgery and Medicine and Nanomedicine: Nanotechnology, Biology and Medicine.

The implant under development, which literally provides a ‘window to the brain,’ will allow doctors to deliver minimally invasive, laser-based treatments to patients with life-threatening neurological disorders, such as brain cancers, traumatic brain injuries, neurodegenerative diseases and stroke. The recent studies highlight both the biocompatibility of the implant material and its ability to endure bacterial infections.

The Window to the Brain project is a multi-institution, interdisciplinary partnership led by Guillermo Aguilar, professor of mechanical engineering in UCR’s Bourns College of Engineering, and Santiago Camacho-López, from the Centro de Investigación Científica y de Educación Superior de Ensenada (CICESE) in Mexico.

The project began when Aguilar and his team developed a transparent version of the material yttria-stabilized zirconia (YSZ) — the same ceramic product used in hip implants and dental crowns. By using this as a window-like implant, the team hopes doctors will be able to aim laser-based treatments into patients’ brains on demand and without having to perform repeated craniotomies, which are highly invasive procedures used to access the brain.

The internal toughness of YSZ, which is more impact resistant than glass-based materials developed by other researchers, also makes it the only transparent skull implant that could conceivably be used in humans. The two recent studies further support YSZ as a promising alternative for currently available cranial implants.

Published July 8 in Lasers in Surgery and Medicine, the most recent study demonstrates how the use of transparent YSZ may allow doctors to combat bacterial infections, which are a leading reason for cranial implant failure. In lab studies, the researchers treated E-Coli infections by aiming laser light through the implant without having to remove it and without damaging the surrounding tissues.

“This was an important finding because it showed that the combination of our transparent implant and laser-based therapies enables us to treat not only brain disorders, but also to tackle bacterial infections that are common after cranial implants. These infections are especially challenging to treat because many antibiotics do not penetrate the blood brain barrier,” said Devin Binder, M.D., a neurosurgeon and neuroscientist in UCR’s School of Medicine and a collaborator on the project.

Another recent study, published in the journal Nanomedicine: Nanotechnology, Biology and Medicine, explored the biocompatibility of YSZ in an animal model, where it integrated into the host tissue without causing an immune response or other adverse effects.

“The YSZ was actually found to be more biocompatible than currently available materials, such as titanium or thermo-plastic polymers, so this was another piece of good news in our development of transparent YSZ as the material of choice for cranial implants,” Aguilar said.

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https://www.sciencedaily.com/releases/2016/07/160712133916.htm Original web page at Science Daily

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What free will looks like in the brain

Johns Hopkins University researchers are the first to glimpse the human brain making a purely voluntary decision to act.

Unlike most brain studies where scientists watch as people respond to cues or commands, Johns Hopkins researchers found a way to observe people’s brain activity as they made choices entirely on their own. The findings, which pinpoint the parts of the brain involved in decision-making and action, are now online, and due to appear in a special October issue of the journal Attention, Perception, & Psychophysics.

“How do we peek into people’s brains and find out how we make choices entirely on our own?” asked Susan Courtney, a professor of psychological and brain sciences. “What parts of the brain are involved in free choice?”

The team devised a novel experiment to track a person’s focus of attention without using intrusive cues or commands. Participants, positioned in MRI scanners, were left alone to watch a split screen as rapid streams of colorful numbers and letters scrolled past on each side. They were asked simply to pay attention to one side for a while, then to the other side — when to switch sides was entirely up to them. Over an hour, the participants switched their attention from one side to the other dozens of times.

Researchers monitored the participants’ brains as they watched the media stream, both before and after they switched their focus.

For the first time, researchers were able to see both what happens in a human brain the moment a free choice is made, and what happens during the lead-up to that decision — how the brain behaves during the deliberation over whether to act.

The actual switching of attention from one side to the other was closely linked to activity in the parietal lobe, near the back of the brain. The activity leading up to the choice — that is, the period of deliberation — occurred in the frontal cortex, in areas involved in reasoning and movement, and in the basal ganglia, regions deep within the brain that are responsible for a variety of motor control functions including the ability to start an action. The frontal-lobe activity began earlier than it would have if participants had been told to shift attention, clearly demonstrating that the brain was preparing a purely voluntary action rather than merely following an order.

Together, the two brain regions make up the core components underlying the will to act, the authors concluded.

“What’s truly remarkable about this project,” said Leon Gmeindl, a research scientist at Johns Hopkins and lead author of the study, “is that by devising a way to detect brain events that are otherwise invisible — that is, a kind of high-tech ‘mind reading’ — we uncovered important information about what may be the neural underpinnings of volition, or free will.”

Now that scientists have a way to track choices made from free will, they can use the technique to determine what’s happening in the brain as people wrestle with other, more complex decisions. For instance, researchers could observe the brain as someone tried to decide between snacking on a doughnut or on an apple — watching as someone weighed short-term rewards against long-term rewards, and perhaps being able to pinpoint the tipping point between the two.

“We now have the ability to learn more about how we make decisions in the real world,” Courtney said.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/07/160713114937.htm Original web page at Science Daily

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New signaling pathway for programmed cell death identified in leukemia cells

When adults develop blood cancer, they are frequently diagnosed with what is referred to as acute myeloid leukemia. The disease is triggered by pathological alterations of bone marrow cells, in which, in addition, an important mechanism is out of action: these cells do not die when they are damaged. Researchers from the Technical University of Munich (TUM) have now discovered a molecular signaling pathway for self-destruction that is suppressed in leukemia cells.

Leukemia involves pathological alterations in the body’s hematopoietic system. In acute myeloid leukemia, it is specifically the bone marrow (Greek: myelos) that is affected. In a healthy body, different blood cells, which perform different functions in the blood, are formed from stem cells and what is referred to as progenitor cells in the bone marrow. A genetic mutation can lead to alterations in stem cells and progenitor cells and turn them into leukemia-initiating cells, which are referred to as LICs for short. Like healthy progenitor cells, LICs multiply in the bone marrow. The genetic mutation, however, causes LICs to remain without function and prevents them from developing into mature blood cells, which ultimately leads to the repression of healthy hematopoiesis in the bone marrow and the onset of leukemia symptoms.

The most frequent genetic alterations in myeloid leukemia include mutations in the FLT3 gene. A team led by Dr. Philipp Jost from the Department of Hematology/Oncology at Klinikum rechts der Isar at the Technical University of Munich has now discovered that the effects of this gene on pathologically altered cells in a way provide certain indications for the treatment of the disease. The mutation causes a permanent activation of the FLT3 gene. As demonstrated by the scientists, this triggers inflammation-like stimuli in the cell, subjecting it to permanent stress.

Under normal circumstances, such permanent inflammatory stimuli would trigger a program known as programmed cell death to replace damaged cells. This is a kind of self-destruction mechanism used by a cell to initiate its own destruction in a coordinated fashion and allow it to be replaced by a healthy one. “By contrast, LICs manage to grow and proliferate despite the inflammation and damage,” states Philipp Jost. “In our study, we have taken a closer look at the molecular causes of this resistance.”

To gain a better understanding of the research project described by the TUM scientists in the medical journal “Cancer Cell,” it is important to understand that cells have different ways of self-destructing. So far, the primary research focus in trying to ascertain why cancer cells survive longer than they should has been placed on a process called apoptosis. However, the fact that inflammatory processes occur in LICs pointed Philipp Jost and his colleagues in a different direction. Another way to initiate cell death is through what is referred to as necroptosis. Whereas, in apoptosis, a cell shrinks in a coordinated fashion, in necroptosis, a sudden destruction occurs, which releases the contents of the dying cell along with numerous messenger substances. This induces a strong inflammatory stimulus in the vicinity of the cell.

Necroptosis is triggered by the activation of a protein called RIPK3, which subsequently initiates processes within the cell that lead to its death. The scientists used cell cultures to discover that leukemia takes a particularly severe course when RIPK3 is blocked inside LICs. This led to the cancer cells surviving particularly long, accompanied by their strong division and conversion to functionless blood cells (blasts). “We conclude from our findings that particularly aggressive cancer cells have the capacity to block RIPK3,” states Ulrike Höckendorf, lead author of the study. “Exactly how they accomplish this, however, remains to be investigated.”

Inducing cell death in a LIC by means of necroptosis has repercussions which also affect neighboring leukemia cells. The inflammatory stimuli triggered by the substances released during necroptosis are significantly stronger than the processes caused by the mutation in the FLT3 gene in a LIC. This inflammation has positive effects on the area surrounding the cell: induced by the messenger substances, neighboring leukemia cells begin to mature similar to healthy cells, leading to a less aggressive progression of leukemia.

With cell death blocked — apoptosis, too, is “neutralized” in many cancer cells — individual LICs manage to survive and proliferate even after chemotherapy or radiotherapy. “The new findings on the impact of the RIPK3 signaling pathway and the messenger substances released could open up new options for the treatment of leukemia,” states Philipp Jost. “If it were possible to artificially reproduce the effect of RIPK3 using medication, one could launch a targeted attack on leukemia cells.”

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https://www.sciencedaily.com/releases/2016/07/160714110910.htm Original web page at Science Daily

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Thinking ‘I can do better’ really can improve performance, study finds

Telling yourself I can do better, can really make you do better at a given task, a study published in Frontiers in Psychology has found.

Over 44,000 people took part in an experiment to discover what motivational techniques really worked. In conjunction with BBC Lab UK, Professor Andrew Lane and his colleagues tested which physiological skills would help people improve their scores in an online game.

This complex study examined if one motivational method would be more effective for any specific aspect of a task. The methods tested were self-talk, imagery, and if-then planning. Each of these psychological skills was applied to one of four parts of a competitive task: process, outcome, arousal-control, and instruction.

People using self-talk, for example telling yourself “I can do better next time” — performed better than the control group in every portion of the task.

The greatest improvements were seen in self-talk-outcome (telling yourself, “I can beat my best score”), self-talk-process (telling yourself, “I can react quicker this time”), imagery-outcome (imagining yourself playing the game and beating your best score), and imagery-process (imagining yourself playing and reacting quicker than last time).

They also found a short motivational video could improve performance. Participants watched a short video before playing the online game. The coach for these videos was, none other than, four-time Olympic gold medalist Michael Johnson, an athlete known for advocating mental preparedness in addition to physical training.

If-then planning was found to be one of the least successful of this study, despite being an effective tool in weight management and other real life challenges.

Professor Lane said: “Working on, ‘Can You Compete?’ was inspirational and educational; since we have been developing online interventions to help people manage their emotions and doing this across a range of specific contexts from delivering a speech to fighting in a boxing ring, from taking an exam to going into dangerous places.”

Over 44,000 people participated in the study, an astounding number considering that the majority of psychological experiments have fewer than 300 participants. The participants were divided into 12 experimental groups and one control group, also impressive, because most studies have two or three experimental groups.

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https://www.sciencedaily.com/releases/2016/06/160630102038.htm  Original web page at Science Daily

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Red meat consumption linked with increased risk of developing kidney failure

A new study indicates that red meat intake may increase the risk of kidney failure in the general population, and substituting red meat with alternative sources of protein from time to time may significantly reduce this risk. The findings appear in an upcoming issue of the Journal of the American Society of Nephrology (JASN).

Increasing numbers of individuals are developing chronic kidney disease (CKD), and many progress to end-stage renal disease (ESRD), which requires dialysis or a kidney transplant. Current guidelines recommend restricting dietary protein intake to help manage CKD and slow progression to ESRD; however, there is limited evidence that overall dietary protein restriction or limiting specific food sources of protein intake may slow kidney function decline in the general population.

To examine the relationship between dietary intake of major sources of protein and kidney function, a team led by Woon-Puay Koh, MBBS (Hons), PhD (Duke-NUS Medical School and Saw Swee Hock School of Public Health in National University of Singapore) analyzed data from the Singapore Chinese Health Study, a prospective study of 63,257 Chinese adults in Singapore. This is a population where 97% of red meat intake consisted of pork. Other food sources of protein included poultry, fish/shellfish, eggs, dairy products, soy, and legumes.

After an average follow-up of 15.5 years, the researchers found that red meat intake was strongly associated with an increased risk of ESRD in a dose-dependent manner. People consuming the highest amounts (top 25%) of red meat had a 40% increased risk of developing ESRD compared with people consuming the lowest amounts (lowest 25%) No association was found with intakes of poultry, fish, eggs, or dairy products, while soy and legumes appeared to be slightly protective. Substituting one serving of red meat with other sources of protein reduced the risk of ESRD by up to 62%.

“We embarked on our study to see what advice should be given to CKD patients or to the general population worried about their kidney health regarding types or sources of protein intake,” said Dr. Koh. “Our findings suggest that these individuals can still maintain protein intake but consider switching to plant-based sources; however, if they still choose to eat meat, fish/shellfish and poultry are better alternatives to red meat.”

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https://www.sciencedaily.com/releases/2016/07/160714193627.htm  Original web page at Science Daily

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Viruses revealed to be a major driver of human evolution

The constant battle between pathogens and their hosts has long been recognized as a key driver of evolution, but until now scientists have not had the tools to look at these patterns globally across species and genomes. In a new study, researchers apply big-data analysis to reveal the full extent of viruses’ impact on the evolution of humans and other mammals.

Their findings suggest an astonishing 30 percent of all protein adaptations since humans’ divergence with chimpanzees have been driven by viruses.

“When you have a pandemic or an epidemic at some point in evolution, the population that is targeted by the virus either adapts, or goes extinct. We knew that, but what really surprised us is the strength and clarity of the pattern we found,” said David Enard, Ph.D., a postdoctoral fellow at Stanford University and the study’s first author. “This is the first time that viruses have been shown to have such a strong impact on adaptation.”

The study was recently published in the journal eLife and will be presented at The Allied Genetics Conference, a meeting hosted by the Genetics Society of America, on July 14.

Proteins perform a vast array of functions that keep our cells ticking. By revealing how small tweaks in protein shape and composition have helped humans and other mammals respond to viruses, the study could help researchers find new therapeutic leads against today’s viral threats.

“We’re learning which parts of the cell have been used to fight viruses in the past, presumably without detrimental effects on the organism,” said the study’s senior author, Dmitri Petrov, Ph.D., Michelle and Kevin Douglas Professor of Biology and Associate Chair of the Biology Department at Stanford. “That should give us an insight on the pressure points and help us find proteins to investigate for new therapies.”

Previous research on the interactions between viruses and proteins has focused almost exclusively on individual proteins that are directly involved in the immune response — the most logical place you would expect to find adaptations driven by viruses. This is the first study to take a global look at all types of proteins.

“The big advancement here is that it’s not only very specialized immune proteins that adapt against viruses,” said Enard. “Pretty much any type of protein that comes into contact with viruses can participate in the adaptation against viruses. It turns out that there is at least as much adaptation outside of the immune response as within it.”

The team’s first step was to identify all the proteins that are known to physically interact with viruses. After painstakingly reviewing tens of thousands of scientific abstracts, Enard culled the list to about 1,300 proteins of interest. His next step was to build big-data algorithms to scour genomic databases and compare the evolution of virus-interacting proteins to that of other proteins.

The results revealed that adaptations have occurred three times as frequently in virus-interacting proteins compared with other proteins.

“We’re all interested in how it is that we and other organisms have evolved, and in the pressures that made us what we are,” said Petrov. “The discovery that this constant battle with viruses has shaped us in every aspect — not just the few proteins that fight infections, but everything — is profound. All organisms have been living with viruses for billions of years; this work shows that those interactions have affected every part of the cell.”

Viruses hijack nearly every function of a host organism’s cells in order to replicate and spread, so it makes sense that they would drive the evolution of the cellular machinery to a greater extent than other evolutionary pressures such as predation or environmental conditions. The study sheds light on some longstanding biological mysteries, such as why closely-related species have evolved different machinery to perform identical cellular functions, like DNA replication or the production of membranes. Researchers previously did not know what evolutionary force could have caused such changes. “This paper is the first with data that is large enough and clean enough to explain a lot of these puzzles in one fell swoop,” said Petrov.

The team is now using the findings to dig deeper into past viral epidemics, hoping for insights to help fight disease today. For example, HIV-like viruses have swept through the populations of our ancestors as well as other animal species at multiple points throughout evolutionary history. Looking at the effects of such viruses on specific populations could yield a new understanding of our constant war with viruses — and how we might win the next big battle.

were divided into 12 experimental groups and one control group, also impressive, because most studies have two or three experimental groups.

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Key to regulating cell’s powerhouse discovered

Aging, neurodegenerative disorders and metabolic disease are all linked to mitochondria, structures within our cells that generate chemical energy and maintain their own DNA. In a fundamental discovery with far-reaching implications, scientists at the University of California, Davis, now show how cells control DNA synthesis in mitochondria and couple it to mitochondrial division.

The work is published July 15 in the journal Science.

“This has very profound implications for human disease,” said Jodi Nunnari, professor and chair of molecular and cellular biology at UC Davis and senior author on the paper.

Mitochondria retain their own DNA from the very distant past, when they were a type of bacteria that moved into other cells and never left. All eukaryotic cells — in plants, animals and fungi — contain mitochondria, which allow oxygen-breathing organisms to obtain energy from respiration.

In human cells, mitochondria are elongated, snaking tubes, with hundreds to thousands of copies of their single chromosome dotted around, packaged in a structure called the nucleoid. While the DNA in the cell’s nucleus comes from both parents, your mitochondrial DNA is inherited only from your mother.

While division of DNA in the cell’s nucleus is tightly controlled, synthesis and division of mitochondrial DNA is “a lot more relaxed,” Nunnari said.

How does the cell decide where all the copies of the mitochondrial DNA should go? And how is their division organized, if it is? Contact points are crucial.

Postdoctoral researcher Samantha Lewis, with undergraduate student Lauren Uchiyama, used microscopy with fluorescent dyes to tag mitochondria, their chromosomes, and the endoplasmic reticulum, a network of tubes that spreads throughout the cell.

They found that dividing mitochondrial chromosomes were located at points where the endoplasmic reticulum touches the outside of a mitochondrion. These also became the points where mitochondria divided into two offspring, a process that requires a sort of lasso of protein around the organelle that squeezes it until it splits.

“The endoplasmic reticulum comes into contact with the mitochondrion, and where they contact is where they divide,” Nunnari said.

The contact between the two organelles “licenses” the mitochondrial DNA to copy and divide, Nunnari said. This DNA division is in turn spatially coupled to division of the mitochondrion itself, and to distribution of the daughter DNA around the cell.

“There are hundreds of contact points around the cell that determine where division takes place and how mitochondria are distributed, but division preferentially occurs at the subset of contacts where mitochondrial DNA is being copied” Nunnari said. “It shows that there is a higher order to this, it is not simply random.”

The discovery has broad implications for understanding cell functions, aging and a broad range of diseases. Nunnari noted that it stemmed entirely from fundamental research.

“We didn’t come to this by studying any specific disease, it’s discovery-based research,” she said. “But this will greatly impact human health.”

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*Battling toxoplasmosis: International team describes step-by-step progress

In the July 14 edition of Scientific Reports (Nature), 39 researchers from 14 leading institutions in the United States, United Kingdom and France suggest novel approaches that could hasten the development of better medications for people suffering from toxoplasmosis. This chronic, currently incurable infection, caused by the parasite Toxoplasma gondii, infects the brain and eye of as many as 2 billion people worldwide.

Their findings provide conceptual and practical roadmaps for improving the efficacy and reducing toxicity of available medicines. They also offer insights into the biology of T. gondii, suggest critical molecular targets for new medicines, and offer renewed hope for the speedy development of much-needed curative medicines for those with toxoplasmosis–and potentially malaria.

The researchers describe three significant steps forward: They characterized a new experimental model, a Brazilian strain of T. gondii, called EGS, which behaves in tissue culture much like the dormant cystic parasites that live in human brain cells. This is “an immensely useful and important advance for medicine development,” said the study’s corresponding author Rima McLeod, professor of ophthalmology and visual sciences and of pediatrics at the University of Chicago. “It allows us to define its genotype and phenotype in depth and to identify what it does to its human host’s blood and primary brain stem cells. Remarkably, this encysted parasite turns on host cell pathways in ways that can alter ribosomal function and cause mis-splicing of transcripts as well as other flaws associated with Alzheimer’s and Parkinson’s disease.”

The researchers found targets critical for the parasite’s various life stages. Especially appealing was the parasite’s mitochondrial protein, cytochrome b. The team was able to develop compounds more soluble than existing cytochrome b inhibiting quinolones. These can limit parasite survival, and have physiochemical properties commensurate with crossing the blood-brain barrier to treat central nervous system infections. This work emphasizes that the cytochrome bc 1 complex is a critical target. Co-crystallography of the enzyme with the inhibitor provides information to optimize inhibitory compounds.

They show that greater understanding of T. gondii could have significant implications for anti-malarial research. Compounds they developed were highly effective against Plasmodium falciparum, the parasite that causes malaria, including all tested drug-resistant strains. Malaria, McLeod emphasized, “kills a child every eleven seconds.”

The team’s findings matter because T. gondii is the most frequent cause of infection leading to destruction of the back of the eye for persons in most countries in the world. It is most damaging for infants and children who acquire infection from their mothers during gestation, but it can also cause life-threatening infections in those with compromised immune systems, such as those with cancer, autoimmune disease or AIDS. Highly virulent strains of Toxoplasma are also now known to cause lethal disease, especially in South America.

A large data analysis by researchers at the University of Chicago, published June 26, 2016, in Clinical Infectious Diseases, found that the estimated annual incidence of toxoplasmosis over the last ten years in the US was 6,137 people, based on diagnostic codes for the disease. An editorial in that journal notes that these data “are the strongest to date to indicate that toxoplasmosis represents a significant disease burden in the United States.”

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https://www.sciencedaily.com/releases/2016/07/160715140753.htm  Original web page at Science Daily

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Four steps for validating stem cells

Scientists at EPFL and in the US have developed a robust method for characterizing human embryonic stem cells and their potential for medical applications.

The key to utilizing stem cells for regenerative medicine and tissue engineering lies in a property of theirs called pluripotency. This refers to the cells’ ability to differentiate into different types of cells. This means that we need to be able to reliably obtain, culture and maintain fully pluripotent stem cells. It has been difficult to generate human embryonic stem cells at the earliest stage of pluripotency, in what is named “ground” or “naïve” state, whereas this is readily done with mouse cells. The labs of Rudolf Jaenisch at MIT, Joe Ecker at the Salk Institute, and Didier Trono at EPFL have now developed a four-step process for determining accurate signatures of human embryonic stem cells and relating them to precise developmental stages. The work, a first for human embryonic stem cells, is published in Cell Stem Cell.

The first criterion involves a rigorous assay to see how much the naïve stem cells contribute to a mouse-human embryo. If the resulting organism (a so-called “chimera”) contains any human DNA, it signals successful engraftment of the stem cells.

The second criterion looks at the expression profile of 4.5 million RNA biomarkers called “transposable elements,” which are genetic units that can move around the genome — in fact, they make up half of the human genome. Because they can cause dangerous mutations by inserting themselves inside genes, transposable elements are actually suppressed in the early developmental stages of the embryo. However, transposable elements also regulate gene expression, and are essential in maintaining the organism’s homeostasis. The researchers demonstrated that profiling which transposable elements are active in the stem cells is an extremely sensitive and highly reproducible indicator of their pluripotency stage.

The third criterion focuses on DNA methylation state of the cells, which is lower in the naïve compared to the primed state. Finally, the fourth criterion is the epigenetic state of the X chromosome in female naïve cells, which resembles that found in the human pre-implantation embryo.

The study provides a roadmap for broadly evaluating stage, state and quality of human pluripotent cells, and can overcome current limitations with using such cells in research and clinical applications. Based on this work, the researchers have developed a startup project named Cellphmed. The company’s mission is to streamline the experimental work of the second criterion, which involves the transcriptional profiling of transposable elements to generate human cell markers for broad research and clinical applications.

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HPV vaccine can protect women across a broad age range

A research paper published in The Lancet Infectious Diseases reported that the human papillomavirus (HPV) vaccine is safe and efficacious across a wide age range of women. The international study found that it protects against HPV infection in women older than 26 years. Vaccination programs worldwide currently target routine vaccination of women 26 years and younger.

The study recruited women in 12 countries across four continents. Cosette Wheeler, PhD, at The University of New Mexico Comprehensive Cancer Center, was the lead author of the report.

The human papillomaviruses cause cancer of the cervix, anus, and middle throat. Five types of HPV account for about 85 percent of all invasive cervical cancer cases. HPV vaccines are expected to prevent most of these cancer cases.

Many countries routinely vaccinate girls and boys 25 years and younger, although vaccination rates in the United States remain low. In the US, only about 40 percent of girls and 21 percent of boys receive the three-dose vaccination series. The earlier the vaccine is given, the more efficacious it can be.

This study focused on the benefit of vaccinating women 26 years and older. Infection with HPV can take place at any time throughout adulthood and women in this age group may have already been exposed to HPV. The study showed that women in this age group were still protected from HPV infections.

The scientists followed each woman for four to seven years. They found that the vaccine protected the women against HPV infections during the follow-up period and that the women were protected from many types of HPV across a broad age range. These study results are essential to new approaches in cancer prevention, particularly those that are investigating combined approaches of cervical screening and vaccination in adult women.

Cosette Wheeler, PhD is a UNM Regents Professor in the Departments of Pathology and Obstetrics and Gynecology at the University of New Mexico Health Sciences Center. She holds the Victor and Ruby Hansen Surface Endowed Chair in Translational Medicine and Public Health. Her New Mexico research group has contributed for over 20 years to understanding the molecular epidemiology of human papillomaviruses (HPV) in cervical precancer and cancer among Native American, Hispanic and non-Hispanic women of the southwest and on a global basis. She has overseen a number of large-scale multidisciplinary population-based projects that have ultimately enabled advances in primary (HPV vaccines) and secondary cervical cancer prevention (Pap and HPV tests).

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Human intelligence measured in the brain

Human intelligence is being defined and measured for the first time ever, by researchers at the University of Warwick.

Led by Professor Jianfeng Feng in the Department of Computer Science, studies at Warwick and in China have been recently undertaken to quantify the brain’s dynamic functions, and identify how different parts of the brain interact with each other at different times — namely, to discover how intellect works.

Professor Jianfeng finds that the more variable a brain is, and the more its different parts frequently connect with each other, the higher a person’s IQ and creativity are.

More accurate understanding of human intelligence could lead to future developments in artificial intelligence (AI). Currently, AI systems do not process the variability and adaptability that is vital, as evidenced by Professor Jianfeng’s research, to the human brain for growth and learning. This discovery of dynamic functions inside the brain could be applied to the construction of advanced artificial neural networks for computers, with the ability to learn, grow and adapt.

This study may also have implications for a deeper understanding of another largely misunderstood field: mental health. Altered patterns of variability were observed in the brain’s default network with schizophrenia, autism and Attention Deficit Hyperactivity Disorder (ADHD) patients. Knowing the root cause of mental health defects brings scientists exponentially closer to treating and preventing them in the future.

Using resting-state MRI analysis on thousands of people’s brains around the world, the research has found that the areas of the brain which are associated with learning and development show high levels of variability, meaning that they change their neural connections with other parts of the brain more frequently, over a matter of minutes or seconds. On the other hand, regions of the brain which aren’t associated with intelligence — the visual, auditory, and sensory-motor areas — show small variability and adaptability.

Professor Jianfeng Feng commented that new technology has made it possible to conduct this trail-blazing study: “human intelligence is a widely and hotly debated topic and only recently have advanced brain imaging techniques, such as those used in our current study, given us the opportunity to gain sufficient insights to resolve this and inform developments in artificial intelligence, as well as help establish the basis for understanding and diagnosis of debilitating human mental disorders such as schizophrenia and depression.”

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Beware of antioxidant supplements, warns scientific review

The lay press and thousands of nutritional products warn of oxygen radicals or oxidative stress and suggest taking so-called antioxidants to prevent or cure disease. Professor Pietro Ghezzi at the Brighton and Sussex Medical School and Professor Harald Schmidt at the University of Maastricht have analyzed the evidence behind this. The result is a clear warning: do not take these supplements unless a clear deficiency is diagnosed by a healthcare professional.

Humans depend on oxygen to produce energy, but oxygen also has the potential to generate so-called oxygen radicals, which may cause oxidative stress and disease. Markers of oxidative stress have been correlated with cardiovascular disease, cancer, diabetes, and other conditions. Because of these associations, antioxidant supplements are taken by millions of people; however, none of the antioxidants tested in randomized clinical trials have demonstrated any benefit. On the contrary, some of them may cause harm.

This is because oxygen radicals not only trigger disease but also perform many important functions in the body, such as for immune defense and hormone synthesis. Thus anti-oxidants will interfere with both healthy and disease-triggering oxygen molecules.

“Oxidative stress could be important in some conditions and only in a small proportion of patients,” said Prof. Ghezzi. “It can be targeted in a totally different manner, with drugs targeted only at those sources of oxygen molecules that are triggers of disease and leave the healthy ones alone,” added Prof. Schmidt. The review is published the British Journal of Pharmacology.

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https://www.sciencedaily.com/releases/2016/07/160719094130.htm  Original web page at Science Daily

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New discovery on how the inner ear works

Researchers have found that the parts of the inner ear that process sounds such as speech and music seem to work differently than other parts of the inner ear. Researchers from Linköping University are part of the team behind the discovery.

“This helps us understand the mechanisms that enable us to perceive speech and music. We hope that more knowledge about the capabilities of the ear will lead to better treatments for the hearing impaired,” says Anders Fridberger, professor of neuroscience at Linköping University.

To perceive speech and music, you must be able to hear low-frequency sound. And to do this, the brain needs information from the receptors, which are located close to the top of the cochlea, the spiral cavity in the inner ear. This part of the inner ear is difficult to study, as it is embedded in thick bone that is hard to make holes in, without causing damage. Now the international research team has been able to measure, in an intact inner ear, how the hearing organ reacts to sound. The results have been published in PNAS, the Proceedings of the National Academy of Sciences.

To measure in the hearing organ, the researchers used optical coherence tomography, a visualization technology for biological matter that is often used to examine the eye.

“We have been able to measure the inner ear response to sound without having to open the surrounding bone structures and we found that the hearing organ responds in a completely different way to sounds in the voice-frequency range. It goes against what was previously thought of how the inner ear works.

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Current stimulation to the brain partially restores vision in patients with glaucoma and optic nerve damage

Vision loss due to glaucoma or optic nerve damage is generally considered irreversible. Now a new prospective, randomized, multi-center clinical trial demonstrates significant vision improvement in partially blind patients after 10 days of noninvasive, transorbital alternating current stimulation (ACS). In addition to activation of their residual vision, patients also experienced improvement in vision-related quality of life such as acuity, reading, mobility or orientation. The results are reported in PLOS ONE.

“ACS treatment is a safe and effective means to partially restore vision after optic nerve damage probably by modulating brain plasticity, re-synchronizing brain networks, which were desynchronized by vision loss. This class 1 evidence is the first ever large-scale multi-center clinical trial in the field of non-invasive brain modulation using electric currents and suggests that visual fields can be improved in a clinically meaningful way,” commented lead investigator Bernhard A. Sabel, PhD, of the Institute of Medical Psychology, Medical Faculty, Otto-von-Guericke University of Magdeburg (Germany).

In a study conducted at three German clinical centers (University of Göttingen, Charité Berlin, and University of Magdeburg), 82 patients were enrolled in a double-blind, randomized, sham-controlled clinical trial, 33 with visual deficits caused by glaucoma and 32 with anterior ischemic optic neuropathy caused by inflammation, optic nerve compression (due to tumors or intracranial hemorrhage), congenital anomalies, or Leber’s hereditary optic neuropathy. Eight patients had more than one cause of optic nerve atrophy.

The groups were randomized so that 45 patients underwent 10 daily applications of ACS for up to 50 minutes per day over a two-week period and 37 patients received sham stimulation. The only difference between groups before treatment was that the stimulation group included more men than the sham group; no other differences were found, including age of the lesion or visual field characteristics. ACS was applied with electrodes on the skin near the eyes. Vision was tested before and 48 hours after completion of treatment, and then again two months later to check if any changes were long-lasting.

Patients receiving ACS showed significantly greater improvements in perceiving objects in the whole visual field than individuals in the sham-treated group. Specifically, when measuring the visual field, a 24% improvement was noted after treatment in the ACS group compared to a 2.5% improvement in the sham group. This was due to significant improvements in the defective visual field sector of 59% in the ACS group and 34% in the sham group which received a minimal stimulation protocol. Further analyses showed improvements in the ACS group at the edges of the visual field. The benefits of stimulation were found to be stable two months later, as the ACS group showed a 25% improvement in the visual field compared to negligible changes (0.28%) in the sham group.

Patient safety measures were maintained at a high level, in line with previous studies. Current flow was assessed using sophisticated computer simulation models. No participants reported discomfort during stimulation, although temporary dizziness and mild headaches were reported in rare cases.

The study results are in line with previous small sample studies in which efficacy and safety were observed. Those studies revealed that well-synchronized dynamic brain functional networks are critical for vision restoration. Although vision loss leads to de-synchronization, these neural networks can be re-synchronized by ACS via rhythmic firing of the ganglion cells of the retina, activating or “amplifying” residual vision. Dr. Sabel added that “while additional studies are needed to further explore the mechanisms of action, our results warrant the use of ACS treatment in a clinical setting to activate residual vision by brain network re-synchronization. This can partially restore vision in patients with stable vision loss caused by optic nerve damage.”

In summary, vision loss, long considered to be irreversible, can be partially reversed. There is now more light at the end of the tunnel for patients with low vision or blindness following glaucoma and optic nerve damage.

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https://www.sciencedaily.com/releases/2016/06/160629145208.htm  Original web page at Science Daily

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Artificial pancreas likely to be available by 2018

 

The artificial pancreas — a device which monitors blood glucose in patients with type 1 diabetes and then automatically adjusts levels of insulin entering the body — is likely to be available by 2018, conclude authors of a paper in Diabetologia (the journal of the European Association for the Study of Diabetes). Issues such as speed of action of the forms of insulin used, reliability, convenience and accuracy of glucose monitors plus cybersecurity to protect devices from hacking, are among the issues that are being addressed.

Currently available technology allows insulin pumps to deliver insulin to people with diabetes after taking a reading or readings from glucose meters, but these two components are separate. It is the joining together of both parts into a ‘closed loop’ that makes an artificial pancreas, explain authors Dr Roman Hovorka and Dr Hood Thabit of the University of Cambridge, UK. “In trials to date, users have been positive about how use of an artificial pancreas gives them ‘time off’ or a ‘holiday’ from their diabetes management, since the system is managing their blood sugar effectively without the need for constant monitoring by the user,” they say.

One part of the clinical need for the artificial pancreas is the variability of insulin requirements between and within individuals — on one day a person could use one third of their normal requirements, and on another 3 times what they normally would. This is dependent on the individual, their diet, their physical activity and other factors. The combination of all these factors together places a burden on people with type 1 diabetes to constantly monitor their glucose levels, to ensure they don’t end up with too much blood sugar (hyperglycaemic) or more commonly, too little (hypoglycaemic). Both of these complications can cause significant damage to blood vessels and nerve endings, making complications such as cardiovascular problems more likely.

There are alternatives to the artificial pancreas, with improvements in technology in both whole pancreas transplantation and also transplants of just the beta cells from the pancreas which produce insulin. However, recipients of these transplants require drugs to supress their immune systems just as in other organ transplants. In the case of whole pancreas transplantation, major surgery is required; and in beta cell islet transplantation, the body’s immune system can still attack the transplanted cells and kill off a large proportion of them (80% in some cases). The artificial pancreas of course avoids the need for major surgery and immunosuppressant drugs.

Researchers globally continue to work on a number of challenges faced by artificial pancreas technology. One such challenge is that even fast-acting insulin analogues do not reach their peak levels in the bloodstream until 0.5 to 2 hours after injection, with their effects lasting 3 to 5 hours. So this may not be fast enough for effective control in, for example, conditions of vigorous exercise. Use of the even faster acting ‘insulin aspart’ analogue may remove part of this problem, as could use of other forms of insulin such as inhaled insulin. Work also continues to improve the software in closed loop systems to make it as accurate as possible in blood sugar management.

A number of clinical studies have been completed using the artificial pancreas in its various forms, in various settings such as diabetes camps for children, and real life home testing. Many of these trials have shown as good or better glucose control than existing technologies (with success defined by time spent in a target range of ideal blood glucose concentrations and reduced risk of hypoglycaemia). A number of other studies are ongoing. The authors say: “Prolonged 6- to 24-month multinational closed-loop clinical trials and pivotal studies are underway or in preparation including adults and children. As closed loop devices may be vulnerable to cybersecurity threats such as interference with wireless protocols and unauthorised data retrieval, implementation of secure communications protocols is a must.”

The actual timeline to availability of the artificial pancreas, as with other medical devices, encompasses regulatory approvals with reassuring attitudes of regulatory agencies such as the US Food and Drug Administration (FDA), which is currently reviewing one proposed artificial pancreas with approval possibly as soon as 2017. And a recent review by the UK National Institute of Health Research (NIHR) reported that automated closed-loop systems may be expected to appear in the (European) market by the end of 2018. The authors say: “This timeline will largely be dependent upon regulatory approvals and ensuring that infrastructures and support are in place for healthcare professionals providing clinical care. Structured education will need to continue to augment efficacy and safety.”

The authors say: “Cost-effectiveness of closed-loop is to be determined to support access and reimbursement. In addition to conventional endpoints such as blood sugar control, quality of life is to be included to assess burden of disease management and hypoglycaemia. Future research may include finding out which sub-populations may benefit most from using an artificial pancreas. Research is underway to evaluate these closed-loop systems in the very young, in pregnant women with type 1 diabetes, and in hospital in-patients who are suffering episodes of hyperglycaemia.”

They conclude: “Significant milestones moving the artificial pancreas from laboratory to free-living unsupervised home settings have been achieved in the past decade. Through inter-disciplinary collaboration, teams worldwide have accelerated progress and real-world closed-loop applications have been demonstrated. Given the challenges of beta-cell transplantation, closed-loop technologies are, with continuing innovation potential, destined to provide a viable alternative for existing insulin pump therapy and multiple daily insulin injections.”

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https://www.sciencedaily.com/releases/2016/06/160630214503.htm  Original web page at Science Daily