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Credit Newswise — If you have trouble sleeping, the neurons in your brain may be firing like those in roundworms randomly seeking food in the absence of clues, says University of Oregon biologist Shawn R. Lockery. That connection is proposed in a theoretical neuroscience paper co-authored by 12 researchers at 10 institutions that is in the journal eLife. The research -- 14 years in the making -- was led by Lockery and supported by the National Institutes of Health. As humans sleep, neurons fire randomly in between brief, alternating states of wakefulness and sleep. Such fragmentation is heightened in sleep disorders. The fragmentation as seen in the worms -- the nematode Caenorhabditis elegans -- offers a new framework to identify genetic and physiological underpinnings of the neural circuitry involved in sleep, the research team concluded. The nematode brain is the smallest known to science, containing just 302 neurons and making it a simple model from which to gather basic information, Lockery said. "Our field has a complete wiring diagram of this worm's brain," said Lockery, a member of the UO Institute of Neuroscience. "You can find the same neuron in any animal you look into and learn to understand how individual neurons function." Researchers in Lockery's lab tested the predictability of mathematically driven equations about random search strategies in the brain. To do so, the worms were removed from access to their usual food -- bacteria in rotting vegetables -- and placed on clean petri dishes with no sensory clues as to where a meal is located. Initially, the movements of the worms and the neural networks involved were mapped as the worms crawled forward, paused, reversed, and then resumed their search in another direction. "Every animal faces the need to find food," Lockery said. "In some instances food is undetectable until you basically fall on it: birds looking for marine invertebrates in the sand will move about and peck until they find their meal. This is called random search." Humans, too, from hunter-gatherers to those who engage in technologically advanced fishing, exhibit similar random-search behaviors but, "no one has known how the nervous system controls this," Lockery said. With the mapping done, researchers used lasers to knock out neurons. They expected the worms to spend more time in reverse when neurons linked to forward movement were eliminated, or vice versa. Instead, the reaction was symmetrical. Shorter times were found in both forward and reverse movements. "There are centers in the human brain stem that promote wakefulness and sleep," Lockery said. "They are coupled just like the system we see in the worms. This involves clusters of neurons that are fighting against each other to be active. We constantly wake up and go back to sleep, but we don't remember it. Sleep is random, just the way the worm's movement is." Researchers have done similar experiments in rats and mice where neurons related to sleep states were manipulated. The findings are consistent. "The same paradoxical effect that we found in our worms also occurs in these other organisms," Lockery said. "This line of research suggests that we now have a simple way to try to understand how this fragmentation occurs. That's the first step in understanding how medical science might be able to pursue therapeutics that could mitigate extreme cases of fragmentation."
Credit Newswise — A fungal disease that poses a serious threat to cacao plants - the source of chocolate - reproduces clonally, Purdue University researchers find. The fungus Moniliophthora roreri causes frosty pod rot, a disease that has decimated cacao plantations through much of the Americas. Because M. roreri belongs to a group of fungi that produces mushrooms - the fruit of fungal sex - many researchers and cacao breeders believed the fungus reproduced sexually. But a study by Purdue mycologists Catherine Aime and Jorge Díaz-Valderrama shows that M. roreri generates billions of cocoa pod-destroying spores by cloning, even though it has two mating types - the fungal equivalent of sexes - and seemingly functional mating genes. The findings could help improve cacao breeding programs and shed light on the fungal mechanisms that produce mushrooms. "This fungus is phenomenally unusual - it has mating types but doesn't undergo sexual reproduction," said Díaz-Valderrama, doctoral student in mycology. "This knowledge is biologically and economically valuable as we seek better insights into how mushrooms come about and how we can reduce this disease's damage to the cocoa industry." Cocoa is one of the few major crops produced almost entirely by small farms, and the instability of cocoa prices often makes fungicides a risky investment for growers. Instead, many growers opt to regularly monitor their crop for symptoms of frosty pod rot, burying pods that display the telltale dark lesions or white dusting to prevent further dispersal of fungal spores. Over the last 60 years, the disease has spread - likely through unwitting transportation of infected pods - through much of South America, all of Central America and into Mexico. Frosty pod rot has dropped cocoa yields in some areas by up to 100 percent, forcing many growers to abandon their plantations altogether. Brazil is the only cocoa-producing country in the continental Americas untouched by frosty pod rot, whose pernicious effects have spurred the majority of global cacao production to relocate to West Africa. These regions remain highly vulnerable to the disease, Díaz-Valderrama said. Understanding the fundamental biology of the fungus could help disease control efforts, but researchers have long been stumped by M. roreri's reproductive habits, which seem to deviate from those of sister species. Fungal reproduction is complicated. Instead of male and female sexes, fungi can have a vast number of different mating types, leading to a wide and varied range of potential mates - up to 20,000 in some species. But many fungi also reproduce clonally under favorable conditions, simply copying their genome and producing billions of offspring. Digging into the genomics and population genetics of M. roreri, Aime and Díaz-Valderrama found indications that the fungus might be able to sexually reproduce: It has two seemingly compatible mating types and what appear to be functional sex pheromone receptors. But they couldn't find any evidence that the mating types were recombining in the field or lab, and no records of M. roreri mushrooms exist - signs that the fungus has ditched sexual reproduction in favor of cloning. "Fungi usually start reproducing via cloning when they're very well suited for their environment," said Aime, associate professor of mycology. "In terms of resources, sex is expensive while cloning is a cheap and easy way to produce a lot of offspring." The researchers found both mating types in South America and only one type in Central America. This supports the hypothesis that the disease originated in South America and was more recently introduced into Central America where it rapidly spread through clonal reproduction. The study also shows that what some researchers believed to be different varieties of the fungus are actually genetic variations in the two mating types. The findings open the door for breeding programs to investigate which mating type is more virulent and possibly develop resistant cacao cultivars. In the meantime, chocolate lovers should stay calm, Díaz-Valderrama said. "We're working on identifying biochemical components that could be useful for controlling frosty pod rot and protecting vulnerable cacao-growing regions."
Credit Newswise — New research looks into the paradox that women who sunbathe are likely to live longer than those who avoid the sun, even though sunbathers are at an increased risk of developing skin cancer. An analysis of information on 29,518 Swedish women who were followed for 20 years revealed that longer life expectancy among women with active sun exposure habits was related to a decrease in heart disease and noncancer/non-heart disease deaths, causing the relative contribution of death due to cancer to increase. Whether the positive effect of sun exposure demonstrated in this observational study is mediated by vitamin D, another mechanism related to UV radiation, or by unmeasured bias cannot be determined. Therefore, additional research is warranted. "We found smokers in the highest sun exposure group were at a similar risk as non-smokers avoiding sun exposure, indicating avoidance of sun exposure to be a risk factor of the same magnitude as smoking," said Dr. Pelle Lindqvist, lead author of the Journal of Internal Medicinestudy. "Guidelines being too restrictive regarding sun exposure may do more harm than good for health."
Credit Newswise — Women can choose from a wide selection of birth control methods, including numerous oral contraceptives, but there’s never been an analogous pill for men. That’s not for lack of trying: For many years, scientists have attempted to formulate a male pill. Finally, a group of researchers has taken a step toward that goal by tweaking some experimental compounds that show promise.The researchers present their work today at the 251st National Meeting & Exposition of the American Chemical Society (ACS). ACS, the world’s largest scientific society, is holding the meeting here through Thursday. It features more than 12,500 presentations on a wide range of science topics. One compound that’s been studied as a potential male contraceptive is testosterone. “At certain doses it causes infertility,” says Jillian Kyzer, a graduate student working on the topic. “But at those doses, it doesn’t work for up to 20 percent of men, and it can cause side effects, including weight gain and a decrease in ‘good’ cholesterol.” Bringing any male contraceptive to market requires it to satisfy several requirements, explains Kyzer’s team leader, Gunda I. Georg, Ph.D., who is based at the University of Minnesota College of Pharmacy. It would have to be soluble so it could be taken by mouth. It would start working fairly quickly, and it wouldn’t diminish libido. It would be safe even if taken for decades. And because some users would eventually want to have children, its impact on fertility would be reversible, with no lingering ill effects on sperm or embryos. “That’s a very high bar for bringing a male contraceptive to market,” Georg points out. These hurdles have driven many investigators from the hunt, yet Georg’s team perseveres. “It would be wonderful to provide couples with a safe alternative because some women cannot take birth control pills,” she says. Drug companies, including Bristol-Myers Squibb (BMS), have created some experimental male contraceptives, but these too have drawbacks, Kyzer says. For instance, one of the company’s test compounds is good at inhibiting fertility but isn’t very soluble, so it can’t be taken by mouth. “No one wants to inject themselves with a needle once a day or once a week for most of their lives,” she notes. Another Bristol-Myers Squibb experimental compound can be taken orally but isn’t very selective in terms of its cellular targets in the body. That means the compound not only interacts with the retinoic acid receptor-α, which is involved in male fertility, but also with two other retinoic acid receptors that are unrelated to fertility. That flaw could cause side effects. Kyzer and several of her colleagues are creating numerous substances that are similar in their chemical structure to the Bristol-Myers Squibb compounds. Although the optimal contraceptive for men remains elusive, Georg’s team has made some progress. For example, the researchers are gaining a better understanding of how tweaks to the chemical structure of their test compounds affect the substances’ cellular interactions in the body. One of those tweaks added a polar group to the molecule, which made the test compounds more soluble. Another tweak replaced an amide bond in the BMS compound with slightly different bonds that are known in the field of medicinal chemistry to mimic an amide bond. As intended, that change improved the test compounds’ stability, meaning they would last longer in the body. Unfortunately, both types of modifications also reduced the specificity of the compounds for the intended retinoic acid receptor-α target. The group continues to refine the chemical structures to achieve the ultimate balance of solubility, specificity and stability as they aim to design a better male pill. They are now investigating hybrid compounds that incorporate scaffolds and structural features from several other compounds known to interact with the retinoic acid receptor. The researchers acknowledge funding from the Contraception Research Branch, Eunice Kennedy Shriver National Institute of Child Health & Human Development.
Credit Newswise — The first time back to the gym after a long break usually results in sore muscles. Fortunately, the return trip a few days later--if it happens--is generally less painful. Scientists have studied this reduced-soreness phenomenon for decades and even have a name for it--the repeated bout effect. Despite all those years of research, they still can't figure out exactly why people feel less sore the second time around. What they do know is the immune system plays some role in how the muscle repairs itself and protects against additional damage. But now exercise science researchers at BYU have produced evidence that shows for the first time the surprising presence of very specific immune workers: T-cells. "You think of T-cells as responding to infections, not repairing muscles--but we found a significant accumulation of T-cells infiltrating damaged muscle fibers," said Robert Hyldahl, assistant professor of exercise science at BYU. "Our study is the first to show T-cells present in human muscle in response to exercise-induced damage." The research appears this month in Frontiers in Physiology and builds off past studies that implicate immune cells in muscle healing. One such study was a 2013 paper out of Harvard showing T-cells active in the skeletal muscles of mice (but not yet humans) after injury. For the study, researchers, put 14 men and women through two vigorous rounds of exercise on an isokinetic dynamometer machine, 28 days apart. ("All of them got really sore," Hyldahl said.) Before and after each bout of exercise, the team took muscle biopsies from the subjects and then used immunohistochemistry and microscopy to analyze the muscle tissue. The BYU group found an expected increase in certain white blood cells after the second bout of exercise, but only identified the T-cells after it was suggested by Amanda Gier, one of two undergraduate coauthors on the paper, who was enrolled in an immunology course at the time. "T-cells, up until recently, were not thought to enter healthy skeletal muscle," said lead author and grad student Michael Deyhle. "We hadn't planned on measuring them because there's no evidence that T-cells play a role in infiltrating damaged muscle tissue. It's very exciting." The presence of the T-cells suggests that muscles become more effective at recruiting immune cells following a second bout of exercise and that these cells may facilitate accelerated repair. In other words, the muscle seems to remember the damaging insult and reacts similarly to when the immune system responds to antigens--toxins, bacteria or viruses. The group was also surprised to find inflammation actually increased after the second round of exercise. Hyldahl, his students and many physiologists have long thought inflammation goes down after the second bout of exercise, contributing to that "less sore" effect. Instead, the slightly enhanced inflammatory response suggests inflammation itself probably does not worsen exercise-induced muscle damage. "Many people think inflammation is a bad thing," Deyhle said. "But our data suggest when inflammation is properly regulated it is a normal and healthy process the body uses to heal itself." Adds Hyldahl: "Some people take anti-inflammatory drugs such as Ibuprofen and Aspirin after a workout, but our study shows it may not actually be effective. The inflammation may not be directly causing the pain, since we see that muscle soreness is reduced concurrent with increases in inflammation."
Credit Newswise — A new study shows that a variety of physical activities from walking to gardening and dancing can improve brain volume and cut the risk of Alzheimer's disease by 50%. This research, conducted by investigators at UCLA Medical Center and the University of Pittsburgh, is the first to show that virtually any type of aerobic physical activity can improve brain structure and reduce Alzheimer's risk. The study, funded by the National Institute of Aging, was published on March 11 in the Journal of Alzheimer's Disease. The researchers studied a long-term cohort of patients in the 30-year Cardiovascular Health Study, 876 in all, across four research sites in the United States. These participants had longitudinal memory follow up, which also included standard questionnaires about their physical activity habits. The research participants, age 78 on average, also had MRI scans of the brain analyzed by advanced computer algorithms to measure the volumes of brain structures including those implicated in memory and Alzheimer's such as the hippocampus. The physical activities performed by the participants were correlated to the brain volumes and spanned a wide variety of interests from gardening and dancing to riding an exercise cycle at the gym. Weekly caloric output from these activities was summarized. The results of the analysis showed that increasing physical activity was correlated with larger brain volumes in the frontal, temporal, and parietal lobes including the hippocampus. Individuals experiencing this brain benefit from increasing their physical activity experienced a 50% reduction in their risk of Alzheimer's dementia. Of the roughly 25% in the sample who had mild cognitive impairment associated with Alzheimer's, increasing physical activity also benefitted their brain volumes. Said lead author Cyrus A. Raji, MD, PhD, of UCLA, "This is the first study in which we have been able to correlate the predictive benefit of different kinds of physical activity with the reduction of Alzheimer's risk through specific relationships with better brain volume in such a large sample." George Perry, PhD, Editor in Chief of Journal of Alzheimer's Disease, added, "Currently the greatest promise in Alzheimer's disease research is lifestyle intervention including increased exercise. Raji et al present a landmark study that links exercise to increases in grey mater and opens the field of lifestyle intervention to objective biological measurement." According to the Alzheimer's Association, Alzheimer's disease currently affects 5.1 million Americans and is projected to increase to13.8 million over the next 30 years. Dr. Raji commented, "We have no magic bullet cure for Alzheimer's disease. Our focus needs to be on prevention."
Credit Newswise — Researchers from The University of Texas Medical Branch at Galveston have found that women who take the birth control pill, which lessen and stabilize estrogen levels, were less likely to suffer serious knee injuries. The findings are currently available in Medicine & Science in Sports & Exercise, the official journal of the American College of Sports Medicine. Female athletes are 1.5 to 2 times more likely than their male counterparts to injure their anterior cruciate ligament, or ACL. The ACL is a ligament that connects the top and bottom portions of the knee. Damage to this ligament is a serious athletic injury that can be career altering. Return-to-play rates after ACL injury are as low as 49 percent among soccer players. Also, this injury may lead to lifelong issues with knee instability, altered walking gait and early onset arthritis. Using a national insurance claims and prescription database of 23,428 young women between 15 and 19, the study found that women with an ACL knee injury who were taking the birth control pill were less likely to need corrective surgery than women of the same age with ACL injuries who do not use the birth control pill. Researchers have proposed that the female hormone estrogen makes women more vulnerable to ACL injury by weakening this ligament. A previous investigation found that more ACL injuries in women occur during the points of their menstrual cycle when estrogen levels are high. "Birth control pills help maintain lower and more consistent levels of estrogen, which may prevent periodic ACL weakness," said lead author and M.D. - Ph.D. student Aaron Gray. "With this in mind, we examined whether oral contraceptive use protected against ACL injuries that require surgery in women." Women between15-19 y in need of ACL reconstructive surgery, the age group with the highest rates of ACL injuries by a wide margin, were 22 percent less likely to be using the birth control pill than non-injured women of the same age. Gray said that puberty might explain the high number of ACL injury cases in young women of this age. During puberty, there is a sharp rise in estrogen levels as well as growth spurts in the legs. Following one of these growth spurts, it takes time for the adolescent to develop good coordination with their newly elongated limbs. "Young athletes currently use birth control pills for various reasons including more predictable cycles and lighter periods," Gray said. "Injury risk reduction could potentially be added to that list with further, prospective investigations."
Credit Newswise — Drug therapies for many conditions end up treating the whole body even when only one part — a joint, the brain, a wound — needs it. But this generalized approach can hurt healthy cells, causing nasty side effects. To send drugs to specific disease locations and avoid unwanted symptoms, researchers developed cellular "backpacks" that are designed to carry a therapeutic cargo only to inflamed disease sites. The researchers present their work today at the 251st National Meeting & Exposition of the American Chemical Society (ACS). ACS, the world’s largest scientific society, is holding the meeting here through Thursday. It features more than 12,500 presentations on a wide range of science topics. "What we want to do is take advantage of immune cells whose job it is to seek out disease in the body, and use them to deliver cargo for us," says Roberta Polak, a postdoctoral research associate. "How do we do that? Our lab developed cellular backpacks that can be loaded with therapeutic compounds and unloaded." Polak and fellow researchers in the Massachusetts Institute of Technology (MIT) labs of Michael Rubner, Ph.D., and Robert Cohen, Ph.D., make the backpacks by stacking ultra-thin layers of polymer materials on top of each other. According to Rubner, they could be used to treat a wide range of diseases from cancer to Parkinson’s. The resulting pack has different functional regions. One is Velcro-like, attaching via antibody-antigen binding to immune cells, such as monocytes and macrophages. These are the body’s defense cells that travel to sites of inflammation — a natural reaction to infection and disease — and gobble up foreign invaders or attack cancer cells. In vitro testing has shown that the backpacks can stick to the surfaces of the immune cells without getting engulfed. In collaboration with the group of Samir Mitragotri at the University of California at Santa Barbara, the MIT team has also demonstrated in mice that these backpack-functionalized immune cells accumulate in locations where inflammation — a sign of disease — occurs. But there was a problem. The medicine they were using to test the backpacks, a cancer drug called doxorubicin, was leaking out — even during the initial fabrication process. So Polak worked on this part of the backpack, its payload region. To stop the premature release of the drug, she trapped it in liposomes, tiny bubbles that have already been used to carry therapeutic compounds for other delivery systems, and then incorporated them into the backpacks. She found that she could fit nine times the amount of doxorubicin in the liposomes than in the backpacks alone, potentially transforming them into an even more potent weapon. To control the release of the drug payload, Polak used liposomes that are echogenic, or sensitive to ultrasound. So in principle, when backpacks infused with these bubbles reach their destination, they can be burst open with ultrasound waves. Now, to see how well they work to treat a specific disease, Polak is collaborating with Elena Batrakova, Ph.D., at the University of North Carolina at Chapel Hill. Batrakova has been working with mice to develop new treatments for brain inflammation, a characteristic of diseases such as Parkinson’s and Alzheimer’s. They want to see if they can use the backpacks to carry an inflammation-fighting enzyme across the blood-brain barrier.
Credit Newswise — Could an unhealthy diet and lack of exercise be making you age faster? Researchers at Mayo Clinic believe there is a link between these modifiable lifestyle factors and the biological processes of aging. In a recent study, researchers demonstrated that a poor diet and lack of exercise accelerated the onset of cellular senescence and, in turn, age-related conditions in mice. Results appear today in Diabetes. Senescent cells are cells that contribute to diseases and conditions associated with age. Researchers from the Mayo Clinic Robert and Arlene Kogod Center on Aging found that exercise prevents premature senescent cell accumulation and protects against the damaging effects of an unhealthy diet, including deficiencies in physical, heart, and metabolic function, equivalent to diabetes. “We think at both a biological level and a clinical level, poor nutrition choices and inactive lifestyles do accelerate aging,” says Nathan LeBrasseur, Ph.D., director of the Center on Aging’s Healthy and Independent Living Program and senior author of the study. “So now we’ve shown this in very fine detail at a cellular level, and we can see it clinically. And people need to remember that even though you don’t have the diagnosis of diabetes or the diagnosis of cardiovascular disease or the diagnosis of Alzheimer’s disease today when you’re in midlife, the biology underlying those processes is hard at work.” In the study, researchers introduced mice to either a normal, healthy diet or a diet that they termed a “fast food diet” – one that was high in saturated fat and cholesterol, along with a sugar-sweetened beverage. Mice on the fast food diet showed harmful changes in health parameters, including body weight and composition, increasing their fat mass by nearly 300 percent over the course of about four months. The fat mass accumulated largely in the midsection surrounding internal organs, an area that is often linked to a number of diseases related to obesity. While the harmful effects of the fast food diet were clear, researchers found significant health improvements after introducing exercise. Half the mice, including mice on both the healthy and unhealthy diets, were given exercise wheels. Mice that had been exposed to the fast food diet but exercised showed suppression in body weight gain and fat mass accumulation, and were protected against the accumulation of senescent cells. Mice on a normal diet benefited from exercise as well. “Some of us believe that aging is just something that happens to all of us and it’s just a predestined fate, and by the time I turn 65 or 70 or 80, I will have Alzheimer’s disease and cardiovascular disease and osteoporosis,” says Dr. LeBrasseur. “And this clearly shows the importance of modifiable factors so healthy diet, and even more so, just the importance of regular physical activity. So that doesn’t mean that we need to be marathon runners, but we need to find ways to increase our habitual activity levels to stay healthy and prevent processes that drive aging and aging-related diseases.”
Credit Newswise — Older patients, minorities, and male patients are more likely to develop substernal thyroid goiters that are difficult to remove surgically, putting them at risk for treatment complications and death, say researchers in the January 6 online in the American Journal of Surgery. A substernal goiter is so large it extends below a person’s collarbones into the upper chest. The study, which looked at almost 111,000 patients from the National Inpatient Sample years 2000-2010 who had surgery to remove their goiters, documents what investigators say appears to be disparity in demographics and outcomes. The findings “raise issues of potential access to care or delays in treatment,” says the study’s senior author, Alliric I. Willis, M.D., an associate professor of surgery at Sidney Kimmel Medical College. “This is the first study to thoroughly describe the demographic and clinical disparities associated with substernal goiters,” he says. “Awareness of such disparities may allow health care providers to better identify patients at risk for this distinct issue and provide more timely care — before the goiters grow so large that they risk health and life.” A goiter is an enlargement of a thyroid gland that swells the neck. In much of the world goiters are caused by a lack of iodine, but in the U.S., where salt is enriched with iodine, goiters develop due to a number of factors — which may include an overactive thyroid (Graves’ disease), an underactive thyroid (Hashimoto’s disease), family history, or differences in anatomy. Substernal goiters grow slowly but steadily over time, and the incidence of these large goiters is between 3 to 13 percent of all goiters, according to different studies that examined goiter surgery. The research team, which included investigators from the University of Pennsylvania and Temple University, examined data on 110,889 patients who underwent thyroidectomy for goiters. In this group, 5,525 patients were diagnosed with a substernal goiter. These patients were substantially more likely to be older, male, Black, Hispanic, or to have Medicare insurance. While the vast majority of goiters occur among women, men were significantly more likely to present with substernal goiters. Compared to patients with typical-sized goiters, researchers found that patients with substernal goiters had higher comorbidity (such as hypertension, diabetes, and obesity), were more likely to be admitted to a hospital on an emergency basis, and to have postoperative complications including hemorrhage, lung collapse, and pulmonary embolism. Furthermore, substernal patients were 73 percent more likely to die during hospital admission. “Reasons for the increased risk of complications and death may be due to the increased complexity of surgery associated with substernal goiters,” says Dr. Willis. He adds that the risk of dying from the surgery is very low overall. Researchers found that there was a significant difference in the frequencies of substernal goiters across different regions of the U.S. Substernal goiters were most common in the South followed by the Northeast. “These findings raise the possibility of disparate access to surgical care for black and Hispanic patients as well as possible delays in seeking treatment along ethnic and gender lines,” says Dr. Willis.