Culture

Decisions to prescribe children drugs to treat chronic pain are not guided by sufficient, high quality evidence, according to an important new study published today (Wednesday 26 June 2019).

Published as part of a special collection of systematic reviews in the Cochrane Library and recently summarised in the journal PAIN, the overview highlights a dearth of information available about treating childhood chronic pain and concludes that much more needs to be done to improve the quality and quantity of evidence available. It is led by researchers at the University of Bath in collaboration with an international team of researchers and physicians.

In adults, chronic pain lasting for three months or more is known to have a devastating effect. What is less well known is that one in five children also report chronic pain, which is both distressing and disabling for children and their parents.

But the new study reveals a stark contrast between the evidence available for the drugs used to treat adults with chronic pain, compared with that conducted in children. For adults with chronic pain, 300,000 patients have been studied in hundreds of individual randomised control trials. Yet only 393 children have participated in just six trials ever undertaken.

The research is a summary of all available systematic reviews of studies in this area and is supported by the National Institute for Health Research (NIHR), Versus Arthritis and also involves Bath's Centre for Pain Services (part of the RUH Foundation Trust).

The team who prepared the overview stress that lack of evidence does not mean evidence of no effect. But they argue there has been very little investment in researching which drugs can best help children with chronic pain and suggest that this issue should be urgently addressed to increase confidence that children are getting the best treatment.

They describe the disparity of knowledge between adults and children - a ratio of around 1000:1 - as 'unacceptable' and suggest that the lessons learnt from research conducted on adults cannot 'simply be applied to children' whose biology and metabolism work differently.

The most common types of chronic pain experienced by children include recurrent abdominal pain, headaches and migraines, and musculoskeletal pain. Children who suffer from chronic pain regularly miss school, become isolated and have more anxiety and depression compared to children without pain. Drug therapy is typically the first resort for treatment.

Professor Christopher Eccleston, Co-ordinating Editor for the Cochrane Pain, Palliative and Supportive Care Review Group and Director of the Centre for Pain Research at the University of Bath, who led the overview, explained: "Overall, there is no high-quality evidence to help us understand the efficacy or safety of the common drugs used to help children with chronic pain. The lack of data means that we are uncertain about how to optimally manage pain. Doctors, children and their families all deserve better.

"This study is a collective effort from 23 leading researchers and physicians from around the world. Healthcare policy-makers need to grapple this issue if we are to break down the barriers that exist to producing sufficient evidence in paediatric chronic pain pharmacotherapy."

The team acknowledges that there are practical and ethical barriers to conducting randomised control trials on children, but suggest that these are no different from other areas of paediatric pharmacological research.

Co-author Dr Emma Fisher, Versus Arthritis Research Fellow from the Centre for Pain Research at the University of Bath, added: "Children are not just small adults so we cannot simply extrapolate evidence acquired from adults and use it in children.

"With the evidence available currently we cannot say for sure whether the drugs used are the best approach. Yet at the current rate of clinical trial reporting - only one every 3.5 years - it would take us over 1,000 years to have a good enough evidence base to properly inform decisions. This lack of knowledge requires new funding and urgent attention."

Stewart Long, Director of Involvement and Services, at Versus Arthritis who supported the study, said: "Living with chronic pain can have a profound physical, emotional and psychological impact, particularly in children. It can stop them joining in things other young people do and affect development of friendships. This can lead to isolation, making children more likely to suffer from anxiety and depression and affect their ability to fulfil their potential and maintain their future aspirations.

"Despite the scale and impact of chronic pain, as well as its socio-economic cost, there is a serious lack of research into effective treatments for adults and children alike. We urgently need chronic pain to be prioritised in policy, funding and research so that the millions of people living in pain today, regardless of their age, are better supported."

Dr Jacqui Clinch, Medical lead consultant for young people at the national Bath Centre for Pain Services explained: "Within BCPS we see and treat children and adolescents from across the UK who have suffered pain and pain associated difficulties often for years. These young people, in addition to overwhelming pain, develop sleep disturbance, memory and concentration difficulties, muscle weakness, cramps, numbness, nausea, and many other pain related symptoms.

"They transform from physically and socially active individuals to missing school, physically inactive and housebound. In short, their lives, and those of their loved ones, fall apart. Our unique dedicated multidisciplinary team has delivered successful rehabilitation for these young people and carers for over 20 years. As part of the international pain community, we strive to optimise research into both further understanding pain pathways in young people and exploring new interventions to alleviate suffering in this vulnerable population and their families."

Other non-drug-based treatments are also available to children and adolescents with chronic pain. Psychological therapies, such as cognitive behavioural therapy (CBT), show small effects at reducing pain and disability in this population, but once again the evidence needs to be improved.

The researchers suggest funding and incentives are needed to drive this field forwards in order to deliver evidence-based research that doctors treating patients can reliably use to inform their decisions.

Want to create a brand new type of protein that might have useful properties? No problem. Just hum a few bars.

In a surprising marriage of science and art, researchers at MIT have developed a system for converting the molecular structures of proteins, the basic building blocks of all living beings, into audible sound that resembles musical passages. Then, reversing the process, they can introduce some variations into the music and convert it back into new proteins never before seen in nature.

Although it's not quite as simple as humming a new protein into existence, the new system comes close. It provides a systematic way of translating a protein's sequence of amino acids into a musical sequence, using the physical properties of the molecules to determine the sounds. Although the sounds are transposed in order to bring them within the audible range for humans, the tones and their relationships are based on the actual vibrational frequencies of each amino acid molecule itself, computed using theories from quantum chemistry.

The system was developed by Markus Buehler, the McAfee Professor of Engineering and head of the Department of Civil and Environmental Engineering at MIT, along with postdoc Chi Hua Yu and two others. As described in the journal ACS Nano, the system translates the 20 types of amino acids, the building blocks that join together in chains to form all proteins, into a 20-tone scale. Any protein's long sequence of amino acids then becomes a sequence of notes.

While such a scale sounds unfamiliar to people accustomed to Western musical traditions, listeners can readily recognize the relationships and differences after familiarizing themselves with the sounds. Buehler says that after listening to the resulting melodies, he is now able to distinguish certain amino acid sequences that correspond to proteins with specific structural functions. "That's a beta sheet," he might say, or "that's an alpha helix."

Learning the language of proteins

The whole concept, Buehler explains, is to get a better handle on understanding proteins and their vast array of variations. Proteins make up the structural material of skin, bone, and muscle, but are also enzymes, signaling chemicals, molecular switches, and a host of other functional materials that make up the machinery of all living things. But their structures, including the way they fold themselves into the shapes that often determine their functions, are exceedingly complicated. "They have their own language, and we don't know how it works," he says. "We don't know what makes a silk protein a silk protein or what patterns reflect the functions found in an enzyme. We don't know the code."

By translating that language into a different form that humans are particularly well-attuned to, and that allows different aspects of the information to be encoded in different dimensions -- pitch, volume, and duration -- Buehler and his team hope to glean new insights into the relationships and differences between different families of proteins and their variations, and use this as a way of exploring the many possible tweaks and modifications of their structure and function. As with music, the structure of proteins is hierarchical, with different levels of structure at different scales of length or time.

The team then used an artificial intelligence system to study the catalog of melodies produced by a wide variety of different proteins. They had the AI system introduce slight changes in the musical sequence or create completely new sequences, and then translated the sounds back into proteins that correspond to the modified or newly designed versions. With this process they were able to create variations of existing proteins -- for example of one found in spider silk, one of nature's strongest materials -- thus making new proteins unlike any produced by evolution.

Although the researchers themselves may not know the underlying rules, "the AI has learned the language of how proteins are designed," and it can encode it to create variations of existing versions, or completely new protein designs, Buehler says. Given that there are "trillions and trillions" of potential combinations, he says, when it comes to creating new proteins "you wouldn't be able to do it from scratch, but that's what the AI can do."

"Composing" new proteins

By using such a system, he says training the AI system with a set of data for a particular class of proteins might take a few days, but it can then produce a design for a new variant within microseconds. "No other method comes close," he says. "The shortcoming is the model doesn't tell us what's really going on inside. We just know it works."

This way of encoding structure into music does reflect a deeper reality. "When you look at a molecule in a textbook, it's static," Buehler says. "But it's not static at all. It's moving and vibrating. Every bit of matter is a set of vibrations. And we can use this concept as a way of describing matter."

The method does not yet allow for any kind of directed modifications -- any changes in properties such as mechanical strength, elasticity, or chemical reactivity will be essentially random. "You still need to do the experiment," he says. When a new protein variant is produced, "there's no way to predict what it will do."

The team also created musical compositions developed from the sounds of amino acids, which define this new 20-tone musical scale. The art pieces they constructed consist entirely of the sounds generated from amino acids. "There are no synthetic or natural instruments used, showing how this new source of sounds can be utilized as a creative platform," Buehler says. Musical motifs derived from both naturally existing proteins and AI-generated proteins are used throughout the examples, and all the sounds, including some that resemble bass or snare drums, are also generated from the sounds of amino acids.

The researchers have created a free Android smartphone app, called Amino Acid Synthesizer, to play the sounds of amino acids and record protein sequences as musical compositions.

Vienna, 26 June 2019: While female fertility comes to an irrevocable end with the menopause (at a consistently average age of 51 years), men are not constrained by similar biological senescence. Studies have shown that sperm counts may decline and DNA damage in sperm cells may increase over time, but the celebrity fatherhood of ageing actors and rock stars perpetuates the myth that male fertility might last forever.

However, the published evidence does show that men are indeed regulated by a biological clock. Studies have demonstrated a decline in natural male fertility and an increase in miscarriage rate as men get older. So far it is not yet known whether paternal age affects outcomes in IVF and ICSI - or if there is (or should be) any age limit to treatment.

Now, an analysis of almost 5000 IVF/ICSI cycles performed at a single centre in London indicates that success rates do decline significantly after a paternal age of 51 years. Miscarriage rate in this study was not affected by the age of the male partner. Nevertheless, the investigators confirm that paternal age over 51 does significantly affect the chance of success in assisted reproduction, adding that this warrants a call for 'a public health message for men to not delay fatherhood'.

The results of the study are presented today by Dr Guy Morris from the Centre for Reproductive and Genetic Health (CRGH) in London, where this observational retrospective study was performed. The research team from CRGH and the Institute for Women's Health at University College London analysed the records of 4271 men involved in 4833 cycles of IVF and ICSI treatment for all causes of sub-fertility between 2009 and 2018. The male partners were grouped into age ranges of 35 and under, 36-40, 41-44, 45-50, and over 51 years for analysis. A male age and female age under 35 years were used as reference control groups for comparison.

The analysis first showed that fewer men over 51 met the standard WHO semen reference values than did men under 51 (42.1% vs 61.1%,). It was similarly found - as expected - that clinical pregnancy rate declined with increasing maternal age over 35 years - from 51.1% for under-35s to 21.7% for over-40s. Both these trends were statistically significant.(1)

The study also showed that clinical pregnancy rates declined with increasing paternal age - from 49.9% in the under 35 group, to 42.5% in the 36-40s, to 35.2% in the 41-45s, to 32.8% in the 46-50s, and to 30.5% in the over 51s. These results were re-analysed in a statistical model which included maternal age and it was found that, for all maternal age subgroups, the probability of pregnancy still decreased significantly with paternal age over 51 years.

Dr Morris and his colleagues noted that 80% of the cohort's couples with male partners over 51 were treated with ICSI, a treatment developed for male infertility and requiring just one viable sperm cell for fertilisation. However, although 42% of these older male partners did have normal semen parameters (sperm count, sperm motility), he points out that 'this may have confounded the results and reduced the perceived effect of increased paternal age'.

Commenting on these results, Dr Morris said: 'There may well be a public perception that male fertility is independent of age. Stories of celebrity men fathering children into their 60s may give a skewed perspective on the potential risks of delaying fatherhood. Indeed, in natural conception and pregnancy it is only recently that evidence of risks associated with later fatherhood has become available. These more recent studies contrast with decades of evidence of the impact that maternal age has on fertility outcomes.(2)

'In the context of this emerging evidence for the deleterious effect of increasing paternal age, our data certainly support the importance of educating men about their fertility and the risks of delaying fatherhood.'

This study was observational and not designed to investigate any biological explanation for its findings. However, Dr Morris said that the data 'suggest that semen quality decreases with increasing age and that this decline mirrors the decline in IVF outcome which we found'. It's for this reason, he explained, that some centres limit the age of their sperm donors (usually up to the age of around 40). While some clinics and health authorities set an upper age limit on female IVF patients, no such limits are known to exist for males.

Africa is projected to be home to nearly 3 billion people by 2100, but rapid population growth will cause widespread environmental degradation unless effective family planning becomes widespread policy, according to new research that tracked increased population pressures on the continent's ecosystems.

Researchers from Flinders University and the University of Helsinki have examined the environmental impacts of population density, variation in the distribution of wealth among citizens, and a country's overall economic activity across the African continent.

Using a combination of ecological footprint, species threat, freshwater removal, forest loss, livestock density, cropping intensity, and greenhouse-gas emissions, the researchers developed sophisticated modelling to determine which socio-economic indicators best explain the relative environmental performance among countries.

"Our finding that the strongest predictor of environmental performance among nations in Africa is population density means that countries with the most people suffered relatively more environmental degradation on average," says lead researcher Professor Corey Bradshaw, from the Global Ecology Laboratory at Flinders University.

"The result brings into question the reality of the United Nations' Sustainability Development Goals because none of the targets mentions reducing human population size as a pathway to achieving their goals."

"Dedicated family planning and government policies that attempt to limit population growth and promote economic development that does not compromise environmental integrity are needed to support sustainability across Africa."

The findings -- published in the Nature journal Scientific Reports -- come after a new United Nations report found that the fastest population growth on Earth is most likely to occur in sub-Saharan Africa, which is expected to double its population in the next 30 years.

"Given the rapid growth of its population, Africa stands to lose many of its already threatened species and ecosystems over the coming decades, especially as overseas demand for timber, minerals, fuels, agricultural products, seafood, and wildlife increases" says co-author Dr Enrico Di Minin, a conservation scientist at the University of Helsinki.

Dr Di Minin highlighted that while there are many policy levers that African nations can use to improve the future state of their environments and the societies that depend on them, limiting excessive human population growth will likely facilitate the best results.

"But there is some relatively good environmental news in at least parts of Africa", states Professor Bradshaw. "Despite having other problems, countries like Central African Republic, Botswana, Namibia, and Congo have been doing a lot better then many of their neighbours in the environment stakes".

"But some of the worst environmental performers are densely populated countries like South Africa, Algeria, and Nigeria", Professor Bradshaw warns.

"As pressures on the environment grow, most African nations will have to focus on mitigating the negative interactions of high population growth and unsustainable development if they want to have any chance of maintaining the beautiful, rich, and unique animals and plants for which Africa is famed".

In an increasingly connected world, translators and interpreters play a key role in the exchange of ideas and information. They serve the vital purpose of accurately conveying meaning from one language to the next. Nowadays, almost every modern industry has the crucial need for translators. But did you know that your brain has need for them too?

Though not in the traditional sense, cells in your brain are actively relaying information and communicating with each other in various languages. Neurons speak using neurotransmitters, molecules and electrical signals. In order to properly understand one another, cells in your brain need the skill of proficient translators. Versed in the unique languages of the brain, specialized proteins precisely decipher incoming information and accurately convey it from one neuron to the next.

An important interpreter in the brain named calcium/calmodulin-dependent protein kinase, or CaMKII, plays a critical role in the process of learning and memory. When we learn new skills or form memories, dynamic changes occur at sites of communication between neurons called synapses. As synapses are repeatedly activated, calcium signals initiate a complex cascade that leads to long-lasting alterations in the strength of a neuron's connections. This process, known as synaptic plasticity, is thought to underlie learning and memory. Playing a critical role in plasticity, CaMKII interprets calcium signals and converts them into the long-lasting changes that help encode memory. But the exact mechanisms behind this process have remained elusive.

Recently published in Nature Communications, a new study from the lab of Ryohei Yasuda, Ph.D., Scientific Director at MPFI has shed light on the unexpected mechanism that allows CaMKII to decode and translate calcium signaling in the brain. Using advanced imaging techniques and novel biosensors, Yasuda and his team have revealed new insights into CaMKII's activity at the single synapse level.

In order to study CaMKII's role in synaptic plasticity, the team developed novel sensors capable of disentangling the protein's two distinct forms of activity. The first sensor, CaMKIIα-CaM, reports CaMKII activity that is dependent on its association with calmodulin (CaM); a protein that mediates the binding of calcium to CaMKII. The second sensor, Camuiα, reports CaMKII's total activation, including both CaM dependent and CaM independent autonomous activity produced when CaMKII undergoes autophosphorylation.

Employing two-photon microscopy and glutamate uncaging to simulate plasticity in single synapses, the team used their newly design sensors to investigate the varying forms of CaMKII activity in neurons. Previously, it was thought that CaMKII decodes calcium signaling primarily through its CaM dependent activity, but MPFI scientists have uncovered that this might not be the case. Using the CaMKIIα-CaM sensor, they noticed a rapid but small increase in CaM dependent activity that quickly plateaued when calcium pulses are evoked in the synapses. As calcium pulses continue, there were no further increases in CaMKIIα-CaM activity within the neuron. Contrastingly, the Camuiα sensor demonstrated more robust activity and a step-wise activation; where increasing the number of calcium pulses directly correlated with increased CaMKII activity.

Intriguingly, these results indicate that at a synaptic level, CaMKII's activity is predominantly driven by its autonomous activation and to a much smaller extent by its interaction with CaM. In addition, these findings reveal that the autonomous activity of CaMKII is responsible for responding to and interpreting the language of calcium signaling during the process of synaptic plasticity.

"CaMKII has been well-established as a critically important player in the process of synaptic plasticity, but due to its complex activation profile, a working model of its activity has been difficult to achieve." notes Yasuda, "With new insights gathered from our novel sensors, we are now able to propose a model that is consistent with our experimental data; broadening our understanding of how molecules contribute to memory."

Increased glucose, transformed into energy, could give people with amyotrophic lateral sclerosis, or ALS, improved mobility and a longer life, according to new findings by a University of Arizona-led research team.

Physicians have long known that people with ALS experience changes in their metabolism that often lead to rapid weight loss in a process called hypermetabolism. According to the study's lead author Ernesto Manzo, a UA alumnus and postdoctoral researcher in the Department of Molecular and Cellular Biology, hypermetabolism can be a relentless cycle.

People with ALS use more energy while resting than those without the disease, while simultaneously they often struggle to effectively make use of glucose, the precise ingredient a body needs to make more energy. Experts have not known exactly what happens in a patient's cells to cause this dysfunction or how to alleviate it.

"This project was a way to parse out those details," said Manzo, who described the results, published online in eLife, as "truly shocking."

The study revealed that when ALS-affected neurons are given more glucose, they turn that power source into energy. With that energy, they're able to survive longer and function better. Increasing glucose delivery to the cells, then, may be one way to meet the abnormally high energy demands of ALS patients.

"These neurons were finding some relief by breaking down glucose and getting more cellular energy," Manzo said.

ALS is almost always a progressive disease, eventually taking away patients' ability to walk, speak and even breathe. The average life expectancy of an ALS patient from the time of diagnosis is two to five years.

"ALS is a devastating disease," said Daniela Zarnescu, UA professor of molecular and cellular biology and senior author on the study. "It renders people from functioning one day to rapidly and visibly deteriorating."

Previous studies on metabolism in ALS patients have focused primarily on what happens at the whole-body level, not the cellular level, Zarnescu explained.

"The fact that we uncovered a compensatory mechanism surprised me," Zarnescu said. "These desperate, degenerating neurons showed incredible resilience. It is an example of how amazing cells are at dealing with stress."

The novelty of the findings partially lies in the fact that metabolism in ALS patients has remained poorly understood, Zarnescu said.

"It's difficult to study, in part because of limited accessibility to the nervous system," she said.

Because scientists can't scrape away neurons from the brain without causing irreparable damage to a patient, the researchers used fruit flies as a model.

"Fruit flies can teach us a lot about human diseases," Manzo said.

In the lab, he and Zarnescu used high-powered microscopes to observe the motor neurons of fruit flies in their larval state, paying close attention to what happened as they provided more glucose.

They found that when they increased the amount of glucose, the motor neurons lived longer and moved more efficiently. When the researchers took glucose away from the neurons, the fruit fly larva moved more slowly.

Their findings were consistent with a pilot clinical trial, which found a high carbohydrate diet was one possible intervention for ALS patients with gross metabolic dysfunction.

"Our data essentially provide an explanation for why that approach might work," Zarnescu said. "My goal is to convince clinicians to perform a larger clinical trial to test this idea."

Free-roaming horses are an icon of the American West, frequently appearing in art and media as exemplars of the spirited freedom that underlies the region's folklore. Viewed through an ecological lens, however, these animals may present a different picture--one of degraded landscapes and shrinking biodiversity.

Writing in BioScience, Kirk W. Davies and Chad S. Boyd describe the ecological threats posed by free-roaming horses in the US West and the challenges faced in managing them. According to the authors, the effects of these horses are extensive, ranging from soil compaction and domination of scarce water resources to the over-grazing of native plant species.

Davies and Boyd catalog the numerous effects on local landscapes, pointing to a study that found that "areas from which horses had been excluded compared with horse-occupied areas in Great Basin uplands had two to three times greater native grass cover and frequency." As a result, the authors caution, "free-roaming-horse use over time could permanently affect the productivity and function of some areas." In addition, horses have numerous effects on local fauna, and the authors note that "horses have repeatedly been shown to limit and even exclude native wildlife's use of water sources."

The authors point out that the problem is vast, with free-roaming horses and burros occupying 31.6 million acres of federal lands, with a population of 81,951 animals, exceeding the Bureau of Land Management's established "appropriate management level" by more than 55,000 individuals. Further complicating matters is the uncertainty that beleaguers attempts to understand the horses' effects. The authors note that "domestic livestock grazing often confounds the ecological effects of free-roaming-horse grazing, giving rise to considerable uncertainty regarding the full extent and degree of impact of horses on rangeland ecological processes." The authors draw clear distinction between continuous year-around grazing by free-roaming horses and planned grazing by livestock, which is comparatively limited in duration, takes place during a specific season, and allows for periodic rest. But the uncertainty, caution Davies and Boyd, makes managing horse population challenging, especially in light of free-roaming horses' prominent place in the public's imagination. Horse populations are growing at a mean average rate of 20 percent per year, and public resistance to horse removal has thus far stymied efforts to address their rising numbers.

The solution the authors pose is rigorous ecological research with an eye toward promoting sociopolitical change. It is Davies and Boyd's expressed hope that "change in the sociopolitical arena around free-roaming horses can be stimulated by rigorous ecological research and using that research to inform scientifically sound management of free-roaming horses." Through this, they argue, it may be possible to address the far-ranging effects of this charismatic but ecologically imposing species.

It is widely accepted that probiotic bacteria are beneficial to human health, but what if they could also be used to reduce wildlife disease and conserve biodiversity?

Researchers from Virginia Tech and UC Santa Cruz did just that in a field trial on the effect of probiotic bacteria on white-nose syndrome in bat populations. They found that it reduces the impact of the disease about five-fold.

These findings were published recently in Scientific Reports.

Bats are dominant night-time insect predators that can greatly benefit agriculture, but their populations are being decimated by the fungal disease called white-nose syndrome.

White-nose syndrome has destroyed bat populations across Eastern North America, and it shows no signs of stopping as it spreads westward.

"Our results suggest that the probiotic bacteria, Pseudomonas fluorescens, is a useful tool for reducing white-nose syndrome impacts on bat populations, particularly if combined with other management tools," said Joseph Hoyt, a research scientist in the Department of Biological Sciences in the College of Science.

"With the severity of white-nose syndrome declines and facing the potential extinction of some species, it's essential that we consider out-of-the-box solutions to reducing population impacts. Given the notorious difficulty of treating fungal infections in mammals, probiotics are a sensible solution for reducing fungal burdens of animals," said Kate Langwig, the second author of this paper and an assistant professor in the Department of Biological Sciences in the College of Science and an affiliated faculty member of the Global Change Center.

White-nose syndrome is a disease that spreads in the winter and causes bats to leave their roosts during hibernation. The fungus, which kills the bats over several months, depletes the bats' fat stores, forcing them to expend even more energy on finding food that isn't available during the harsh winter. Eventually, most bats die of starvation or exposure to the cold.

Researchers are seeing declines that are rendering some bat species functionally extinct. Specifically, the little brown bat, Northern long-eared bat, Indiana bat, and the tri-colored bat populations have declined by 70 to 99 percent across 44 states since 2006.

"Little brown bats were not an uncommon species prior to the emergence of this disease. It would be like losing robins from the bird community. These are abundant backyard species that you would see at nighttime that have essentially been removed," Hoyt said.

One species, the Northern long-eared bat, has been extirpated from most of its range by white-nose syndrome. "As far as mainland populations go, if we see a single bat all winter - that's a lot," Hoyt said. "At this point, it may be too late for that species in terms of trying save it. I think its demise happened so quickly that it was not something that anyone could respond to fast enough."

Populations of little brown bats, Northern long-eared bats, tri-colored bats, and the big brown bats were sampled for the bacteria Pseudomonas fluorescens to make sure similar bacteria were naturally present before introducing a higher dosage in the experimental treatment.

In an abandoned mine in Wisconsin, Hoyt and his research team tested the efficacy of P. fluorescens in two simultaneous experiments with caged and free-flying little brown bats. All the bats were tagged with a passive integrated transponder (PIT), which allowed researchers to identify and keep track of when individual bats emerged from the mine.

The purpose of doing the free-flying experiment was to conduct a natural field trial, where bats can move freely and interact with the environment the way that they normally would. Researchers found that measuring the amount of pathogen associated with each bat helped them to better predict the bat's survival time. Interestingly, researchers also saw that treatment with P. fluorescens lengthened the amount of time that bats stayed in the mine.

"Our treatment delayed emergence time, which would put more bats emerging during spring-time when there are insects available for them to eat, allowing them to recover from the disease," Hoyt said.

The caged experiment was meant to counteract the uncertainty of the free-flying experiment by keeping them in a controlled area, while providing researchers key information about how or why they died. However, Hoyt said that, in general, bats are challenging to work with.

"In our caged experiment, there were some individuals that got really sick and likely influenced, or biased, our survival estimates for other individuals." In the end, the researchers found that the amount of fat that a bat had was the only important factor in predicting their survival in the cage trial, not how infected they were.

In the free-flying experiment, their controls had only 10 percent survivability while their treatment group had 50 percent. Hoyt and his team are thinking of ways that the probiotic treatment can be developed to further increase survival. Currently, researchers are testing to see if pairing probiotics with other forms of treatment can increase survival even more.

This is one of the first published papers that show that a probiotic can reduce the impact of pathogens on wildlife. "It's some potential hope that with the right organism and by tinkering around with different techniques, we can start to develop things similar to what has been done with humans," Hoyt said.

As far as what you can do to help the bats, there are many ways to be "bat-friendly." For instance, there are guidelines that you can follow that will help reduce the impact that we have on bats. Putting up bat-boxes, protecting waterways, and changing landscaping to provide insects for bats are good places to start.

Therapies to improve recovery after a heart attack could be developed following fresh insights into how key cells are formed.

Scientists have developed a system that allows them to study cells that line the walls of blood vessels, called endothelial cells.

Researchers say the findings shed light on how the cells can be best grown in the lab for use as therapies. They could also help develop drugs to prompt patients' own endothelial cells to regenerate and grow new blood vessels.

Such treatments could potentially help people with heart disease and other conditions that affect the blood supply, such as peripheral vascular disease - a disorder that can lead to the loss of lower limbs.

Endothelial cells are vital to the process of supplying blood to damaged tissue following a heart attack. The team at the University of Edinburgh studied embroyonic stem cells - early stage cells that are not yet developed - and turned them into endothelial cells in the lab.

They used advanced techniques to visualise the genes that are turned on or off in individual cells as they undergo the transition to become endothelial cells.

Understanding these genetic cues sheds new light on the signals that drive endothelial cell formation and maturation. The researchers say this is a step towards developing treatments that could prompt the growth of functioning new blood vessels in patients.

The research was led by the British Heart Foundation Centre for Cardiovascular Science at the University of Edinburgh and is published in the European Heart Journal. It was funded by the Medical Research Council, Wellcome, the European Research Council and the British Heart Foundation.

Professor Andrew Baker, Head of Centre for Cardiovascular Science at the University of Edinburgh, said: "This study used new technology to map how endothelial cells are formed. We can now harness this information to understand how to activate these processes in patients or use these cells as a cell therapy approach by directly injecting them into damaged tissue."

Keeping physically active or becoming more active during middle and older age is associated with a lower risk of death, regardless of past activity levels or existing health conditions, suggests a large UK study published by The BMJ today.

At the population level, meeting and maintaining at least the minimum public health recommendations (150 minutes per week of moderate-intensity physical activity) would potentially prevent 46% of deaths associated with physical inactivity, say the researchers.

Previous studies have linked physical activity to lower risk of death, cardiovascular disease, and certain cancers. But few studies have looked at how changes in physical activity over time are associated with subsequent risk of death.

So to address this knowledge gap, researchers from the MRC Epidemiology Unit at the University of Cambridge analysed how long term changes in physical activity are associated with risk of all-cause, cardiovascular and cancer deaths.

They used data for 14,599 men and women aged 40-79 from the European Prospective Investigation into Cancer and Nutrition-Norfolk (EPIC-Norfolk) study, who were recruited between 1993-1997.

Participants were assessed at the start of the study and then a further three times over an average of 7.6 years, along with other risk factors up to 2004. From this point in time, mortality was assessed up to 2016, for an average of 12.5 years of follow-up.

Physical activity energy expenditure (PAEE) was derived from questionnaires and calibrated against combined movement and heart monitoring measurements.

Overall physical activity included activity at work (e.g. sedentary office work, standing work, physical and heavy manual work) and leisure-time activity, such as cycling, sports and recreational activities.

During the study period, there were 3,148 deaths, including 950 deaths from cardiovascular disease and 1,091 deaths from cancer.

After controlling for existing physical activity and other risk factors such as diet, bodyweight, medical history, blood pressure and cholesterol levels, higher physical activity levels and increases in physical activity over time were associated with a lower risk of death.

For each 1kJ/kg/day per year increase in PAEE (equivalent to being inactive at the start of the study and gradually, over five years, meeting minimum physical activity guidelines), the researchers found a 24% lower risk of death from any cause, a 29% lower risk of cardiovascular death, and an 11% lower risk of cancer death.

Results were similar in those with and without a history of cardiovascular disease and cancer. What's more, compared with consistently inactive people, those who became more active over time had a lower risk of death from all causes, regardless of past activity levels.

But the benefits were greatest for those with existing high levels of physical activity who became even more active over time, with a 42% lower risk of mortality.

This is an observational study, and as such, can't establish cause. And the authors point out that the sample was made up of people who were available for follow-up almost a decade after initial recruitment, which may influence generalisability of the results.

But they say that this is a large study with long follow-up and repeat monitoring, that controlled for established risk factors.

"These results are encouraging, not least for middle aged and older adults with existing cardiovascular disease and cancer, who can still gain substantial longevity benefits by becoming more active, lending further support to the broad public health benefits of physical activity," they write.

"In addition to shifting the population towards meeting the minimum physical activity recommendations, public health efforts should also focus on the maintenance of physical activity levels, specifically preventing declines over mid to late life," they conclude.

UNIVERSITY PARK, Pa. -- Malaria parasites develop faster in mosquitoes at lower temperatures than previously thought, according to researchers at Penn State and the University of Exeter. The findings suggest that even slight climate warming could increase malaria risk to hundreds of thousands, if not millions, of people -- including travelers -- in areas that are currently too cold for malaria parasites to complete their development.

"The rate of malaria transmission to humans is strongly determined by the time it takes for the parasites to develop in the mosquito," said Matthew Thomas, professor and Huck scholar in ecological entomology, Penn State. "The quicker the parasites develop, the greater the chance that the mosquito will survive long enough for the parasites to complete their development and be transmitted to humans."

According to Thomas, previous work suggested that in cooler temperatures malaria parasites developed too slowly to be transmitted to people during mosquitoes' lifetimes. That work, he said, was conducted almost 100 years ago using a Russian species of mosquito.

"Our study is the first since the 1930s to investigate the relationship between temperature and malaria parasite development," said Thomas. "Our results challenge this long-standing model in malaria biology."

The researchers used two of the most important malaria-hosting mosquito species in the world -- Anopheles stephensi and Anopheles gambiae -- to conduct their experiments. They maintained these malaria-infected mosquitoes in the laboratory under a variety of temperatures ranging from 16 to 20 degrees Celsius, or 60 to 68 degrees Fahrenheit. They maintained a separate control set of mosquitoes at 27 degrees Celsius, or about 80 degrees Fahrenheit, which is the temperature at which malaria transmission is typically highest.

In addition, the team varied the daily temperatures by 10 degrees Celsius -- 5 degrees Celsius above and below the daily mean -- since such variation in temperature is common in natural settings when it is cooler at night and warmer in the daytime. The findings appear in the June 26 issue of Biology Letters.

The traditional model estimates that parasites in the mosquito take 56 days to develop at temperatures just above the minimum threshold for development -- a cool 18 degrees Celsius, or 64 degrees Fahrenheit. However, the current study shows that as few as 31 days are required for such development for Anopheles stephensi.

The researchers also found that variation in temperature at this cooler end of the range promotes faster parasite development. Parasites developed in as few as 27 days at 18 degrees Celsius, or 64 degrees Fahrenheit, under realistic variable temperature conditions.

"Our work shows that even small increases in temperature could dramatically increase malaria infections in humans because the parasites develop much faster at these lower temperatures than has been previously estimated," said Jessica Waite, senior scientist, Penn State. "Parasite development rate further increases when temperatures fluctuate naturally, from cooler at night to warmer in the day."

According to Waite, the findings have implications for potentially millions of people living in the higher elevations of Africa, such as the Kenyan and Ethiopian highlands, and in South America.

"As temperatures increase with climate change, infectious mosquitoes in areas surrounding mountains, for example, may be able to transmit the parasite higher up the mountains than they have in the past," she said. "Our results suggest that small rises in temperature could lead to greater increases in transmission risk than previously thought."

In many ways, a cell is like a city. Proteins or people do daily work to keep the economy going, and items are imported and exported for trade. Imports are shipped into cells by way of endocytosis. Before reaching their final destination, they are kept at the early endosome, a structure that determines whether the material will be disposed, recycled or delivered to a specific region in the cell. A new study in iScience by researchers at the Nara Institute of Science and Technology (NAIST), Japan, demonstrates how ankyrin repeat and KH domain-containing protein 1 (ANKHD1) are instrumental in forming the early endosome.

Endocytosis describes the formation of vesicles at the membrane and then transports inside the cell.

"The cell moves material through vesicles that are cut from the membrane. Only a small number of proteins are known to execute membrane scission, and these proteins include BAR domain proteins," notes NAIST Professor Shiro Suetsugu, who managed the study.

"ANKHD1 contains an ankyrin repeat domain [ARD], which we previously found to have lipid-binding ability," he continues. Ankyrins are proteins that bind to proteins, but their membrane binding capacity is relatively unexplored.

To investigate more about ARD, the study began with 600 candidates, but settled with ANKHD1 when liposome sedimentation assays indicated its ARD had strong vesiculation activity.

The ARD of ANKHD1 contains 25 ankyrin repeats that the scientists divided into one group of 15 and another group of 10. To test the function of these two groups, they established a series of ANKHD1 constructs: one ARD with all 25 ankyrin repeats, one with only the group of 15 and one with only the group of 10, with the first two including the N-terminal, and tested how these constructs reacted with liposomes.

"We found that the two groups had different roles, vesiculation and dimerization," says Suetsugu.

The vesiculation ability of the group of 10 broke liposomes down into small vesicles and was attributed to an amphipathic helix and electrostatic interactions with the liposome, but this ability was enhanced by the dimerization of the group of 15. This process resembled how BAR proteins interact with membranes.

Moreover, reducing the ANKHD1 expression in mammalian cells increased the size of the early endosome, indicating a membrane-deformation function that could impact intracellular trafficking.

"The vesiculation of early endosomes is a crucial and early step in intracellular trafficking, but very little is known about the proteins that regulate this system. Abnormalities at this stage can have a tremendous impact on many cellular functions," says Suetsugu.

Losing a limb, either through illness or accident, can present emotional and physical challenges for an amputee, damaging their quality of life. Prosthetic limbs can be very useful but are often expensive and difficult to use. The Biological Systems Engineering Lab at Hiroshima University has developed a new 3D printed prosthetic hand combined with a computer interface, which is their cheapest, lightest model that is more reactive to motion intent than before. Previous generations of their prosthetic hands have been made of metal, which is heavy and expensive to make.

Professor Toshio Tsuji of the Graduate School of Engineering, Hiroshima University describes the mechanism of this new hand and computer interface using a game of "Rock, Paper, Scissors". The wearer imagines a hand movement, such as making a fist for Rock or a peace sign for Scissors, and the computer attached to the hand combines the previously learned movements of all 5 fingers to make this motion.

"The patient just thinks about the motion of the hand and then the robot automatically moves. The robot is like a part of his body. You can control the robot as you want. We will combine the human body and machine like one living body." explains Tsuji.

Electrodes in the socket of the prosthetic equipment measure electrical signals from nerves through the skin-- similar to how an ECG measures heart rate. The signals are sent to the computer, which only takes five milliseconds to make its decision about what movement it should be. The computer then sends the electrical signals to the motors in the hand.

The neural network (named Cybernetic Interface), that allows the computer to "learn", was trained to recognize movements from each of the 5 fingers and then combine them into different patterns to turn Scissors into Rock, pick up a water bottle or to control the force used to shake someone's hand.

"This is one of the distinctive features of this project. The machine can learn simple basic motions and then combine and then produce complicated motions." Tsuji says.

Hiroshima University Biological Systems Engineering Lab tested the equipment with patients in the Robot Rehabilitation Center in the Hyogo Institute of Assistive Technology, Kobe. The researchers also collaborated with the company Kinki Gishi to develop the socket to accommodate the amputee patients' arm.

Seven participants were recruited for this study, including one amputee who had worn a prosthesis for 17 years. Participants were asked to perform a variety of tasks with the hand that simulated daily life, such as picking up small items, or clenching their fist. The accuracy of prosthetic hand movements measured in the study for single simple motion was above 95 %, and complicated, unlearned motions was 93%.

However, this hand is not quite ready for all wearers. Using the hand for a long time can be burdensome for the wearer as they must concentrate on the hand position in order to sustain it, which caused muscle fatigue. The team are planning on creating a training plan in order to make the best use of the hand and hope it will become an affordable alternative on the prosthetics market.

People who report a declining quality of sleep as they age from their 50s to their 60s have more protein tangles in their brain, putting them at higher risk of developing Alzheimer's disease later in life, according to a new study by psychologists at the University of California, Berkeley.

The new finding highlights the importance of sleep at every age to maintain a healthy brain into old age.

"Insufficient sleep across the lifespan is significantly predictive of your development of Alzheimer's disease pathology in the brain," said the study's senior author, Matthew Walker, a sleep researcher and professor of psychology. "Unfortunately, there is no decade of life that we were able to measure during which you can get away with less sleep. There is no Goldilocks decade during which you can say, 'This is when I get my chance to short sleep.'"

Walker and his colleagues, including graduate student and first author Joseph Winer, found that adults reporting a decline in sleep quality in their 40s and 50s had more beta-amyloid protein in their brains later in life, as measured by positron emission tomography, or PET. Those reporting a sleep decline in their 50s and 60s had more tau protein tangles. Both beta-amyloid and tau clusters are associated with a higher risk of developing dementia, though not everyone with protein tangles goes on to develop symptoms of dementia.

Based on the findings, the authors recommend that doctors ask older patients about changes in sleep patterns and intervene when necessary to improve sleep to help delay symptoms of dementia. This could include treatment for apnea, which leads to snoring and frequent halts in breathing that interrupt sleep, and cognitive behavioral therapy for insomnia (CBT-I), a highly effective way to develop healthy sleep habits. It may even include simple sleep counseling to convince patients to set aside time for a full eight hours of sleep and simple sleep hygiene tricks to accomplish that.

"The idea that there are distinct sleep windows across the lifespan is really exciting. It means that there might be high-opportunity periods when we could intervene with a treatment to improve people's sleep, such as using a cognitive behavioral therapy for insomnia," Winer said. "Beyond the scientific advance, our hope is that this study draws attention to the importance of getting more sleep and points us to the decades in life when intervention might be most effective."

The 95 subjects in the study were part of the Berkeley Aging Cohort Study (BACS), a group of healthy older adults -- some as old as 100 years of age -- who have had their brains scanned with PET, the only technique capable of detecting both beta-amyloid tangles and, very recently, tau tangles, in the brain.

Winer, Walker and their colleagues reported their results online last week in the Journal of Neuroscience.

Brain waves out of sync

The team also made a second discovery. They found that people with high levels of tau protein in the brain were more likely to lack the synchronized brain waves that are associated with a good night's sleep. The synchronization of slow brain waves throughout the cortex of the sleeping brain, in lockstep with bursts of fast brain waves called sleep spindles, takes place during deep or non-rapid eye movement (NREM) sleep. The team reported that the more tau protein older adults had, the less synchronized these brain waves were. This impaired electrical sleep signature may therefore act as a novel biomarker of tau protein in the human brain.

"There is something special about that synchrony," given the consequences of this tau protein disruption of sleep, Walker said. "We believe that the synchronization of these NREM brain waves provides a file-transfer mechanism that shifts memories from a short-term vulnerable reservoir to a more permanent long-term storage site within the brain, protecting those memories and making them safe. But when you lose that synchrony, that file-transfer mechanism becomes corrupt. Those memory packets don't get transferred, as well, so you wake up the next morning with forgetting rather than remembering."

Indeed, last year, Walker and his team demonstrated that synchronization of these brain oscillations helps consolidate memory, that is, hits the "save" button on new memories.

Several years ago, Walker and his colleagues initially showed that a dip in the amplitude of slow wave activity during deep NREM sleep was associated with higher amounts of beta-amyloid in the brain and memory impairment. Combined with these new findings, the results help identify possible biomarkers for later risk of dementia.

"It is increasingly clear that sleep disruption is an underappreciated factor contributing to Alzheimer's disease risk and the decline in memory associated with Alzheimer's," Walker said. "Certainly, there are other contributing factors: genetics, inflammation, blood pressure. All of these appear to increase your risk for Alzheimer's disease. But we are now starting to see a new player in this space, and that new player is called insufficient sleep."

The brain rhythms were recorded over a single eight-hour night in Walker's UC Berkeley sleep lab, during which most of the 31 subjects wore a cap studded with 19 electrodes that recorded a continual electroencephalogram (EEG). All had previously had brain scans to assess their burdens of tau and beta-amyloid that were done using a PET scanner at the Lawrence Berkeley National Laboratory and operated by study co-author William Jagust, professor of public health and a member of Berkeley's Helen Wills Neuroscience Institute.

Is sleep a biomarker for dementia?

Doctors have been searching for early markers of dementia for years, in hopes of intervening to stop the deterioration of the brain. Beta-amyloid and tau proteins are predictive markers, but only recently have they become detectable with expensive PET scans that are not widely accessible.

Yet, while both proteins escalate in the brain in old age and perhaps to a greater extent in those with dementia, it is still unknown why some people with large burdens of amyloid and tau do not develop symptoms of dementia.

"The leading hypothesis, the amyloid cascade hypothesis, is that amyloid is what happens first on the path to Alzheimer's disease. Then, in the presence of amyloid, tau begins to spread throughout the cortex, and if you have too much of that spread of tau, that can lead to impairment and dementia," Winer said.

Walker added that, "A lack of sleep across the lifespan may be one of the first fingers that flicks the domino cascade and contributes to the acceleration of amyloid and tau protein in the brain."

The hypothesis is supported, in part, by Jagust's PET studies, which have shown that higher levels of beta-amyloid and tau protein tangles in the brain are correlated with memory decline, tau more so than amyloid. Tau occurs naturally inside the brain's neurons, helping to stabilize their internal skeleton. With age, tau proteins seem to accumulate inside cells of the medial temporal lobe, including the hippocampus, the seat of short-term memory. Only later do they spread more widely throughout the cortex.

While Jagust has run PET scans on the brains of many healthy people, as well as those with dementia, many more subjects are needed to confirm the relationship between protein tangles and dementias like Alzheimer's disease. Because PET scanners are currently expensive and rare, and because they require injection of radioactive tracers, other biomarkers are needed, Walker said.

The new study suggests that sleep changes detectable in a simple overnight sleep study may be less intrusive biomarkers than a PET scan.

"As wearable technology improves, this need not be something you have to come to a sleep laboratory for," said Walker. "Our hope is that, in the future, a small head device could be worn by people at home and provide all the necessary sleep information we'd need to assess these Alzheimer's disease proteins. We may even be able to track the effectiveness of new drugs aimed at combating these brain proteins by assessing sleep."

"I think the message is very clear," Walker added. "If you are starting to struggle with sleep, then you should go and see your doctor and find ways, such as CBT-I, that can help you improve your sleep. The goal here is to decrease your chances of Alzheimer's disease."

The summer's annual conference of the American Society for Horticultural Science in Las Vegas, will deliver a variety of crucial issues facing today's world and how the realm of horticulture is addressing them. There is one presentation that holds all the intrigue of a murder mystery and all the painstaking, arduous pursuit of an archeological dig, along with a touch of serendipity.

Gary Bachman, Christine Coker, and Patricia Knight of the Mississippi State University Coastal Research and Extension Center will detail their relevant experiences in Horticulture CSI: Search for the Long Beach Radish https://ashs.confex.com/ashs/2019/meetingapp.cgi/Session/9270.

According to the speakers, this is an instance of solving the mystery of the disappearance, and ultimately the rediscovery, of the Long Beach red radish (LBR). The LBR was a prominent vegetable that very few people know about at all today. Although it holds singular responsibility for securing Long Beach, Mississippi, as a significant economic force in truck cropping in the early 20th century, the Long Beach Red disappeared completely. It was large enough to appear as a red carrot, attractive, and delicious and therefore sought after by distant markets. Each winter up to 300 railroad boxcars were filled with LBR and delivered to the Northern states. The demand was plentiful.

But something happened. Production markets opened up in Florida and other areas, and The Long Beach Red radish was no more. Clues about this peculiar disappearance were scant, and the trail has gone cold. No seed companies carry LBR seeds in the modern age. Extension records yielded no results.

The Long Beach Red radish might still be thought extinct if not for the tenacious efforts of Bachman, Coker and Knight. The result of their efforts might be the restoration of a one-time food staple to its position of glory. Their investigative tale is an inspiration, and well worth a listen.

Bachman adds, "Extension problem solving is really all about listening because sometimes the answer to a problem comes from a very unlikely time or source."