Culture

Osaka, Japan - The early development of embryos is not well understood. One necessary stage is the formation of the blastocyst, a collection of cells present by about 4 days after fertilization of the egg, before implantation in the uterus. From that tiny collection of cells, all the different cells in the body must be created. Accordingly, there need to be mechanisms in the blastocyst to ensure normal gene expression and cell differentiation; those regulatory mechanisms are still largely unknown.

It is known that the proteins in the tumor-suppression "Hippo pathway" act in cells throughout the body to regulate normal organ growth and tissue regeneration. These proteins ensure that organs reach the sufficient size, while countering excessive enlargement. Therefore, researchers have theorized that Hippo-pathway proteins contribute to regulation of normal blastocyst development. That theory was confirmed recently when Masakazu Hashimoto and Hiroshi Sasaki, of the Graduate School of Frontier Biosciences at Osaka University, demonstrated that the Hippo-pathway proteins TEAD and YAP serve an important regulatory function in blastocysts. Together, these proteins support pluripotency (i.e., the ability to become any type of cell) in the blastocyst before implantation.

In their study, published in the journal Developmental Cell, Drs. Hashimoto and Sasaki used genetically modified mouse cells to alter the amounts and timing of TEAD activation during blastocyst formation. Results showed that accumulation of YAP in cell nuclei activated TEAD and, subsequently, activated transcription factor MYC. This activation sequence then induces a previously unknown process of cell competition within the blastocyst.

"We were able to measure levels of activated TEAD-YAP in the epiblast (a layer of the blastocyst) of day 4 after fertilization, and show that levels differed between cells. Higher levels of TEAD are associated with greater pluripotency, so cells with low TEAD, and thus low pluripotency, must be eliminated from the epiblast," says corresponding author Dr. Sasaki.

That elimination is achieved when cell competition, through encountering neighboring cells with higher levels of TEAD, induces apoptosis (cell self-destruction) in cells of low pluripotency.

First author Dr. Hashimoto adds that "Appropriate control of the Hippo pathway in epiblasts acts as a quality-control mechanism, ensuring that all cells have the maximum potential to develop into the many different cell types that are required for the growing embryo."

The information gained in this study could aid in improved induction of pluripotent stem cells, of potential use in various clinical trials, and in the maintenance of embryos for in-vitro fertilization.

(Boston)--Increasing the levels of the anti-aging protein hormone Klotho improves the neurological deficits and prolongs life span in an experimental model with Amyotrophic Lateral Sclerosis (ALS). In addition, brain immune cells called microglia play an important role in protecting the brain against inflammation and, likely, motor neuron loss in this model.

ALS or Lou Gehrig's disease, is a devastating neurodegenerative disease characterized by the loss of upper and lower motor neurons, leading to progressive muscle atrophy and paralysis, which is fatal within three to five years of diagnosis.

Researchers from Boston University School of Medicine (BUSM) have previously shown that increasing Klotho protein levels is beneficial in experimental models of Alzheimer's disease and multiple sclerosis. "Here we now show that Klotho is also neuroprotective in an ALS model. Thus, increasing Klotho levels would be a logical treatment for age-related neurodegenerative and neuroinflammatory diseases," explained corresponding author Carmela Abraham, PhD, professor of biochemistry at BUSM.

Unfortunately, very few treatments are available to ALS patients today. "We propose that increasing the levels of the Klotho protein would significantly alleviate the neurologic manifestations, improve the quality of life and prolong life span in patients with ALS. If one was to extrapolate the results of this study, increasing Klotho by only 50 percent would prolong life by approximately 300 days."

According to Abraham, anything that increases Klotho levels is neuroprotective. For example, it has been shown that exercise increases Klotho. "This may be relevant for healthy individuals or patients newly diagnosed with ALS. Additionally, in the cases of familial ALS, family members who wish to be tested and discover that they are carriers of an ALS gene could start exercising or start Klotho boosting therapy, once it becomes available."

Water is a vital resource for people and the environment. One of the most important sources is groundwater which is renewed from precipitation or surface water. Population growth as well as agriculture and industry strongly influence the quantity and quality of groundwater. To be able to investigate groundwater resources more easily, cost-effectively and comprehensively than in the past, researchers at Karlsruhe Institute of Technology (KIT) have developed a new method with Australian colleagues which they are now unveiling in the Reviews of Geophysics journal.

According to the German Environment Agency, more than 70 percent of drinking water originates from groundwater in Germany alone. Production is increasing so rapidly across the world that groundwater levels are falling, quality is deteriorating and whole cities are facing groundwater-related subsidence. Therefore, it is important to explore subsurface properties for managing resources more sustainably.

"Current testing methods require active pumping of water from a specially designed water extraction well while observing the water level in other wells in the vicinity," says Dr. Gabriel Rau from the Institute of Applied Geosciences (AGW) at KIT. To do this, two or three people would need to set up a pump test and supervise measurements for an extended period of time. This method is very expensive, can last anywhere from a few hours to several months depending on the subsurface properties, and the result is only valid for the tested location. "Underground aquifers vary greatly in space, and it is much too expensive and intrusive to build extraction wells everywhere."

Together with the University of New South Wales (UNSW) in Sydney and the Deakin University in Melbourne, KIT has now developed a new method which evaluates information about tidal effects on groundwater levels. Similar to tides in the ocean, the groundwater level is affected by tidal forces, with the change in gravitation squeezing the porous rocks in the subsurface and causing measurable pressure changes. In addition, there are atmospheric tides which cyclically change subsurface pressure. "We can measure this change at low cost and using less complex procedures and fewer personnel to quantify subsurface properties," says Rau. Engineers require no special extraction wells for this but can place an automated water pressure data logger at a conventional groundwater measuring point. The pressure sensor then measures the groundwater level regularly for at least a month. Using the measurements, researchers can calculate the physical properties of the subsurface such as porosity, hydraulic conductivity and compressibility and translate the findings into the sustainable use of groundwater resources. "Since it is much cheaper to drill monitoring boreholes than to create entire wells, we can carry out measurements in more locations, significantly increasing the number and coverage of the subsurface properties calculated," says Rau.

The researchers have studied and summarized international studies and articles from various disciplines for their method: "We have seen that the recent advances in groundwater research show potential for much cheaper long-term groundwater studies," says Timothy McMillan from the Connected Waters Initiative Research Center at UNSW Sydney. "In our method we use a combination of engineering, science and maths, and the impact of tides on groundwater to calculate the subsurface properties." These findings can also contribute to predicting spatial and temporal fluctuations of the climate system and its impact on groundwater resources. "We are facing enormous challenges in the future. Our method makes it easier to investigate subsurface resources and therefore to manage them more sustainably," says Rau.

Insights into how a gene that increases the risk of Alzheimer's disease disrupts brain cells have been revealed by scientists.

Brain tissue from people with Alzheimer's showed that a protein called clusterin builds up in vital parts of neurons that connect cells and may damage these links.

Scientists say the findings shed light on the causes of the disease and will help to accelerate the search for a treatment.

The study, led by Professor Tara Spires-Jones at the University of Edinburgh, focused on synapses - connections between brain cells that allow the flow of chemical and electrical signals. These signals are vital for forming memories and are key to brain health, experts say.

Researchers showed that synapses in people who had died with Alzheimer's contained clumps of clusterin, which could contribute to dementia symptoms. These synapses also contained clumps of amyloid beta, the damaging protein that is found in the brains of people with Alzheimer's.

People with a common risk gene, called apolipoprotein E4, had more clusterin and amyloid beta clumps in their synapses than people with Alzheimer's without the risk gene.

Those without dementia symptoms had even less of the damaging proteins in their synapses.

The discovery was made using powerful technology that allowed the scientists to view detailed images of more than one million synapses. Individual synapses are around 5000 times smaller than the thickness of a sheet of paper.

Synapse loss in Alzheimer's disease was previously established, but the clumping of damaging proteins together in synapses was unknown until now because of difficulties in studying them due to their tiny size.

Alzheimer's disease is the most common form of dementia, affecting around 500,000 people in the UK. It can cause severe memory loss and there is no cure.

Professor Spires-Jones, Programme Lead at the UK Dementia Research Institute at the University of Edinburgh, said: "We have identified another player in the host of proteins that damage synapses in Alzheimer's disease. Synapses are essential for thinking and memory, and preventing damage to them is a promising target to help prevent or reverse dementia symptoms. This work gives us a new target to work towards in our goal to develop effective treatments."

Using cutting-edge electron microscopy, researchers from Aarhus University have determined the first structures of a lipid-flippase. The discoveries provide a better understanding of the basics of how cells work and stay healthy, and can eventually increase our knowledge of neurodegenerative diseases such as Alzheimer's.

All cells are surrounded by a cell membrane that defines and protects the interior of the cell from the outside world. The membrane consists of two layers of fats called lipids, and the distribution of specific types of lipids between the two sides of the membrane is of great importance for the cell to remain healthy and act dynamically. As lipid flippases are a membrane protein, they are located in the cell's membranes, and they are of great importance to the properties of the membrane, where they move lipids from the cell membrane's exterior to the inner layer.

The researchers have studied the lipid flippase Drs2/Cdc50, which is found in yeast cells, where it actively moves lipids from one side of the cell membrane to the other. Similar proteins are found in many variants in humans, where they are also linked to very active processes in brain cells and thus to mechanisms that are central to neurological diseases and dementia, e.g. Alzheimer's disease.

A protein roughly consists of a long chain of amino acids that folds into a three-dimensional structure that is crucial to their function. The experimental determination of the 3D structures of protein molecules requires advanced techniques and is often a great challenge - especially for membrane proteins which are extremely difficult to handle.

It is not possible to take regular photos of proteins as they are too small, but with the technology of cryo-electron microscopy, a group of researchers from Professor Poul Nissen's research group at Aarhus University have succeeded in determining the three-dimensional structure of Drs2/Cdc50 by taking many hundreds of thousands of "electron photographs" of the molecule. It is the first time anyone has determined a structure from this important family of proteins, the lipid flippases, and the results have just been published in the world-leading journal Nature.

Culmination of over 10 years of work

With the new publication, over 10 years of focused work culminates for a number of students and researchers from Poul Nissen's research group, who also involved collaborative partners at Université Paris-Saclay and the Max Planck Institute of Biophysics in Frankfurt.

"It's fantastic to have been part of the project's final part, see the results fall into place and suddenly be able to explain observations that were detected several years, and which now gives us completely new insights," says PhD student Milena Timcenko, who has been working on the determination of the structure of Drs2/Cdc50 for the past four years together with Assistant Professor Joseph Lyons.

Joseph Lyons adds: "It's great to finally to see these membrane protein structures for the first time. The fun begins now to piece together the big picture of how these transport proteins work. It has been an amazing development to be part of."

Cryo-electron microscopy means that the proteins are cooled down to -170°C in an ultra-thin layer, after which they are "X-rayed" with a powerful beam of electrons and form small shadows on an image chip.

"It's a bit like when you take an X-ray in the hospital, just with electrons instead of X-rays and magnified almost 150,000 times," says Milena Timcenko. "The protein molecules should preferably lie completely motionless to get a sharp image, while the cold temperatures protect the proteins from being destroyed by the powerful electron beam triggered by a voltage of 300,000 volts. That's why we cool them down. The trick is to freeze the samples quickly enough so that no ice crystals are formed, and in a layer that is thin enough that the proteins do not shade one another. We have become quite good at this in Aarhus."

The results attract huge international international attention

By combining thousands of images where the protein is observed in all possible random directions, one can put together a 3D image that allows to build a model of the protein molecule, atom by atom, thousands of atoms. The model contributes to the basic understanding of how lipid flippases work and can therefore explain some of the diseases that arise from mutations in this family of proteins. This means that small changes have occurred in the 3D structure, and the researchers can now describe the effect of these changes.

This is the first time a completely new membrane protein structure is determined by cryo-electron microscopy in Denmark, and the results attract huge international attention. The work on the large datasets has been made possible by a great effort also to develop research infrastructure in the area, which after several years of work is now in place in Aarhus.

Professor Poul Nissen is very pleased with this development: "With this research infrastructure and strongly growing expertise in cryo-electron microscopy, we are at the forefront of the world competition for new knowledge and opportunities to understand cell biology, drugs and biotechnology at the molecular level. This enables us to maintain and develop Denmark's competitive position in structural biology. We are soon expanding the microscopy facilities with support from the infrastructure program from the Ministry of Research and Innovation and can thus open up access for research groups at all Danish universities, industry and start-up companies. This is essential for our ability to discover new mechanisms in the interaction of physics, chemistry, biology and medicine and to develop new and innovative technologies."

Many work processes would be almost unthinkable today without robots. But robots operating in manufacturing facilities have often posed risks to workers because they are not responsive enough to their surroundings. To make it easier for people and robots to work in close proximity in the future, Prof. Matthias Althoff of the Technical University of Munich (TUM) has developed a new system: IMPROV.

When companies use robots to produce goods, they generally have to position their automatic helpers in safety cages to reduce the risk of injury to people working nearby. A new system could soon free the robots from their cages and thus transform standard practices in the world of automation: Prof. Matthias Althoff has developed a toolbox principle for the simple assembly of safe robots using various components. The modules can be combined in almost any way desired, enabling companies to customize their robots for a wide range of tasks - or simply replace damaged components. Prof. Althoff's system is presented in a paper in the June 2019 issue of Science Robotics.

Built-in chip enables the robot to program itself

Robots that can be configured individually using a set of components have been seen before. However, each new model required expert programming before going into operation. Prof. Althoff has equipped each module in his IMPROV robot toolbox with a chip that enables every modular robot to program itself on the basis of its own individual toolkit.

Keeping an eye on the people working nearby

"Our modular design will soon make it more cost-effective to build working robots. But the toolbox principle offers an even bigger advantage: With IMPROV, we can develop safe robots that react to and avoid contact with people in their surroundings," says Althoff. With the chip installed in each module and the self-programming functionality, the robot is automatically aware of all data on the forces acting within it as well as its own geometry. That enables the robot to predict its own path of movement.

At the same time, the robot's control center uses input from cameras installed in the room to collect data on the movements of people working nearby. Using this information, a robot programmed with IMPROV can model the potential next moves of all of the nearby workers. As a result, it can stop before coming into contact with a hand, for example - or with other approaching objects. "With IMPROV we can guarantee that the controls will function correctly. Because the robots are automatically programmed for all possible movements nearby, no human will be able to instruct them to do anything wrong," says Althoff.

IMPROV shortens cycle times

For their toolbox set, the scientists used standard industrial modules for some parts, complemented by the necessary chips and new components from the 3D printer. In a user study, Althoff and his team showed that IMPROV not only makes working robots cheaper and safer - it also speeds them up: They take 36% less time to complete their tasks than previous solutions that require a permanent safety zone around a robot.

Early disease stages of MS are primarily characterised by immune cell infiltration of the CNS. This causes inflammation that damages the so-called myelin sheaths. Myelin sheaths are electrically insulating structures established by specialised glial cells of the CNS, referred to as 'oligodendrocytes'. These structures protect, nourish and stabilise axons, which transmit electrical signals between neurons.

There is a large therapeutic repertoire of immunomodulatory drugs available that can effectively target the inflammatory aspects of relapsing multiple sclerosis (RMS). But when MS progresses, damage accumulates which ultimately results in irreversible deficits and clinical disability. Unfortunately, despite decades of intense research disease progression is still untreatable as there are no therapies available that either prevent damage or repair injured axons.

In a new study published online on June 18 in the renowned journal PNAS a research team led by Prof. Dr. Patrick Küry from the Department of Neurology (chaired by Prof. Dr. Hans-Peter Hartung) has shed light on a novel axon damage mechanism which could be highly relevant for progressive MS (PMS) patients.

As outlined by the first author of this research paper, Dr. David Kremer, the envelope (ENV) protein of the pathogenic human endogenous retrovirus type W (pHERV-W) was found to be a major contributor to nerve damage in MS. In collaboration with research teams in Cleveland (OH, USA) and Montreal (CAN) the authors demonstrated that the ENV protein drives CNS resident microglial cells to contact and damage myelinated axons.

Alongside the scientific research into determining how the damage mechanism works, clinical developments aiming at neutralising the harmful ENV protein in MS patients have also progressed. Two clinical studies conducted under the supervision of Prof. Hartung have already successfully tested the ENV-neutralising antibody temelimab. MRI scans of the participants treated in the study showed reduced damage to the nerve tissue.

The Düsseldorf-based researchers and their colleagues can therefore explain why neurodegeneration is decreased in patients treated with temelimab. This antibody specifically binds to the ENV protein of the retrovirus and blocks its activity in the CNS. As stated by Prof. Hartung, future clinical studies in progressive MS patients will now have to demonstrate whether temelimab treatment can also improve clinical symptoms resulting from neurodegeneration.

Professor Atsushi Sato of the University of Toyama and Ai Matsuo, a researcher at The Open University of Japan, in cooperation with Professor Michiteru Kitazaki of Toyohashi University of Technology have found that social contingency modulates one's perceptual representation of the environment. Volunteer participants who were given the ability to display an image of a smiling person with the press of a button were found to perceive an afterimage of the same person, but with a neutral expression, to be smaller than participants who were unable to display the image of a smiling person with the press of a button. Thus, when the participant's intentional action affects the other's reaction, the perceptual distance between self and other will shorten.

Social contingency, namely the contingent reactions of the other to one's own actions, is important for attachment formation and enhancement, and for the development of social cognition. Thus, social contingency is a critical factor in our social distance. It is known that body size, motivation, action capability, and controllability affect the perceived distance between the self and objects/others. However, it is not clear whether social contingency directly modulates the perceived distance between self and other.

Recently, a research team from the Faculty of Human Development at the University of Toyama, in collaboration with the Department of Computer Science and Engineering from Toyohashi University of Technology, designed an experimental method to investigate the effect of social contingency on perceptual distance by measuring the size of an afterimage online.

Sixty-six volunteer participants were assigned to one of three conditions in the manipulation phase (Figure 1). In the contingent condition, each participant was shown a photograph of a neutral female face. This photograph changed to a photograph of a smiling face after the participant pressed a button provided to them by the researchers. In the non-contingent condition, the neutral face changed to the smiley face at random times, irrespective of the participant's button-pressing. In the unresponsive condition, the neutral face was constantly presented although participants pressed the button in the same manner as in the other conditions. One hundred trials were performed in the manipulation phase.

In the following test phase, participants observed the neutral face for 30 seconds at a viewing distance of 57cm, and were presented with an afterimage projected on a screen at three different viewing distances: 114, 171, and 228 cm. The perceived size of the afterimage increased with the viewing distance. It was basically consistent with Emmert's law.

Participants who were able to manipulate the presentation of the smiley face through the pressing of the button (the contingent condition) perceived the afterimage to be smaller than participants who were exposed at random to the smiley face (the non-contingent condition) or the constantly neutral face (the unresponsive condition). Figure 2 shows the perceptual distance that was mathematically calculated according to Emmert's law. The perceptual distance was shorter for those who were able to manipulate the presentation of the smiley face with their button press (the contingent condition) than for those placed in the other conditions, and this effect increased with physical distance.

Professor Atsushi Sato, the leader of the research team at the University of Toyama said, "Previous studies are criticized for not showing the true top-down effects on perception because of pitfalls such as an inability to disentangle post-perceptional judgment from actual online perception, task demands, and differences in the low-level visual features of the stimuli across experimental conditions. Our method of using a perceptual mechanism of size constancy can avoid such pitfalls and test directly the effect of social contingency on online perception."

Professor Michiteru Kitazaki, a perceptual psychologist at Toyohashi University of Technology explained, "The present study suggests that the social contingency can modulate the distance between self and other in a perceptual processing level that is automatic and nearly independent of our knowledge. Thus, social cognition seems more implicit than expected, and crucially connected to low-level perceptual processing in the brain."

Do you feel the other closer to you when she/he contingently responds to your action? The findings tell us that it is not just your false belief, but it is based on your automatic perception.

Experts led by the Institute for Sustainable Food at the University of Sheffield reveal how plants provide a steady flow of air to every cell

Study shows humans have bred wheat plants to have fewer pores on their leaves and use less water

Findings pave the way to develop more drought-resistant crops

Scientists have discovered how plants create networks of air channels - the lungs of the leaf - to transport carbon dioxide (CO2) to their cells.

Botanists have known since the 19th century that leaves have pores - called stomata - and contain an intricate internal network of air channels. But until now it wasn't understood how those channels form in the right places in order to provide a steady flow of CO2 to every plant cell.

The new study, led by scientists at the University of Sheffield's Institute for Sustainable Food and published in Nature Communications, used genetic manipulation techniques to reveal that the more stomata a leaf has, the more airspace it forms. The channels act like bronchioles - the tiny passages that carry air to the exchange surfaces of human and animal lungs.

In collaboration with colleagues at the University of Nottingham and Lancaster University, they showed that the movement of CO2 through the pores most likely determines the shape and scale of the air channel network.

The discovery marks a major step forward in our understanding of the internal structure of a leaf, and how the function of tissues can influence how they develop - which could have ramifications beyond plant biology, in fields such as evolutionary biology.

The study also shows that wheat plants have been bred by generations of people to have fewer pores on their leaves and fewer air channels, which makes their leaves more dense and allows them to be grown with less water.

This new insight highlights the potential for scientists to make staple crops like wheat even more water-efficient by altering the internal structure of their leaves. This approach is being pioneered by other scientists at the Institute for Sustainable Food, who have developed climate-ready rice and wheat which can survive extreme drought conditions.

Professor Andrew Fleming from the Institute for Sustainable Food at the University of Sheffield said: "Until now, the way plants form their intricate patterns of air channels has remained surprisingly mysterious to plant scientists.

"This major discovery shows that the movement of air through leaves shapes their internal workings - which has implications for the way we think about evolution in plants.

"The fact that humans have already inadvertently influenced the way plants breathe by breeding wheat that uses less water suggests we could target these air channel networks to develop crops that can survive the more extreme droughts we expect to see with climate breakdown."

Dr Marjorie Lundgren, Leverhulme Early Career Fellow at Lancaster University, said: "Scientists have suspected for a long time that the development of stomata and the development of air spaces within a leaf are coordinated. However, we weren't really sure which drove the other. So this started as a 'what came first, the chicken or the egg?' question.

"Using a clever set of experiments involving X-ray CT image analyses, our collaborative team answered these questions using species with very different leaf structures. While we show that the development of stomata initiates the expansion of air spaces, we took it one step further to show that the stomata actually need to be exchanging gases in order for the air spaces to expand. This paints a much more interesting story, linked to physiology."

The X-ray imaging work was undertaken at the Hounsfield Facility at the University of Nottingham. The Director of the Facility, Professor Sacha Mooney, said: "Until recently the application of X-ray CT, or CAT scanning, in plant sciences has mainly been focused on visualising the hidden half of the plant - the roots - as they grow in soil.

"Working with our partners in Sheffield we have now developed the technique to visualise the cellular structure of a plant leaf in 3D - allowing us to see how the complex network of air spaces inside the leaf controls its behaviour. It's very exciting."

In the past few years, thrill-seekers from Hollywood, Silicon Valley and beyond have been travelling to South America to take part in so-called Ayahuasca retreats. Their goal: to partake in a brewed concoction made from a vine plant Banisteriopsis caapi, traditionally used by indigenous people for sacred religious ceremonies. Drinkers of Ayahuasca experience short-term hallucinogenic episodes many describe as life-changing.

The active ingredient responsible for these psychedelic visions is a molecule called dimethyltryptamine (DMT). For the first time, a team led by Michigan Medicine has discovered the widespread presence of naturally-occurring DMT in the mammalian brain. The finding is the first step toward studying DMT-- and figuring out its role -- within the brains of humans.

"DMT is not just in plants, but also can be detected in mammals," says Jimo Borjigin, Ph.D., of the Department of Molecular and Integrative Physiology. Her interest in DMT came about accidentally. Before studying the psychedelic, her research focused on melatonin production in the pineal gland.

In the seventeenth century, the philosopher Rene Descartes claimed that the pineal gland, a small pinecone-shaped organ located deep in the center of the brain, was the seat of the soul. Since its discovery, the pineal gland, known by some as the third eye, has been shrouded in mystery. Scientists now know it controls the production of melatonin, playing an important role in modulating circadian rhythms, or the body's internal clock. However, an online search for notes to include in a course she was teaching opened Borjigin's eyes to a thriving community still convinced of the pineal gland's mystical power.

The core idea seems to come from a documentary featuring the work of researcher Rick Strassman, Ph.D. with the University of New Mexico School of Medicine. In the mid-1990s, he conducted an experiment in which human subjects were given DMT by IV injection and interviewed after its effects wore off. In a documentary about the experiment, Strassman claims that he believed the pineal gland makes and secretes DMT.

"I said to myself, 'wait, I've worked on the pineal gland for years and have never heard of this,'" she said. She contacted Strassman, requesting the source of his statement. When Strassman admitted that it was just a hypothesis, Borjigin suggested they work together to test it. "I thought if DMT is an endogenous monoamine, it should be very easy to detect using a fluorescence detector."

Using a process in which microdialysis tubing is inserted into a rat brain through the pineal gland, the researchers collected a sample that was analyzed for -- and confirmed -- the presence of DMT. That experiment resulted in a paper published in 2013.

However, Borjigin was not satisfied. Next, she sought to discover how and where DMT was synthesized. Her graduate student, Jon Dean, lead author of the paper, set up an experiment using a process called in situ hybridization, which uses a labeled complementary strand of DNA to localize a specific RNA sequence in a tissue section.

"With this technique, we found brain neurons with the two enzymes required to make DMT," says Borjigin. And they were not just in the pineal gland.

"They are also found in other parts of the brain, including the neocortex and hippocampus that are important for higher-order brain functions including learning and memory."

The results are published in the journal Scientific Reports.

Her team's work has also revealed that the levels of DMT increase in some rats experiencing cardiac arrest. A paper published in 2018 by researchers in the U.K. purported that DMT simulates the near death experience, wherein people report the sensation of transcending their bodies and entering another realm. Borjigin hopes to probe further to discover the function of naturally occurring levels of DMT in the brain -- and what if any role it plays in normal brain functions.

"We don't know what it's doing in the brain. All we're saying is we discovered the neurons that make this chemical in the brain, and they do so at levels similar to other monoamine neurotransmitters."

A change is as good as a rest when it comes to remembering more, according to new research by neuroscientists at the University of Sussex.

Dr Michael Crossley, Senior Research Fellow in Neuroscience, used pond snails to study the factors impacting on memory interference.

He found that, when tasked with learning two similar things, snails were only able to store and recall the first memory.

Conversely, when faced with learning two totally unrelated tasks, the snails were able to retain all the information and successfully store both memories.

Dr Crossley said: "The brain of a snail is much simpler than ours but there are some key parallels which mean studying them can help us to understand more about our own abilities for learning and memory.

"We know that multiple learning events occurring in quick succession can lead to competition between memories. This is why, when introduced to multiple people in one go, we can't usually remember every name.

"Up until now though, we weren't sure which factors were causing a memory to be remembered or forgotten."

With colleagues from Sussex Neuroscience, Dr Crossley trained snails using food-reward and aversive conditioning .

Using brain recording, they realised that the same neuron was used when snails tried to learn two similar things. This prompted an overlapping mechanism, which caused only one memory (the first one) to survive, known as proactive interference.

In contrast, when two different tasks were learnt, two separate neurons were used, resulting in no competition, no overlap and the successful storing of both memories.

Dr Crossley explained: "We realised that there is an overlapping or non-overlapping mechanism which plays a key role in determining which memories survive.

"So if we want to learn multiple things quickly, we should try learning different rather than similar topics."

For students, this means that they should practice interweaving - switching between multiple different subjects in one day - to retain the most information.

However, in the study published in the Nature group journal Communications Biology, Dr Crossley and his colleagues also found that the timing of new learning can play a big role in the interference of memories.

When they introduced new learning to a snail during a memory lapse (the stage at which information is temporarily forgotten as it is transferred from short to longer term memory) researchers found that an older memory was always lost. This is known as retroactive interference.

Dr Ildiko Kemenes, senior author on the paper, said: "In effect, we think the brain is deciding to replace the older learning, which hasn't yet been committed to long-term memory, for a newer one which it thinks might be more relevant.

"Interestingly, it's only when trying to learn something new during a memory lapse that this interference happens.

"This suggests that the older memory was only vulnerable due to new memories being formed. This makes sense when we think about humans as we wouldn't want a system where our memories are vulnerable if someone bumps into us at the wrong time!"

Scientists believe that the findings of their research, funded by BBSRC, gives us useful information about how memory is stored and how best we can learn and retain information.

A group of scientists from Japan--led by Prof Takashi Kamakura of Tokyo University of Science--has demonstrated, for the first time, the molecular and cellular basis of the "adverse" effects of the antibiotic chloramphenicol on eukaryotic cells. Concluding their study published in Scientific Reports, they state, "Identification of the molecular target of chloramphenicol may lead to better elucidation and resolution of its side effects in humans."

Antibiotics are often the treatment of choice for bacterial or fungal infections. Chloramphenicol is an example of a broad-spectrum antibiotic that's active against most bacteria and widely used in human and veterinary medicine. However, it has varied side effects--such as human aplastic anemia, bone marrow suppression, and gray baby syndrome--which limit its prescription. A drug's side effects are usually thought to be due to its interaction with entities other than the "target" molecules. The causes of the side effects of chloramphenicol have remained unknown to date, but this team of scientists from Japan has demonstrated one of the possible mechanisms of the effect of chloramphenicol on eukaryotic cells. The researchers state, "High doses of chloramphenicol have been known to cause mitochondrial damage in eukaryotes," but also go on to say, "Our study shows that drugs have novel secondary targets in eukaryotes."

As the model eukaryotic organism for the study, they used the rice blast fungus Pyricularia (Magnaporthe) oryzae. When asked about the significance of this model organism, Prof Kamakura says, "The rice blast fungus is an economically important pathogen that causes destructive disease in rice, which is the staple food of Japan. Thus, from the perspective of food security, it is important to understand the infection strategy of this pathogen and implement ways to control the damage to crops." He also cites another interesting fact, "the genome of this fungus has considerably less 'junk' DNA--the 'noncoding' part of the genome that does not code for any functional proteins. This, along with the low number of targetable functional proteins, makes the rice blast fungus an ideal model for the screening of novel molecular targets of drugs."

The rice blast fungus uses a peculiar structure called the "appressorium," which functions in surface recognition, binding, and subsequent infection. The fungus infects the plant using a 3-cell structure called "conidium," which has a "germ tube" with the appressorium at the end. The appressorium initiates contact with the host (plant) cell and is crucial in the infection cycle. This entire process is known to be dependent on the mitotic division of the single-cell germ tube and cell differentiation. Given the fact that cell differentiation depends on several different molecular components, these molecules can also be "targets" of several drugs. It is this principle, validated by previous studies in the field, that was exploited by the research team led by Prof Kamakura.

The researchers first exposed a suspension of the fungal "conidia" to different concentrations of chloramphenicol. After 6 hours, they found via microscopic observation that the germination of the conidia or the length of the germ tube remained unaffected, but the percentage of appressorium formation significantly dwindled. Prof Kamakura's team thus concluded that chloramphenicol specifically targets appressorium formation in the rice blast fungus, which is a novel finding.

Next, they "screened" for chloramphenicol targets in the entire genome of the rice blast fungus. Of the 86 peptides that were targeted, 14 were known rice blast fungus peptides, and only 2 were functionally active proteins (proteins from the "coding region" of a gene). One of these was extremely similar to a highly conserved eukaryotic protein called Dullard, and the researchers termed this "MoDullard." The Dullard protein is known to play a role in cell differentiation in eukaryotes. The researchers found that MoDullard was expressed the most at the appressorium formation stage. They also performed functional analysis by "knocking out" the MoDullard gene, and found that mutants with no MoDullard were not able to produce the appressorium, but were also resistant to chloramphenicol. This confirmed that chloramphenicol targets this protein.

Finally, to determine the target in humans, they identified 5 candidate peptides from the human genome that bore resemblance to MoDullard. They isolated the gene for each of these peptides and transferred it into the MoDullard-knockout mutant. They found that one of the peptides, called CTDSP1, complemented the "lost" function of MoDullard in the mutant cells--meaning that the cells with CTDSP1 introduced were able to produce appressorium. Chloramphenicol was again found to block the formation of this appressorium, which led the researchers to confirm that CTDSP1 is indeed a target of chloramphenicol in humans.

To put these results into perspective, Prof Kamakura states, "A more detailed analysis of the mechanism of inhibition of appressorium formation revealed for the first time here may lead to the development of new control methods for the rice blast fungus. Also, drug screening using the rice blast fungus may lead to the elucidation of yet-unknown side effects or drug repositioning to discover novel effects of existing drugs whose safety profiles have been confirmed."

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.