Culture

New research provides a roadmap to help the millions of older Britons struggling with 'shopping lists' of medication, as fears grow that the current coronavirus lockdown could be further isolating the most vulnerable.

With the over-70s and people with existing medical conditions being encouraged to 'shield' or self-isolate in lockdown as much as possible, there are concerns many could be avoiding seeking help from GPs and pharmacies in managing multiple medications, known as 'polypharmacy'.

Around half of the UK's 12m people aged 65 or over regularly take five or more separate medicines for long-term health conditions, also known as comorbidities. And even before the coronavirus crisis, it was estimated that errors such as taking the wrong medication cause or contribute to over 2,400 deaths per year.

The new research from Aston University, conducted between 2017 and 2019 and in collaboration with the universities of Oxford, Sheffield, Bradford and Wollongong and the NHS, has been published in the journal BMC Geriatrics. It aims to provide clinicians such as GPs and pharmacists with a more structured way of managing their patients' medicines.

The team behind the MEMORABLE (MEdication Management in Older people: Realist Approaches Based on Literature and Evaluation) study, funded by the National Institute for Health Research (NIHR) and led by Dr Ian Maidment, say a new approach rooted in real-world experience is needed to tackle the "unrivalled complexity" many older people and family carers face.

Retired dental secretary Sue Boex, 73, took part in the study while caring for her mother, Edna, who passed away in February 2019 at the age of 96. Towards the end of her life, Edna had dementia while also suffering from heart and digestive problems which meant taking at least six different medicines.

"She didn't know why or what she was taking and relied on me totally," said Sue, from Stourbridge, West Midlands. "It was incredibly stressful. It's not as though you get any training to be a carer, so we had to make it up as we went along."

Sue recalled how her mother would get confused and angry when medicines from different manufacturers were prescribed, because she relied on shape and colour to tell them apart. At one point, she became seriously dehydrated after refusing to take a thickening agent with her drinks to help with a swallowing problem.

Sue's husband Nick, 72, also suffers from a number of long-term conditions for which he takes 12 different tablets. She said that although they were lucky to have an "excellent" local GP and pharmacist who have been able to deliver his medication throughout the COVID-19 crisis, she worried about how others were coping.

"I once visited an elderly gentleman who kept his medicines in an old tobacco tin. He was hospitalised several times for taking too many or not taking them at all. I dread to think how someone in that sort of situation must be coping right now. I think a lot of older people, particularly if they live on their own and don't use technology, must be feeling like they can't ask for help even if they need it."

In the MEMORABLE study, the researchers reviewed existing academic literature and carried out 50 in-depth interviews with older people, their family carers and health and care practitioners.

They identified five 'key burdens' faced by older people and their family carers. These included 'ambiguity', where the purpose of medicines was not explained clearly, through to 'fragmentation' from having to deal with lots of different health and care practitioners and 'exclusion' when older people and family carers were not involved in care decisions.

In response, the team behind the MEMORABLE study propose a five-stage framework for clinicians to help older people and family carers manage medication more effectively. It places greater emphasis on the need for regular reviews of the medications older people are taking involving patients and their carers - something that isn't always done routinely at present.

Clair Huckerby is Chief Pharmacist for Our Health Partnership, a 'super partnership' of 37 GP practices in Birmingham and the wider West Midlands, serving a population of around 400,000.

She said: "The MEMORABLE study is really important because I think historically the NHS perhaps hasn't put enough emphasis on talking to patients about how the complexity of their medication regimes can affect them. It also encourages us to have a more structured approach to medication review and that may well mean deprescribing items that the patient no longer needs."

Our Health Partnership is now looking to 'risk stratify' its large population to identify more vulnerable patients and take a more proactive approach in helping them manage their medication.

Dr Ian Maidment, from Aston University's School of Life and Health Sciences, said:

"The reality is that many older people are taking what amounts to a 'shopping list' of different medicines. They may all be necessary, but older people and their family carers have told us what a huge burden it can be to remember how and when to take them all. And that was in ordinary times without the added pressures of lockdown.

"Many older people may struggle to access their GP and pharmacy right now and with such bad news every day, may even be avoiding asking for help because they don't want to be putting further strain on the NHS. We urgently need further research on the impact of COVID and I am planning future research in this area.

"What we're hoping to show with this study is that practitioners need to be aware that the burden and risk with medication is often hidden. There needs to be a simpler way of identifying people who are struggling and more emphasis on fitting managing medication into older people's day-to-day lives. When prescribing new drugs, GPs will often consider things like side effects, but they equally need to think about how someone will actually manage taking them.

"That human side needs to be front and centre."
Jo Rycroft-Malone, NIHR Programme Director and Chair of the Health Services and Delivery Research (HS&DR) Programme said:

"This research provides important, usable insight into the issues facing older people when it comes to managing their medication. The proposed five step approach will be very useful to practitioners when working with patients and their carers particularly at a time when people may be more concerned about asking for help."

By delving deeper into metabolism problems, the research team has found that the nutrient sensing capacity of Enterochromaffin (EC) cells - which line the gastrointestinal tract and are the source of almost all serotonin in the body - have changed in mice under the influence of high?fat diet?induced obesity and metabolic disease.

Dr Alyce Martin is part of a Flinders University research group under the supervision of Professor Damien Keating that made this discovery, and their recently published paper in the journal Neurogastroenterology & Motility has been chosen as the stand-out article for the August issue and is the monthly feature for the journal's podcast.

"Our newly published work builds upon previous work from our lab published during my PhD, showing that the EC cells which produce serotonin in the gut act as important sensory cells within their environment." says Dr Martin. "It also builds upon our work in humans showing that circulating serotonin and duodenal EC cell numbers are increased in obese humans."

Despite the known metabolic roles of gut-derived serotonin, the underlying causes of increased serotonin with obesity and diabetes remains unknown.

However, Dr Martin says the new research offers novel insights into the mechanisms by which functional changes to EC cells occur, which may contribute to the altered circulating serotonin seen with obesity and metabolic disease, and associated gastrointestinal disorders including gastroparesis and nausea.

"We've already shown that these cells have the ability to sense and release serotonin in response to select nutrients under healthy conditions, which is dependent upon their location within the gut," says Dr Martin. "Now we have shown that nutrient sensing by these cells, as well as the number of cells, is impacted by diet in an obese, diabetic model."

The study - Diet differentially regulates enterochromaffin cell serotonin content, density and nutrient sensitivity in the mouse small and large intestine, by Alyce Martin, Lauren Jones, Claire Jessup, Emily Sun and Damien Keating - has been published by the Wiley journal Neurogastroenterology & Motility.

The new paper also builds on a significant study by Flinders researchers published in the Proceedings of the National Academy of Science in 2019, which showed that gut bacteria communicate with EC cells, to impact metabolism even under healthy conditions. This was the first evidence to highlight gut-derived serotonin as a pathway by which bacteria impact metabolism.

The activity of gut?derived serotonin in these metabolic processes has direct implications of such metabolic disorders as obesity and type 2 diabetes.

Current additional work by the Flinders researchers involves looking at how serotonin from EC cells influences gut motility - also examining how these EC cells respond to mechanical stimulation and communicate with neurons in the gut as part of the gut-brain-axis.

"We are progressing on several fronts to understand the dynamic relationship that serotonin-producing EC cells have with their gut environment, to ultimately impact physiological processes such as gut function and metabolism," says Dr Martin.

At a glance:

Fruit fly study finds death by sleep deprivation is preceded by the accumulation of molecules known as reactive oxidative species (ROS) in the gut

Neutralizing ROS in the gut allows severely sleep-deprived fruit flies to have normal lifespans

Buildup of ROS in the gut due to insufficient sleep occurs across species

Findings potentially inform future efforts to counteract the harmful effects of sleep deprivation in humans

The first signs of insufficient sleep are universally familiar. There's tiredness and fatigue, difficulty concentrating, perhaps irritability or even tired giggles. Far fewer people have experienced the effects of prolonged sleep deprivation, including disorientation, paranoia and hallucinations.

Total, prolonged sleep deprivation, however, can be fatal. While it has been reported in humans only anecdotally, a widely cited study in rats conducted by Chicago-based researchers in 1983 showed that a total lack of sleep inevitably leads to death. Yet, despite decades of study, a central question has remained unsolved: why do animals die when they don't sleep?

Now, Harvard Medical School neuroscientists have identified an unexpected, causal link between sleep deprivation and premature death. In a study on sleep-deprived fruit flies, researchers found that death is always preceded by the accumulation of molecules known as reactive oxidative species (ROS) in the gut.

When fruit flies were given antioxidant compounds that neutralize and clear ROS from the gut, sleep-deprived flies remained active and had normal lifespans. Additional experiments in mice confirmed that ROS accumulate in the gut when sleep is insufficient.

The findings, published in Cell on June 4, suggest the possibility that animals can indeed survive without sleep under certain circumstances. The results open new avenues of study to understand the full consequences of insufficient sleep and may someday inform the design of approaches to counteract its detrimental effects in humans, the authors said.

"We took an unbiased approach and searched throughout the body for indicators of damage from sleep deprivation. We were surprised to find it was the gut that plays a key role in causing death," said senior study author Dragana Rogulja, assistant professor of neurobiology in the Blavatnik Institute at HMS.

"Even more surprising, we found that premature death could be prevented. Each morning, we would all gather around to look at the flies, with disbelief to be honest. What we saw is that every time we could neutralize ROS in the gut, we could rescue the flies," Rogulja said.

Scientists have long studied sleep, a phenomenon that appears to be fundamental for life, yet one that in many ways remains mysterious. Almost every known animal sleeps or exhibits some form of sleeplike behavior. Without enough of it, serious consequences ensue. In humans, chronic insufficient sleep is associated with heart disease, type 2 diabetes, cancer, obesity, depression and many other conditions.

Previous research has shown that prolonged, total sleep restriction can lead to premature death in animal models. In attempts to answer how sleep deprivation culminates in death, most research efforts have focused on the brain, where sleep originates, but none have yielded conclusive results.

Gut accumulation

Spearheaded by study co-first authors Alexandra Vaccaro and Yosef Kaplan Dor, both research fellows in neurobiology at HMS, the team carried out a series of experiments in fruit flies, which share many sleep-regulating genes with humans, to search for signs of damage caused by sleep deprivation throughout the body. To monitor sleep, the researchers used infrared beams to constantly track the movement of flies housed in individual tubes.

They found that flies can sleep through physical shaking, so the team turned to more sophisticated methods. They genetically manipulated fruit flies to express a heat-sensitive protein in specific neurons, the activity of which are known to suppress sleep. When flies were housed at 29 degrees C (84 degrees F), the protein induced neurons to remain constantly active, thus preventing the flies from sleeping.

After 10 days of temperature-induced sleep deprivation, mortality spiked among the fruit flies and all died by around day 20. Control flies that had normal sleep lived up to approximately 40 days in the same environmental conditions.

Because mortality increased around day 10, the researchers looked for markers of cell damage on that and preceding days. Most tissues, including in the brain, were indistinguishable between sleep-deprived and non-deprived flies, with one notable exception.

The guts of sleep-deprived flies had a dramatic buildup of ROS--highly reactive, oxygen-containing molecules that in large amounts can damage DNA and other components within cells, leading to cell death. The accumulation of ROS peaked around day 10 of sleep deprivation, and when deprivation was stopped, ROS levels decreased.

Additional experiments confirmed that ROS builds up in the gut of only those animals that experienced sustained sleep loss, and that the gut is indeed the main source of this apparently lethal ROS.

"We found that sleep-deprived flies were dying at the same pace, every time, and when we looked at markers of cell damage and death, the one tissue that really stood out was the gut," Vaccaro said. "I remember when we did the first experiment, you could immediately tell under the microscope that there was a striking difference. That almost never happens in lab research."

The team also examined whether ROS accumulation occurs in other species by using gentle, continuous mechanical stimulation to keep mice awake for up to five days. Compared to control animals, sleep-deprived mice had elevated ROS levels in the small and large intestines but not in other organs, a finding consistent with the observations in flies.

Death rescue

To find out if ROS in the gut play a causal role in sleep deprivation-induced death, the researchers looked at whether preventing ROS accumulation could prolong survival.

They tested dozens of compounds with antioxidant properties known to neutralize ROS and identified 11 that, when given as a food supplement, allowed sleep-deprived flies to have a normal or near-normal lifespan. These compounds, such as melatonin, lipoic acid and NAD, were particularly effective at clearing ROS from the gut. Notably, supplementation did not extend the lifespan of non-deprived flies.

The role of ROS removal in preventing death was further confirmed by experiments in which flies were genetically manipulated to overproduce antioxidant enzymes in their guts. These flies had normal to near-normal lifespans when sleep-deprived, which was not the case for control flies that overproduced antioxidant enzymes in the nervous system.

The results demonstrate that ROS buildup in the gut plays a central role in causing premature death from sleep deprivation, the researchers said, but cautioned that many questions remain unanswered.

"We still don't know why sleep loss causes ROS accumulation in the gut, and why this is lethal," said Kaplan Dor. "Sleep deprivation could directly affect the gut, but the trigger may also originate in the brain. Similarly, death could be due to damage in the gut or because high levels of ROS have systemic effects, or some combination of these."

Insufficient sleep is known to interfere with the body's hunger signaling pathways, so the team also measured fruit fly food intake to analyze whether there were potential associations between feeding and death. They found that some sleep-deprived flies ate more throughout the day compared with non-deprived controls. However, restricting access to food had no effect on survival, suggesting that factors beyond food intake are involved.

The researchers are now working to identify the biological pathways that lead to ROS accumulation in the gut and subsequent physiological disruptions.

The team hopes that their work will inform the development of approaches or therapies to offset some of the negative consequences of sleep deprivation. One in three American adults gets less than the recommended seven hours of sleep per night, according to the U.S. Centers for Disease Control and Prevention, and insufficient sleep is a normal part of life for many around the world.

"So many of us are chronically sleep deprived. Even if we know staying up late every night is bad, we still do it," Rogulja said. "We believe we've identified a central issue that, when eliminated, allows for survival without sleep, at least in fruit flies."

"We need to understand the biology of how sleep deprivation damages the body, so that we can find ways to prevent this harm," she said.

Cancer cells can turn on error-prone DNA copy pathways to adapt to cancer treatment, a breakthrough study published in the journal Science has revealed. Bacteria use the same process, termed stress-induced mutagenesis, to develop antibiotic resistance.

The cells of the human body are constantly dividing, and each time need to copy a three billion-letter DNA code with high precision to ensure cell survival. The same is not true for cancers, researchers have discovered.

A team led by Professor David Thomas at the Garvan Institute of Medical Research has shown how a broad range of cancers, including melanoma, pancreatic cancer, sarcomas and breast cancer, generate a high number of errors when they copy their DNA when exposed to cancer treatments, leading to drug resistance.

"Resistance to treatment is arguably the major issue facing patients with advanced cancers, for whom even effective treatments ultimately fail. We have uncovered a fundamental survival strategy that cancer cells use to develop resistance, and which has given us new possible therapeutic strategies," says Professor Thomas, Garvan's Cancer Research Theme Leader and Director of The Kinghorn Cancer Centre.

Resisting cancer treatment

Resistance to cancer therapy affects hundreds of thousands of cancer patients every year, leading to devastating health outcomes even for the most advanced treatments.

Researchers have long known that cancer cells accumulate genetic variations that make it possible for them to evade treatment. But how this happens - and whether the process could be targeted to improve cancer treatment - has been elusive.

The authors of the current study began to investigate the underlying drivers of treatment resistance by analysing biopsy samples from cancer patients, before and after they were treated with targeted cancer therapies. Targeted therapies block the growth of cancer by interfering with molecules that are needed for tumour growth, and are a common treatment for many forms of cancer.

They were surprised to discover that the cancer cells from patients that had received targeted therapies showed much higher levels of DNA damage than pre-treatment samples - even when these treatments did not directly damage DNA. Further, the researchers used whole genome sequencing to analyse how treatment resulted in accelerated evolution of the cancer genome.

"Our experiments revealed that cancer cells exposed to targeted therapies undergo a process called stress-induced mutagenesis - they generate random genetic variation at a much higher rate than cancer cells not exposed to anti-cancer drugs," says first author Dr Arcadi Cipponi.

"This process is ancient - single-celled organisms, such as bacteria, use the same process to evolve when they encounter stress in their environment."

Cancer's two-step strategy for resistance

To pinpoint the mechanisms underlying stress-induced mutagenesis in human cancer cells, the researchers carried out a large-scale screen to silence every gene in cancer cells individually, looking to identify the specific pathways contributing to drug resistance.

When they silenced the gene for MTOR - a stress sensor protein - they discovered that cancer cells stopped growing, but paradoxically accelerated evolution in the presence of a cancer treatment.

"MTOR is a sensor protein that tells normal cells to stop growing because there is a stress in the environment. But we found that in the presence of a cancer treatment, MTOR signalling allowed cancer cells to change expression of genes involved in DNA repair and replication, for example shifting from high-fidelity polymerases, the enzymes that copy DNA, to production of error-prone polymerases," says Dr Cipponi. "This resulted in more genetic variation, ultimately fuelling resistance to treatment."

The shift to low-fidelity DNA repair and replication was temporary - once cancer cells acquired resistance to a cancer treatment, they reactivated high-fidelity pathways.

"Genomic instability can itself be harmful to cells--which is why some of our chemotherapies and therapeutic radiation work. We found that once cancer cells had developed resistance to a treatment, they switched back to high-fidelity DNA polymerases to ensure the cells that had evolved resistance to treatment could survive," explains Dr Cipponi.

New approach for cancer treatments

Combining conventional targeted cancer therapy with drugs that target DNA repair mechanisms, the researchers say, may lead to more effective therapeutic strategies.

As a proof-of-principle, the researchers tested such a drug combination in a mouse model of pancreatic cancer. By combining the cancer treatment palbociclib with rucaparib, a drug which selectively targets cells with impaired DNA repair, they were able to reduce cancer growth by almost 60% over 30 days, compared to palbociclib alone.

"Our findings have opened up new potential strategies that either prevent stress-induced mutagenesis in cancers, or are more effective in cancers that have already developed resistance," says Professor Thomas.

In less than three decades, most of Southeast Asia's peatlands have been wholly or partially deforested, drained, and dried out. This has released carbon that accumulated over thousands of years from dead plant matter, and has led to rampant wildfires that spew air pollution and greenhouse gases into the atmosphere.

The startling prevalence of such rapid destruction of the peatlands, and their resulting subsidence, is revealed in a new satellite-based study conducted by researchers at MIT and in Singapore and Oregon. The research was published in the journal Nature Geoscience, in a paper by Alison Hoyt PhD '17, who is now a postdoc at the Max Planck Institute for Biogeochemistry, MIT professor of civil and environmental engineering Charles Harvey, and two others.

Tropical peatlands are permanently flooded forest lands, where the debris of fallen leaves and branches is preserved by the wet environment and continues to accumulate for centuries, rather than continually decomposing as it does in dryland forests. When drained and dried, either to create plantations or to build roads or canals to extract the timber, the peat becomes highly flammable. Even when unburned it rapidly decomposes, releasing its accumulated store of carbon. This loss of stored carbon leads to subsidence, the sinking of the ground surface, in vulnerable coastal areas.

Until now, measuring the progression of this draining and drying process has required arduous treks through dense forests and wet land, and help from local people who know their way through the remote trackless swampland. There, poles are dug into the ground to provide a reference to measure the subsidence of the land over time as the peat desiccates. The process is arduous and time-consuming, and thus limited in the areas it can cover.

Now, Hoyt explains, the team was able to use precise satellite elevation data gathered over a three-year period to get detailed measurements of the degree of subsidence over an area of 2.7 million hectares mostly in Malaysia and Indonesia -- more than 10 percent of the total area covered by peatlands in the Southeast Asia region. Over 90 percent of the peatland area they studied was subsiding, at an average of almost an inch a year (over 1 foot every 15 years). This subsidence poses a threat to these ecosystems, as most coastal peatlands are at or just above sea level.

"Peatlands are really unique and carbon rich environments and wetland ecosystems," Hoyt says. While most previous attempts to quantify their destruction have focused on a few locations or types of land use, by using the satellite data, she says this work represents "the first time that we can make measurements across many different types of land uses rather than just plantations, and across millions of hectares." This makes it possible to show just how widespread the draining and subsidence of these lands has been.

"Thirty years ago, or even 20 years ago, this land was covered with pristine rainforest with enormous trees," Harvey says, and that was still the case even when he began doing research in the area. "In 13 years, I've seen almost all of these rainforests just removed. There's almost none at all anymore, in that short period of time."

Because peat is composed almost entirely of organic carbon, measuring how much that land has subsided provides a direct measure of the amount of carbon that has been released into the atmosphere. Unlike other kinds of subsidence seen in drier ecosystems, which can result from compaction of soil, in this case the missing depth of peat reflects matter that has actually been decomposed and lost to the air. "It's not just compaction. It's actually mass loss. So measuring rates of subsidence is basically equivalent to measuring emissions of carbon dioxide," says Harvey, who is also a principal investigator at the Singapore-MIT Alliance for Research and Technology (SMART), MIT's research enterprise in Singapore.

Some analysts had previously thought that the draining of peatland forests to make way for palm oil plantations was the major cause of peatland loss, but the new study shows that subsidence is widespread across peatlands under a diverse set of land uses. This subsidence is driven by the drainage of tropical peatlands, mostly for the expansion of agriculture, as well as from other causes, such as creating canals for floating timber out of the forests, and digging drainage ditches alongside roads, which can drain large surrounding areas. All of these factors, it turns out, have contributed significantly to the extreme loss of peatlands in the region.

One longstanding controversy that this new research could help to address is how long the peatland subsidence continues after the lands are drained. Plantation owners have said that this is temporary and the land quickly stabilizes, while some conservation advocates say the process continues, leaving large regions highly vulnerable to flooding as sea levels rise, since most of these lands are only slightly above sea level. The new data suggest that the rate of subsidence continues over time, though the rate does slow down.

The satellite measurements used for this study were gathered between 2007 and 2011 using a method called Interferometric Synthetic Aperture Radar (InSAR), which can detect changes in surface elevation with an accuracy of centimeters or even millimeters. Though the satellites that produced these data sets are no longer in operation, newer Japanese satellites are now gathering similar data, and the team hopes to do followup studies using some of the newer data.

"This is definitely a proof of concept on how satellite data can help us understand environmental changes happening across the whole region," Hoyt says. That could help in monitoring regional greenhouse gas output, but could also help in implementing and monitoring local regulations on land use. "This has really exciting management implications, because it could allow us to verify management practices and track hotspots of subsidence," she says.

While there has been little interest in the region in curbing peatland drainage in order to curb greenhouse gas emissions, the serious risk of uncontrollable fires in these dried peatlands provides a strong motivation to try to preserve and restore these ecosystems, Harvey says. "These plumes of smoke that engulf the region are a problem that everyone there recognizes."

Osaka, Japan and Houston, Texas, USA - For a sperm produced in the testis of a man to fertilize a woman's egg, the sperm must first mature in a man's epididymis. Now, an international team of researchers has identified a chain of events in which a protein secreted by the testis travels in the luminal fluid, binds to a receptor on the epididymis to induce its differentiation and secretion of a second protein that matures the sperm and enables each sperm to be motile in females.

In a new study published in Science, researchers from Osaka University and Baylor College of Medicine have identified NELL2, a secreted protein factor that acts on the epididymis through this novel "lumicrine" pathway to mediate sperm maturation.

Sperm are produced in the seminiferous tubules of the testis and transit through the epididymis, a long, convoluted tube linked to the vas deferens. When the sperm enter the epididymis, they are not motile and are incapable of fertilization; however, in their passage through the epididymis, the sperm are provided an appropriate environment for maturation and storage pending ejaculation.

It has been hypothesized that proteins released by the testis (upstream) could act on the epididymis (downstream); however, until now, the proteins working through this intriguing lumicrine system of signaling have remained elusive. While it was known that the orphan receptor tyrosine kinase ROS1 expressed in the initial segment of the epididymis is necessary for its differentiation, neither the testicular factors that regulate initial segment differentiation nor the process of sperm maturation had been fully understood.

The researchers zeroed in on NELL2, secreted by testicular germ cells, as a putative lumicrine regulator of fertility. "Using innovative genome editing technology, we generated knockout mice lacking the Nell2 gene and showed that these knockout males are sterile due to a defect in sperm motility," explains Daiji Kiyozumi, lead author. "Moreover, their infertility could be rescued with a germ-cell-specific transgene, thus excluding other sites of expression. We also illustrated lumicrine signaling by demonstrating tagged NELL2 in the epididymal lumen."

The research team observed that spermatogenesis proceeds normally in Nell2 knockout mouse testes but their epididymis was poorly differentiated, similar to Ros1 knockout mice. Following mating, neither Nell2 knockout nor Ros1 knockout spermatozoa can enter the uterine tubes or fertilize an egg. Further investigation showed that the Nell2 knockout epididymis is incapable of making a key protease, OVCH2, that processes a sperm surface protein, ADAM3, essential for male fertility.

Elaborating on the significance of these novel studies, Professors Masahito Ikawa and Martin M. Matzuk, senior authors, say, "We discovered a complicated cascade of events in which disruption of any point in this lumicrine pathway causes a male to be infertile. Our findings have important translational implications for diagnostic and therapeutic research in male infertility and male contraceptive development. This unique transluminal communication pathway between tissues and organs likely functions elsewhere in our bodies."

Do you have what is known as problematic alcohol use? Then statistically you will also be particularly genetically predisposed to develop e.g. depression and insomnia. And to become dependent on drugs and tobacco. This is shown by a new international study in which researchers from iPSYCH are involved.

The researchers have looked at the role played by genes when a person year after year drinks such large amounts of alcohol, that he or she ends up experiencing serious psychological, social and health damage.

The question of the role of genes is central because, in the majority of social circles, problematic alcohol use is one of the most significant causes of disease, early death and social problems.

For this reason, researchers have spent years attempting to identify what are known as risk genes behind problematic alcohol use - among other things in the hope of being able to develop new forms of treatment for alcohol dependence.

Until now, science has been aware of ten genetic variants that have been seen as risk genes in relation to problematic alcohol use. That number has now increased to 29 thanks to the new study, which has just been published in Nature Neuroscience.

The study was carried out by a group of international researchers from the USA, UK, Germany, Sweden and Denmark.

The Danish participants are Associate Professor Mette Nyegaard and Professor Anders Børglum, both from the Department of Biomedicine at Aarhus University, and the national psychiatric project, the Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH.

Fine-combing large databases

When trying to understand what risk genes actually are, it can be useful to begin by looking at how they are uncovered. To be able to carry out this type of search, first of all you need to have somewhere to look, says Associate Professor Mette Nyegaard:

"You need to have access to a very large amount of DNA material in the form of the complete genetic profiles from several hundred thousand people. In this case, a total of 435,000 people."

The genetic data from these people is stored in three databases - UK Biobank, the US Million Veteran Program, and with the International Research Forum Psychiatric Genetics Consortium - together with a lot of other information about the health and lifestyle of the 435,000 people.

And with access to these databases, it was possible to begin hunting for risk genes for problematic alcohol use, says Mette Nyegaard:

"DNA from all of the 435,000 people was systematically analysed. Millions of different DNA variants, that's to say, special versions of certain genes, was compared between individuals with and without problematic alcohol use.

The purpose of this was to pinpoint which gene variants were more frequently found among participants with problematic alcohol than in the general population.

The pattern of these risk genes was compared with the pattern of risk genes for other diseases, after which the researchers could see:

That problematic alcohol use is genetically closely related to a range of psychiatric diseases

And also that problematic alcohol use is also closely related to drug abuse and smoking.

The fact that there was a correlation became clear once the researchers completed their calculations. The genetic overlap with mental disease is interesting, because this relationship is not found for alcohol consumption in general, pinpointing important differences between alcohol consumption and problematic alcohol use says Mette Nyegaard:

"In more general terms, we're now beginning to see the outline of a genetic architecture. A form of relationship between alcohol abuse and the abuse of other substances - and between alcohol abuse and psychiatric disorders such as ADHD and depression. In other words, there is a genetic component in play here, but the study also shows that the genes are not the entire story and that they alone don't determine the outcome as a whole. Other factors such as environment can also contribute to a great extent," says Mette Nyegaard.

The risk genes identified by the research group provide new insight into the biological mechanisms that are involved in the development of problematic alcohol use. The hope is for this knowledge to contribute to the development of new medicines in the long term, and that these can significantly dampen - and ideally completely extinguish - alcohol dependency in humans.

It is still unclear whether there are candidates for medications of this calibre among the 29 risk genes behind problematic alcohol use that have now been mapped. But the study in Nature Neuroscience does show that 16 of them are actually drug targets, which means that they can be affected by already known pharmaceutical drugs.

The study also shows that problematic alcohol use is genetically related to insomnia.

The international study "Resistance to targeted therapies as a multifactorial, gradual adaptation to inhibitor specific selective pressures", recently published in the scientific journal Nature Communications, has taken a further step in the development of new therapeutic strategies to treat lung cancer.

This study, the result of more than three years of research, was conducted at the Moffitt Cancer Center in Tampa (Florida, USA) and makes progress toward the evolution of resistance to different tumor inhibitors. Scientist Robert Vander Velde is the main author of it.

"Although the use of specific inhibitors targeted against a tumor often induces good clinical results at initial stages, certain cell populations might not be completely eliminated, acquiring resistance to treatments and developing relapse as tumor recurs", explains Diego Lozano, researcher of the Supercomputing and Bioinnovation Center (SCBI) of the University of Malaga (UMA) and one of the authors of this study.

Resistance to tumor inhibitors

Using an in vitro model of isolated ALK positive cells of a specific type of lung cancer, namely, non-small or non-microcytic cell lung cancer, researchers explored the evolution of resistance to different clinical ALK inhibitors.

"We demonstrated that the acquisition of resistance to tumor inhibitors not only arises from the pre-existence of cell subpopulations in mutations that enable tumors to survive drugs, or due to emergence of point mutations that confer such resistance, but from a gradual and predictable adaptation to the selective pressures of the different ALK inhibitors, at the genetic and epigenetic level", says the researcher of the UMA.

Opportunity for more effective therapies

Lozano explains that during the evolution of drug resistance, intermediate cell populations present collateral sensitivity to other inhibitors, thus providing a temporarily opportunity to apply effective therapies.

"The findings of this study could be transferred to other similar scenarios, where tumors also acquire therapy resistance", clarifies Lozano, who guarantees that by understanding the evolutionary mechanisms and trajectories of drug resistance in tumor cells, evolutionary-informed therapies could be designed.

New modern physical school spaces require open communication between stakeholders in order to be transformed into meaningful learning environments, a new study from the University of Eastern Finland shows. Pre-existing pedagogies or good practices as such cannot be transferred from one space to another.

New modern school buildings are designed to meet the needs of twenty-first century learners, aiming to facilitate, e.g., flexibility in teaching and learning, as well as collaboration and critical thinking. However, pre-existing pedagogies or good practices as such cannot be transferred from one space to another; instead, active negotiations and interaction between all stakeholders is needed.

Researchers at the University of Eastern Finland explored new teaching and learning spaces in order to gain a better understanding of the change from physical spaces to learning environments by examining how, and through which processes, learning spaces are transformed, produced and developed.

Although open and flexible physical spaces can lead to multiple positive outcomes, studies have also shown that they don't always lead to a change in pedagogy.

"A key question is whether the space is modified to meet learner needs, or whether learners are expected to adapt to the requirements of the space," Early Stage Researcher Anna Kokko from the University of Eastern Finland says.

The researchers used a comparative ethnography approach and collected observation material from two Finnish schools at different development phases. The material was supplemented by focus-group interviews with teachers and individual interviews with school principals.

"The teachers we interviewed were well aware of the potential and limitations of the physical spaces. If a physical space was seen as something static and pre-determined, it was often described as setting limitations for its use. If, however, a physical space was seen as a platform for continuous rebuilding and re-creation, it was often described as being adaptable to specific needs and pedagogically meaningful purposes," Kokko says.

According to the researchers, the results suggest that no ready-made models exist which fit into a new context. Rather, practices are constructed in physical spaces through active negotiations and meaning making. This involves cyclic processes of interaction between teachers, between students and teachers, and between students. Through these cyclic processes and with strong support from teachers, students had possibilities to find tools to build learning environments suited to their needs, which further could enable the expansion of learning environments inside and outside school walls.

Nevertheless, changes in practices required an overall change in every aspect of the school. Therefore, when using facilities such as physical spaces for the development of education, it is important that the continuous rebuilding of authentic and functional learning environments be invested in as much as the design phases. Focusing on the processes of change, results provide information from a systemic perspective on how schools can manage continuous change when developing physical spaces into learning environments.

A paper published in Science in 2017 described hundreds of massive, kilometer -wide, craters on the ocean floor in the Barents Sea. Today more than 600 gas flares are identified in and around these craters, releasing the greenhouse gas steadily into the water column. Another study, published the same year in PNAS, mapped several methane mounds, some 500m wide, in the Barents Sea. The mounds were considered to be signs of soon-to-happen methane expulsions that have created the said craters.

The most recent study in Scientific Reports looks into the depths far beneath these craters in the ocean floor and reveals the geological structures that have made the area prone to crater formation and subsequent methane expulsions.

"It turns out that this area has a very old fault system - essentially cracks in bedrock that likely formed 250 million years ago. Craters and mounds appear along different fault structures in this system. These structures control the size, placement, and shape of the craters. The methane that is leaking through the seafloor originates from these deep structures and is coming up through these cracks." according to Malin Waage, a postdoc at CAGE, Centre for Arctic Gas Hydrate, Environment and Climate, and the first author of the study.

Cutting edge 3D seismic technology

The deep origin of craters and mounds was discovered using cutting edge 3D seismic technology which can penetrate deep into the ocean floor, and help scientists visualize the structures in the hard bedrock underneath.

"Our previous studies in the area hypothesized that climate warming and the retreat of the ice sheet some 20.000 years ago, caused the gas hydrates beneath the ice to melt leading to abrupt methane release and creating craters."

Gas hydrates are a solid form of methane, among others, that is stable in cold temperatures and under pressure, which an enormous ice sheet provides. As the ocean warmed up, and the pressure of the ice sheet lifted, the methane ice in the seafloor melted and thus the craters were formed.

"This study, however, ads several layers to that picture, as we now see that there has been a structural weakness beneath these giant craters, for much longer than the last 20.000 years. Deep below the seafloor, the expansion of gas and release of water build up a muddy slurry which eventually erupted through the fractures and caused seafloor collapses and craters in the hard bedrock. Think of it as a building: A roof of a building can cave in if the ground structure is weak. We believe that this is what happened in the crater area after the last glaciation." says Waage.

The Barents Sea is poorly understood

The exploration of petroleum resources in the Barents Sea is a hot topic in Norway and beyond as the area is a part of a vulnerable Arctic ecosystem. But the area's geological system is poorly understood.

"Our 3D survey covered approximately 20 percent of the entire crater area. We believe that it is important to understand if similar fault systems exist in the larger context of the Barents Sea because they potentially could pose a threat to marine operations."

Some of the questions that scientists, society and the industry does not know the answer to are: Will these weak structures lead to unpredictable and explosive methane release? Can such release and related geohazards be triggered by drilling? And can the gas reach the atmosphere in case of abrupt blow-outs, adding to the greenhouse gas budget?

"There is still very much that we don't know about this system. But we are currently collecting and analyzing new data in the Barents Sea, dominated by similar crater structures. This can help us map in bigger detail the fault systems and associated weakness. " says Waage.

In the last two decades, the life sciences have seen a growing partnership with information technology. The main drive behind this is the need to process and integrate enormous volumes of data from different fields including genetics, biochemistry, cell and molecular biology, and physiology in order to gain a deeper understanding of biological systems, processes, and even entire organisms.

The problem is that putting together data from numerous interconnected biological networks across different strata of biological analysis (e.g. genetic vs biochemical) has proven too complicated. The sheer volume and complexity of data across multiple fields is difficult to standardize and process, and has partly caused the proliferation of different "omics" fields (e.g. genomics, transcriptomics, proteomics, metabolomics, etc), which try to characterize and quantify pools of biological molecules in a way that relates to their structure and function in an organism.

One way that scientists have addressed the issue in the context of genes and metabolism analysis is by developing genome-scale metabolic models, or GEMs. These are computer models built from genetic and biochemical data, and associate genes with metabolic pathways in the cell.

GEMs are rapidly becoming a common tool for researchers. "They are powerful tools for integrating experimental data for a specific physiology and building context-specific models that can identify changes in the metabolism of diseased cells, such as cancer cells," says Maria Masid, a PhD student from the lab of Vassily Hatzimanikatis at EPFL.

Working to further simplify the GEMs, Masid and her colleagues have now published a paper in Nature Communications that introduces a new mathematical method to analyze human metabolism by reducing the complexity of the human genome-scale GEMs by simply focusing on certain parts of metabolism while minimizing the information loss from the other pathways.

The study of cell metabolism is highly relevant because metabolic alterations have been recognized as a sign of several human diseases, including cancer, diabetes, obesity, Alzheimer's, and cardiovascular diseases. Therefore, understanding the relationships between metabolic mechanisms and genes can guide drug discovery and the design of new therapies.

The researchers named their method redHUMAN, and describe it as "a workflow for reconstructing reduced models that focus on parts of the metabolism relevant to a specific physiology". redHUMAN generates reduced size metabolic models that contain the pathways of interest and the metabolic routes required to study nutrient metabolism and biomass synthesis, all this taking into account bioenergetics of the cell. By doing this, the redHUMAN model guarantees the consistency of its predictions, overcoming a major hurdle of the current GEMs.

"By combining these metabolic models with gene-expression data, we can identify functional changes that cannot be extracted directly from the data," says Masid, and "we can also formulate hypotheses to guide experimental design."

At a glance:

Two studies from Harvard Medical School provide new insights into normal and abnormal DNA recombination during sperm and egg cell formation

Using new technology for analyzing human sperm genomes, researchers report variable rates of chromosome abnormalities and find evidence that a single biological process regulates the number, location and spacing of crossovers where parents' DNA recombines

Separate study in developing worm eggs suggests crossovers are suppressed in certain regions of the chromosome to reduce errors

In the famous words of movie character Forrest Gump, "Life is like a box of chocolates; you never know what you're gonna get."

The same principle applies to human genetics. When the body forms sperm or egg cells in a special type of cell division called meiosis, our DNA mixes and matches in seemingly infinite and unpredictable combinations.

Later, when just two of the great variety of sperm and egg cells meet, they produce children who are different from their parents.

Meiosis would go terribly wrong without crossovers: the swapping of DNA segments between closely aligned pairs of chromosomes, one inherited from each parent.

Faulty crossover formation can leave cells with too many or too few chromosomes, known as aneuploidy. Since aneuploidy in turn can lead to infertility, miscarriages and conditions such as Down syndrome, learning how crossovers are regulated is key to understanding human reproduction and improving reproductive health.

Two studies from geneticists in the Blavatnik Institute at Harvard Medical School provide new insights into this fundamental process.

The first study, published online June 3 in Nature, simultaneously analyzes crossovers and aneuploidy on all chromosomes in more than 30,000 human sperm cells using a new genome-wide sequencing tool.

The researchers measured a five-fold range of aneuploidy rates from person to person in the most comprehensive estimate to date and propose that a single biological process helps regulate the number, location and spacing of crossovers. The findings help answer a longstanding question about why and how crossover rates vary across sperm cells and across people.

The work was conducted in the lab of Steven McCarroll, the Dorothy and Milton Flier Professor of Biomedical Science and Genetics at HMS and director of genomic neurobiology in the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard.

"The genome of each individual sperm tells a detailed story about human inheritance--what went well, what went wrong, what went differently than in other sperm," said McCarroll. "Collectively, tens of thousands of such stories teach us a lot about the meiotic processes and their vulnerabilities."

The second study, which looked at meiosis in developing worm egg cells, helps explain why crossovers occur more often in some locations along chromosomes than in others. The team found that crossovers are likelier to go wrong at the centers or extreme ends of chromosomes, suggesting that egg cells minimize crossovers in those areas while allowing them in more reliable locations.

Findings from the lab of Monica Colaiácovo, professor of genetics at HMS who specializes in meiosis, were published in Current Biology in April along with a commentary.

"It's terrific to see how findings in male and female meiosis and in different species can complement and inform each other," said Colaiácovo.

The sperm factor

Though infertility can result from either partner, treatments have tended to focus on the egg side. This is in part because eggs are known to have much higher rates of aneuploidy than sperm and because little can be measured about sperm beyond counts and motility.

Still, the contribution of sperm genetics to infertility and miscarriages has been relatively understudied, said Avery Davis Bell, a former PhD student in biological and biomedical sciences in the McCarroll lab.

"We wanted to get a baseline for 'the male factor' in human infertility and reproductive health, namely, how often aneuploidy occurs in sperm," said Bell, first author of the Nature study and now a postdoctoral fellow at the Georgia Institute of Technology.

Bell and colleagues needed to study tens of thousands of sperm genome-wide to generate robust statistics, but no technology existed that could easily do so. So at HMS, she took a technology that analyzes DNA from large numbers of individual cells using tiny droplets and further developed it to study sperm cells. The team dubbed the new approach Sperm-seq.

The researchers obtained samples from 20 donors, analyzing a total of 31,228 sperm cells. Sperm-seq allowed the team to detect every crossover in every sperm cell--more than 813,000 in all.

They found that the number of aneuploid sperm ranged from 1 percent to 5 percent from person to person, with an average of 2.5 percent. This estimate aligns with previous studies that used microscopy to visually examine subsets of chromosomes.

Expanding knowledge about how people have different sperm aneuploidy rates could further assist sperm banks and fertility clinics as they try to maximize sperm viability and improve prospective parents' fertility, said Bell.

Analyses revealed individual sperm with many other kinds of genetic anomalies beyond simple aneuploidies.

The researchers further discovered that the number, location and spacing of crossovers vary together, across sperm cells and across people. In cells with a lot of crossovers, the team found, the crossovers tend to be closer together and located proportionally more in the central regions of chromosomes than at the ends.

"Seeing the same patterns in people and in cells is really interesting because it suggests an underlying regulation," said Bell.

The team suspects that these variations are driven by the degree to which chromosomes get compacted during meiosis. Previous research in the field showed that compaction is linked with crossover rates.

Sperm-seq also revealed that aneuploidy happens at different frequencies at different stages of meiosis from chromosome to chromosome and from person to person.

The McCarroll lab has made Sperm-seq protocols freely available to advance genetics research.

Location, location, location

During meiosis, proteins deliberately snap the double strands of DNA at many sites along the chromosomes. These breaks kick-start repair. Researchers have long wondered why, in organisms from yeast to humans, breaks on the arms of chromosomes often turn into crossover repair sites while those at the chromosome centers and ends mostly do not.

To find out, Colaiácovo's team broke DNA at different positions along chromosomes in developing Caenorhabditis elegans worm egg cells and examined whether crossovers at those sites proceeded normally or not.

Led by Elisabeth Altendorfer, a PhD student in the lab, the researchers found that location determined crossover success. Crossovers on the chromosome arms went well, while those at the centers and ends concluded badly.

"The 'glue' that keeps chromosomes attached after crossover formation is removed from the wrong places, and chromosomes fall apart and randomly separate," said Colaiácovo. "So you end up with aneuploid eggs."

The findings imply that the reason some portions of the chromosome resist crossovers in most species is that they can't support healthy chromosome organization or separation, resulting in abnormalities that are detrimental to offspring.

"This is the first direct demonstration in a metazoan [multicellular animal] that the position of crossovers has to be tightly regulated to ensure normal chromosome segregation and avoid aneuploidy," said Colaiácovo.

HOUSTON - (June 4, 2020) - Eggs that would otherwise be wasted can be used as the base of an inexpensive coating to protect fruits and vegetables, according to Rice University researchers.

The Brown School of Engineering lab of materials scientist Pulickel Ajayan and colleagues have developed a micron-thick coating that solves problems both for the produce and its consumers, as well as for the environment.

When the coating was applied to produce by spraying or dipping, it showed a remarkable ability to resist rotting for an extended period comparable to standard coatings like wax but without some of the inherent problems.

The work by Rice undergraduate students Seohui (Sylvia) Jung and Yufei (Nancy) Cui is detailed in Advanced Materials.

The coating relies on eggs that never reach the market. As the United States produces more than 7 billion eggs a year and manufacturers reject 3% of them, the researchers estimate more than 200 million eggs end up in landfills.

Even before the impact of the new coronavirus, the world wasted a third of the food produced around the globe, the researchers wrote.

"Reducing food shortages in ways that don't involve genetic modification, inedible coatings or chemical additives is important for sustainable living," Ajayan said. "The work is a remarkable combination of interdisciplinary efforts involving materials engineers, chemists and biotechnologists from multiple universities across the U.S."

Along with being edible, the multifunctional coating retards dehydration, provides antimicrobial protection and is largely impermeable both to water vapor to retard dehydration and to gas to prevent premature ripening. The coating is all-natural and washes off with water.

"If anyone is sensitive to the coating or has an egg allergy, they can easily eliminate it," Jung said.

Egg whites (aka albumen) and yolks account for nearly 70 percent of the coating. Most of the rest consists of nanoscale cellulose extracted from wood, which serves as a barrier to water and keeps produce from shriveling, a small amount of curcumin for its antimicrobial powers and a splash of glycerol to add elasticity.

Lab tests on dip-coated strawberries, avocadoes, bananas and other fruit showed they maintained their freshness far longer than uncoated produce. Compression tests showed coated fruit were significantly stiffer and more firm than uncoated and demonstrated the coating's ability to keep water in the produce, slowing the ripening process.

An analysis of freestanding films of the coating showed it to be extremely flexible and able to resist cracking, allowing better protection of the produce. Tests of the film's tensile properties showed it to be just as tough as other products, including synthetic films used in produce packaging. Further tests proved the coating to be nontoxic, and solubility tests showed a thicker-than-usual film is washable.

Rinsing in water for a couple of minutes can completely disintegrate it, Ajayan said.

The researchers continue to refine the coating's composition and are considering other source materials. "We chose egg proteins because there are lots of eggs wasted, but it doesn't mean we can't use others," said co-corresponding author Muhammad Rahman, a research scientist in Ajayan's Rice lab, who mentored and led the team.

Jung noted the team is testing proteins that could be extracted from plants rather than animal produce to make coatings.

WEST LAFAYETTE, Ind. -- Highly energetic, "hot" electrons have the potential to help solar panels more efficiently harvest light energy.

But scientists haven't been able to measure the energies of those electrons, limiting their use. Researchers at Purdue University and the University of Michigan built a way to analyze those energies.

"There have been many theoretical models of hot electrons but no direct experiments or measurements of what they look like," said Vladimir "Vlad" Shalaev (shal-AYV), Purdue University's Bob and Anne Burnett Distinguished Professor of Electrical and Computer Engineering, who led the Purdue team in this collaborative work.

In a paper published in the journal Science on Thursday (June 4), the researchers demonstrated how a technique using a scanning tunneling microscope integrated with lasers and other optical components reveals the energy distribution of hot electrons.

"Measuring energy distribution means quantifying how many electrons are available at a certain amount of energy. That crucial piece of information was lacking for expanding the use of hot electrons," said Harsha Reddy, a Ph.D. student in Purdue's School of Electrical and Computer Engineering and an equally contributing lead author on this paper.

Hot electrons are typically generated through shining a certain frequency of light on a carefully engineered nanostructure made of metals such as gold or silver, exciting so-called "surface plasmons." These plasmons are believed to eventually lose some of their energy to electrons, making them hot.

While hot electrons can have temperatures as high as 2,000 degrees Fahrenheit, it's their high energy - rather than the material temperature - that makes them useful for energy technologies. In solar panels, energies from hot electrons could be more efficiently converted to electrical energy compared to conventional approaches.

Hot electrons also could improve the efficiency of energy technology such as hydrogen-based fuel cells in cars by speeding up chemical reactions.

"In a typical chemical reaction, the reactants need to have enough energy to cross a threshold for completing the reaction. If you have these high-energy electrons, some of the electrons would lose their energy to the reactants and push them across that threshold, making the chemical reaction faster," Reddy said.

Reddy worked with Kun Wang, a postdoctoral researcher in a University of Michigan group under professors Edgar Meyhofer and Pramod Reddy, who co-led the research effort. Together, they spent more than 18 months developing the experimental setup and another 12 months measuring the hot electron energies.

The researchers built a system that allowed them to detect the difference in charge currents generated with and without exciting the plasmons. This difference in currents contains the crucial information needed to determine the energy distribution of the hot electrons in the metallic nanostructure.

Shining a laser light onto a gold film with tiny ridges excites plasmons in the system, generating hot electrons. The researchers measured the energies of the electrons by drawing them through carefully engineered molecules into a gold electrode at the tip of a scanning tunneling microscope. Researchers at the University of Liverpool synthesized some of the molecules for these experiments.

This method could be used for enhancing a wide range of energy-related applications.

"This multidisciplinary basic research effort sheds light on a unique way to measure the energy of charge carriers. These results are expected to play a crucial role in developing future applications in energy conversion, photocatalysis and photodetectors, for instance, that are of great interest to the Department of Defense," said Chakrapani Varanasi, a program manager for the Army Research Office, which supported this study.

Ludwig-Maximilian-Universitaet (LMU) in Munich researchers have discovered a hitherto unknown molecular function of a specific microRNA that preserves integrity of the endothelium and reduces the risk of atherosclerosis.

Short RNA molecules known as microRNAs (miRNAs) play a vital role in the regulation of gene expression. Anomalies in miRNAs expression and function have been implicated in pathological processes, such as the development of chronic diseases like atherosclerosis. The regulatory functions of miRNAs usually take place in the cytoplasm, where they interact with target RNA transcripts to inhibit their translation into protein or promote their decay. However, Professor Christian Weber's group in the Institute for Cardiovascular Prevention (IPEK) at the LMU Medical Center has now described an exceptionally different mode of action. By investigating a miRNA named miR-126-5p, Weber's team demonstrates that this molecule can unexpectedly be transferred into the cell nucleus and, by simply interacting with it, suppresses the activity of an enzyme, named caspase-3, which is responsible for killing the cell by programmed cell death. In this way, the molecule protects vascular integrity and reduces the extent of atherosclerotic lesions.

Atherosclerosis is often referred to as "hardening of the arteries" and underlies the development of cardio- and cerebrovascular diseases which represent the main cause of death worldwide. The condition occurs almost exclusively at bifurcations of the arterial tree, where turbulence of blood flow promotes damage to the endothelial cells that line the vessels, favoring the recruitment of inflammatory cells and the eventual development of atherosclerotic plaques. Endothelial cells express particularly high concentrations of miR-126-5p to protect them from damage. The new study set out to uncover the molecular mechanisms that mediate this function. The results demonstrate that the protective effect is initiated by the high shear stress imposed on the endothelial cells by the laminal flow of blood over their surfaces.

"High shear stress triggers a multi-step process in the endothelial cells, which results in the formation of a molecular complex between miR-126-5p and an RNA-binding protein. The complex is then transported into the cell nucleus," says Donato Santovito, postdoc in Weber's group and lead author of the new paper. Once inside the nucleus, miR-126-5p is released from the complex and binds to an enzyme called caspase-3, thus inhibiting its activity. Caspase-3 itself is a crucial mediator of programmed cell death (apoptosis). Multiple factors known to increase the risk of atherosclerosis - such as turbulence in the blood flow, high level of cholesterol or glucose - promote apoptosis in endothelial cells. Hence, by inhibiting the enzyme caspase-3, nuclear miR-126-5p protects endothelial cells from induced cell death. In doing so, it also reduces the endothelium's susceptibility to damage at sites of high shear stress, which indeed are typically protected from development of atherosclerosis. And by maintaining the integrity of the endothelial surface, the miRNA also makes an important contribution to the function of the vasculature as a whole.

"This hitherto unknown function of miR-126-5p represents a new principle of biological regulation that serves to complement previously well described mechanisms," Weber adds. Together with an interdisiciplinary network of international collaborators and within the framework of the Transregio-SFB TR267, the team plans to investigate whether other miRNAs can also act in a similar way. In addition, further insights into the mechanisms that modulate the action of this signaling pathway might well open up new options for the treatment of vascular diseases.