Vitamin K prevents cell death: New function for a long-known molecule

A team of researchers located at Helmholtz Munich reports on a novel function of vitamin K, which is generally known for its importance in blood clotting. The researchers discovered that the fully reduced form of vitamin K acts as an antioxidant efficiently inhibiting ferroptotic cell death. Ferroptosis is a natural form of cell death in which cellular iron plays an important role and which is characterized by the oxidative destruction of cellular membranes. In addition, the team identified FSP1 as the warfarin-insensitive enzyme reducing vitamin K, the identity of which had been postulated but remained unknown for more than half a century.
During the last years, ferroptosis has been implicated as a driver of Alzheimer’s disease and acute organ injuries among many other diseases. Thus, the present findings put forward the concept that vitamin K treatment might be a new powerful strategy to ameliorate these ferroptosis-related diseases.
Vitamin K is a potent ferroptosis suppressor
Since ferroptosis prevention is considered a highly promising approach for the therapy of many degenerative diseases, new mechanisms and compounds regulating ferroptosis are extensively being explored. To identify these new molecules, a team of researchers led by Dr. Eikan Mishima and Dr. Marcus Conrad, both from the Institute of Metabolism and Cell Death at Helmholtz Munich, along with collaborators from Tohoku University (Japan), University of Ottawa (Canada) and Technical University of Dresden (Germany), systematically studied a number of naturally occurring vitamins, as well as their derivatives. “Surprisingly, we identified that vitamin K, including phylloquinone (vitamin K1) and menaquinone-4 (vitamin K2), is able to efficiently rescue cells and tissues from undergoing ferroptosis” Dr. Eikan Mishima, first author of the study explained.
Unraveling the long sought-after vitamin K reducing enzyme FSP1
In 2019 a team of researchers around Dr. Marcus Conrad already identified an enzyme as a novel and strong inhibitor of ferroptosis: ferroptosis suppressor protein-1, short FSP1. The research team now found that the fully reduced form of vitamin K (i.e., vitamin K hydroquinone) acts as a strong lipophilic antioxidant and prevents ferroptosis by trapping oxygen radicals in lipid bilayers. In addition, they identified that FSP1 is the enzyme that efficiently reduces vitamin K to vitamin K hydroquinone, thereby driving a novel non-canonical vitamin K cycle. Since vitamin K is critically involved in blood clotting processes, the team further showed that FSP1 is responsible for the vitamin K-reduction pathway insensitive against warfarin, one of the most commonly prescribed anticoagulants.
Breakthrough in understanding vitamin K metabolism
Unraveling the identity of this enzyme solved the last riddle of vitamin K metabolism in blood clotting and elucidated the molecular mechanism of why vitamin K constitutes the antidote for overdosing of warfarin. “Our results therefore link the two worlds of ferroptosis research and vitamin K biology. They will serve as the stepping stone for the development of novel therapeutic strategies for diseases where ferroptosis has been implicated,” Dr. Marcus Conrad highlighted. In addition, since ferroptosis most likely constitutes one of the oldest types of cell death, the researchers hypothesize that vitamin K might be one of the most ancient types of naturally occurring antioxidants. “Thus, new aspects of the role of vitamin K throughout the evolution of life are expected to be unveiled” Dr. Marcus Conrad explained.
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Inflammatory bowel disease increases risks for pregnant women

Pregnant women with inflammatory bowel disease (IBD) and their babies face increased risks and complications compared to pregnant women without IBD. Those are the findings from a new University of Missouri School of Medicine study that examined outcomes of more than 8 million pregnancies.
IBD is a term used for Crohn’s disease and ulcerative colitis, which are characterized by chronic inflammation of the gastrointestinal tract. IBD mainly affects young people, which includes women who are in their peak reproductive years.
“IBD is an incurable disease, and its relapsing and remitting nature is stressful for the estimated 3 million U.S. men and women diagnosed,” said senior author Yezaz Ghouri, MD, assistant professor of clinical medicine. “Because this disease tends to affect women during their peak fertility period, we wanted to know the impact of IBD on maternal and fetal outcomes. To our knowledge, this study is the most comprehensive of its kind, using data from multiple institutions in 48 states.”
The research team reviewed more than 8 million pregnancies between 2016 and 2018. Of those, 14,129 mothers had IBD. Results showed the pregnant women with IBD had higher incidence of gestational diabetes, postpartum hemorrhage, hypertensive complications, preterm delivery, fetal growth restriction and fetal death. Pregnant women with IBD also had longer hospital stays after delivering. They averaged an additional half-day length of stay and faced more than $2,700 in associated medical costs.
“Based on our findings, we suggest that women who have moderate to severe IBD should get pre-conceptional counseling and be treated aggressively to achieve remission prior to getting pregnant,” Ghouri said. “Our study results illustrate the importance that IBD be optimally controlled prior to conception.”
Ghouri’s MU School of Medicine collaborators include first author Zahid Ijaz Tarar, MD, assistant professor of clinical medicine; and Ghulam Ghous, MD, assistant professor of clinical medicine.
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Cool room temperature inhibited cancer growth in mice

Turning down the thermostat seems to make it harder for cancer cells to grow, according to a study in mice by researchers at Karolinska Institutet in Sweden. The study, published in the journal Nature, found that chilly temperatures activate heat-producing brown fat that consumes the sugars the tumors need to thrive. Similar metabolic mechanisms were found in a cancer patient exposed to a lowered room temperature.
“We found that cold-activated brown adipose tissue competes against tumors for glucose and can help inhibit tumor growth in mice,” says Professor Yihai Cao at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, and corresponding author. “Our findings suggest that cold exposure could be a promising novel approach to cancer therapy, although this needs to be validated in larger clinical studies.”
The study compared tumor growth and survival rates in mice with various types of cancer, including colorectal, breast and pancreatic cancers, when exposed to cold versus warm living conditions. Mice acclimatized to temperatures of 4 degrees Celsius had significantly slower tumor growth and lived nearly twice as long compared with mice in rooms of 30 degrees Celsius.
To find out why that is, the researchers analyzed markers in the tissue to study cellular reactions and used imaging tests to examine glucose metabolism. Cancer cells typically need large amounts of glucose, or sugar, to grow.
They found that cold temperatures triggered significant glucose uptake in brown adipose tissue, also known as brown fat, a type of fat that is responsible for keep the body warm during cold conditions. At the same time, the glucose signals were barely detectable in the tumor cells.
When the researchers removed either the brown fat or a protein crucial for its metabolism called UCP1, the beneficial effect of the cold exposure was essentially wiped out and the tumors grew at a pace on par with those that were exposed to higher temperatures. Similarly, feeding tumor-bearing mice with a high sugar drink also obliterated the effect of cold temperatures and restored tumor growth.
“Interestingly, high sugar drinks seem to cancel out the effect of cold temperatures on cancer cells, suggesting that limiting glucose supply is probably one of the most important methods for tumor suppression,” Yihai Cao says.
To study the human relevance of the findings, the researchers recruited six healthy volunteers and one patient with cancer undergoing chemotherapy. Using positron emission tomography (PET) scanning, the researchers identified a significant amount of brown fat activated in the neck, spine and chest area of healthy adults wearing shorts and T-shirts while being exposed to a slightly chilly room temperature of 16 degrees Celsius for up to six hours per day for two weeks.
The patient with cancer wore light clothing while spending time in rooms of 22 degrees Celsius for a week and then in rooms of 28 degrees Celsius for four days. Prior research has shown that even though there are significant individual differences, 28 degrees Celsius is generally considered a comfortable environmental temperature (the thermoneutral temperature) for most inactive humans. The imaging scans picked up increased brown fat and lowered tumor glucose uptake during the lower versus the higher temperature.
“These temperatures are considered tolerable by most people,” Yihai Cao says. “We are therefore optimistic that cold therapy and activation of brown adipose tissue with other approaches such as drugs could represent another tool in the toolbox for treating cancer.”
The study was funded by the European Research Council, the Swedish Research Council, the Swedish Cancer Society, the Swedish Childhood Cancer Fund, the Strategic research area in stem cells and regenerative medicine at Karolinska Institutet, the Torsten Söderberg Foundation, the Maud and Birger Gustavsson Foundation, the Novo Nordisk Foundation and the Knut and Alice Wallenberg Foundation.
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The brain already benefits from moderate physical activity, study shows

Even moderate physical activity has a positive effect on the brain. DZNE researchers led by Dr. Dr. Ahmad Aziz deduce this from examinations of 2,550 participants of the Bonn “Rhineland Study.” According to their findings, certain areas of the brain are larger in physically active individuals than in those who are less active. In particular, brain regions that have a relatively high oxygen demand benefit from this effect. The research results are published in Neurology®, the medical journal of the American Academy of Neurology.
Exercise keeps body and mind healthy — but little is known about exactly how and where physical activity affects our brains. “In previous research, the brain was usually considered as a whole,” says Fabienne Fox, neuroscientist and lead author of the current study. “Our goal was to take a more detailed look at the brain and find out which regions of the brain physical activity impacts most.”
Extensive Data from the Rhineland study
For their research, Fox and colleagues used data from the Rhineland Study, a large-scale population-based study conducted by DZNE in the Bonn city area. Specifically, they analyzed physical activity data from 2,550 volunteers aged 30 to 94 years, as well as brain images obtained by magnetic resonance imaging (MRI). To sample physical activity, the study participants wore an accelerometer on their upper thigh for seven days. The MRI scans provided information particularly on brain volume and thickness of the cortex.
The More Active, the Greater the Effects
“We were able to show that physical activity had a noticeable effect on almost all brain regions investigated. Generally, we can say that the higher and more intense the physical activity, the larger the brain regions were, either with regard to volume or cortical thickness,” Fabienne Fox summarizes the research results. “In particular, we observed this in the hippocampus, which is considered the control center of memory. Larger brain volumes provide better protection against neurodegeneration than smaller ones.” However, the dimensions of the brain regions do not increase linearly with physical activity. The research team found the largest, almost sudden volume increase when comparing inactive and only moderately physically active study participants — this was particularly evident in older individuals over the age of 70.

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Map of immune system connections reveals new therapeutic opportunities

A first of its kind comprehensive map of the network of connections that make up the human immune system has been created, which could lead to new immunotherapies to treat cancer, infectious diseases, and other conditions where immune responses play a role.
In creating the immune system map, scientists from the Wellcome Sanger Institute, ETH Zürich, and collaborators show how immune cells across the body link up and communicate.
This research, published today (3 August 2022) in Nature, includes the discovery of many previously unknown interactions that together shed light on the organisation of the body’s immune defences. This offers answers to longstanding questions about current immunotherapies that are already used to treat patients. In the future, this public and detailed immune system map could also be vital in identifying new therapies.
The immune system is made up of specialised cells, some of which individually travel through the body to scan for signs of injury or disease. Once these cells detect a threat, they need to communicate the message to other cells in order to mount an effective immune response. One way this cell-to-cell signalling is done is through proteins on the surfaces of cells that bind on to matching ‘receptor’ proteins on the surfaces of other cells. Previously, scientists and clinicians only had an incomplete map of these receptor connections between all of the different types of immune cells in the body.
An in-depth understanding of the interactions between immune cells, and how this communication fits into the human body as a whole, is vital if we are to develop treatments that enhance the immune system in order to fight disease, known as immunotherapies.
Immunotherapies have already demonstrated great potential in treating disease, most notably with certain cancers. However, these only work well in certain groups of patients and for particular conditions. Knowing the map of immune receptor connections could help explain why immunotherapies sometimes only work in a subset of patients, and offer new targets for designing future immunotherapies that may work for patients who currently do not benefit from these cutting-edge treatments.

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Technology restores cell, organ function in pigs after death

Within minutes of the final heartbeat, a cascade of biochemical events triggered by a lack of blood flow, oxygen, and nutrients begins to destroy a body’s cells and organs. But a team of Yale scientists has found that massive and permanent cellular failure doesn’t have to happen so quickly.
Using a new technology they developed that delivers a specially designed cell-protective fluid to organs and tissues, the researchers restored blood circulation and other cellular functions in pigs a full hour after their deaths, they report in the Aug. 3 edition of the journal Nature.
The findings may help extend the health of human organs during surgery and expand availability of donor organs, the authors said.
“All cells do not die immediately, there is a more protracted series of events,” said David Andrijevic, associate research scientist in neuroscience at Yale School of Medicine and co-lead author of the study. “It is a process in which you can intervene, stop, and restore some cellular function.”
The research builds upon an earlier Yale-led project that restored circulation and certain cellular functions in the brain of a dead pig with technology dubbed BrainEx. Published in 2019, that study and the new one were led by the lab of Yale’s Nenad Sestan, the Harvey and Kate Cushing Professor of Neuroscience and professor of comparative medicine, genetics, and psychiatry.
“If we were able to restore certain cellular functions in the dead brain, an organ known to be most susceptible to ischemia [inadequate blood supply], we hypothesized that something similar could also be achieved in other vital transplantable organs,” Sestan said.

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RNA diversity in human tissues mapped with emerging sequencing technology

Research on RNA diversity in human tissues, led by scientists from the New York Genome Center and the Broad Institute, is described in a recent study published in Nature. When the genetic code is transcribed to RNA, one gene typically produces several different forms of RNA molecules, or transcripts, with different functions. While this phenomenon has been known for decades, the catalog of human transcripts has remained incomplete.
“Equipped with the latest sequencing technology, we were able to read segments of over one thousand nucleotides, compared to less than one hundred with standard approaches,” describes Dr. Beryl Cummings, one of the leaders of the project and formerly a postdoctoral fellow at the Broad Institute. “Importantly, we were able to do this at scale of over 80 samples from many tissues, which led to discovery of tens of thousands of novel transcripts,” she adds.
The researchers used their data to characterize how genetic and environmental differences can manifest in differences in the transcriptome. “Genetic differences between individuals can affect how genes are regulated. We were able to describe with a finer resolution than before how transcript structures are affected. This helps to understand molecular underpinnings of variants that contribute to disease risk,” explains Dr. Dafni Glinos from the New York Genome Center and co-first author of the study.
“We believe the discoveries, data, and tools we present pave the way for a new era of transcriptome research. About a decade ago, high-through analysis of small DNA or RNA segments revolutionized genomics. I think we’re at the cusp of a new revolution with long read sequencing” says Professor Tuuli Lappalainen from the New York Genome Center and one of the leaders of the study.
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A ‘Reversible’ Form of Death? Scientists Revive Cells in Dead Pigs’ Organs.

Researchers who previously revived some brain cells in dead pigs succeeded in repeating the process in more organs.The pigs had been lying dead in the lab for an hour — no blood was circulating in their bodies, their hearts were still, their brain waves flat. Then a group of Yale scientists pumped a custom-made solution into the dead pigs’ bodies with a device similar to a heart-lung machine.What happened next adds questions to what science considers the wall between life and death. Although the pigs were not considered conscious in any way, their seemingly dead cells revived. Their hearts began to beat as the solution, which the scientists called OrganEx, circulated in veins and arteries. Cells in their organs, including the heart, liver, kidneys and brain, were functioning again, and the animals never got stiff like a typical dead pig.Other pigs, dead for an hour, were treated with ECMO, a machine that pumped blood through their bodies. They became stiff, their organs swelled and became damaged, their blood vessels collapsed, and they had purple spots on their backs where blood pooled.The group reported its results Wednesday in Nature.The researchers say their goals are to one day increase the supply of human organs for transplant by allowing doctors to obtain viable organs long after death. And, they say, they hope their technology might also be used to prevent severe damage to hearts after a devastating heart attack or brains after a major stroke.But the findings are just a first step, said Stephen Latham, a bioethicist at Yale University who worked closely with the group. The technology, he emphasized, is “very far away from use in humans.”The group, led by Dr. Nenad Sestan, professor of neuroscience, of comparative medicine, of genetics and of psychiatry at the Yale School of Medicine, was stunned by its ability to revive cells.“We did not know what to expect,” said Dr. David Andrijevic, also a neuroscientist at Yale and one of the authors of the paper. “Everything we restored was incredible to us.”Others not associated with the work were similarly astonished.“It’s unbelievable, mind blowing,” said Nita Farahany, a Duke law professor who studies ethical, legal and social implications of emerging technologies.And, Dr. Farahany added, the work raises questions about the definition of death.“We presume death is a thing, it is a state of being,” she said. “Are there forms of death that are reversible. Or not?”The work began a few years ago when the group did a similar experiment with brains from dead pigs from a slaughterhouse. Four hours after the pigs died, the group infused a solution similar to OrganEx that they called BrainEx and saw that brain cells that should be dead could be revived.That led them to ask if they could revive an entire body, said Dr. Zvonimir Vrselja, another member of the Yale team.Representative images of electrocardiogram tracings in the heart, top, immunostainings for albumin in the liver, middle and actin in the kidney, comparing control organs, left, and those treated with OrganEx.David Andrijevic, Zvonimir Vrselja, Taras Lysyy, Shupei Zhang; Sestan Laboratory; Yale School of MedicineThe OrganEx solution contained nutrients, anti-inflammatory medications, drugs to prevent cell death, nerve blockers — substances that dampen the activity of neurons and prevented any possibility of the pigs regaining consciousness — and an artificial hemoglobin mixed with each animal’s own blood.When they treated the dead pigs, the investigators took precautions to make sure the animals did not suffer. The pigs were anesthetized before they were killed by stopping their hearts, and the deep anesthesia continued throughout the experiment. In addition, the nerve blockers in the OrganEx solution stop nerves from firing in order to ensure the brain was not active. The researchers also chilled the animals to slow chemical reactions. Individual brain cells were alive, but there was no indication of any organized global nerve activity in the brain.There was one startling finding: The pigs treated with OrganEx jerked their heads when the researchers injected an iodine contrast solution for imaging. Dr. Latham emphasized that while the reason for the movement was not known, there was no indication of any involvement of the brain.Yale has filed for a patent on the technology. The next step, Dr. Sestan said, will be to see if the organs function properly and could be successfully transplanted. Some time after that, the researchers hope to test whether the method can repair damaged hearts or brains.The journal Nature asked two independent experts to write commentaries about the study. In one, Dr. Robert Porte, a transplant surgeon at the University of Groningen in the Netherlands, discussed the possible use of the system to expand the pool of organs available for transplant.In a telephone interview, he explained that OrganEx might in the future be used in situations in which patients are not brain-dead but brain injured to the extent that life support is futile.In most countries, Dr. Porte said, there is a five-minute “no touch” policy after the respirator is turned off and before transplant surgeons remove organs. But, he said, “before you rush to the O.R., additional minutes will pass by,” and by that time organs can be so damaged as to be unusable.And sometimes patients don’t die immediately when life support is ceased, but their hearts beat too feebly for their organs to stay healthy.“In most countries, transplant teams wait two hours” for patients to die, Dr. Porte said. Then, he said, if the patient is not yet dead, they do not try to retrieve organs.As a result, 50 to 60 percent of patients who died after life support was ceased and whose families wanted to donate their organs cannot be donors.If OrganEx could revive those organs, Dr. Porte said, the effect “would be huge” — a vast increase in the number of organs available for transplant.The other comment was by Brendan Parent, a lawyer and ethicist who is director of transplant ethics and policy research at New York University’s Grossman School of Medicine.In a telephone interview, he discussed what he said were “tricky questions around life and death” that OrganEx raises.“By the accepted medical and legal definition of death, these pigs were dead,” Mr. Parent said. But, he added, “a critical question is: What function and what kind of function would change things?”Would the pigs still be dead if the group did not use nerve blockers in its solution and their brains functioned again? That would create ethical problems if the goal was to preserve organs for transplant and the pigs regained some degree of consciousness during the process.But restoring brain functions could be the goal if the patient had had a severe stroke or was a drowning victim.“If we are going to get this technology to a point where it can help people, we will have to see what happens in the brain without nerve blockers,” Mr. Parent said.In his opinion, the method would eventually have to be tried on people who could benefit, like stroke or drowning victims. But that would require a lot of deliberation by ethicists, neurologists and neuroscientists.“How we get there is going to be a critical question,” Mr. Parent said. “When does the data we have justify making this jump?Another issue is the implications OrganEx might have for the definition of death.If OrganEx continues to show that the length of time after blood and oxygen deprivation before which cells cannot recover is much longer than previously thought, then there has to be a change in the time when it is determined that a person is dead.“It’s weird but no different than what we went through with the development of the ventilator,” Mr. Parent said.“There is a whole population of people who in a different era might have been called dead,” he said.

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Pig organs partially revived hour after death

Published16 hours agoSharecloseShare pageCopy linkAbout sharingImage source, Getty ImagesPig organs have been partially revived an hour after the animals were killed, in a breakthrough with the potential to transform medicine, say US researchers. The technique could increase the number of organs available for transplant and buy doctors more time to save a life if applied to people. The study also challenges assumptions about what happens in the moments between life and death.Experts said the findings were “truly remarkable” and “incredibly significant”.When the heart stops beating, the body is starved of oxygen and the nutrients it needs to survive. Organs swell in size, blood vessels collapse and cells – the building blocks of the body’s organs – begin to die. This cellular death was thought to be rapid and permanent, but researchers at Yale University have undone some of that damage in animals which have been dead for an hour. “We can restore some functions of cells, across multiple vital organs, that should have been dead,” said Prof Nenad Sestan.”These cells are functioning hours after they should not be.”From brain to bodyThe research team performed a similar feat on just pig brains in 2019. Now they have adapted their technology – called OrganEx – to work across a whole body. It uses:A synthetic blood to carry oxygen around the body. This does not clot so it can navigate the collapsing blood vessels within the pigA cocktail of 13 compounds to interrupt the chemical processes that culminate in cells dying (known as apoptosis) and to calm the immune systemA device to rhythmically pump the fluid around the body to mimic the pulse of a beating heart The experiments, published in the journal Nature, involved about 100 pigs and were given ethical approval before going ahead.Scientists deeply anaesthetised the animals and then stopped their hearts. After being dead for an hour, they were connected to the OrganEx system and given the restorative cocktail for six hours. The anaesthetic was maintained throughout the experiments.After the six hours, the scientists dissected the pigs’ organs such as the heart, liver and kidneys. and showed they were partially revived with some functions restored.There was restoration of electrical activity in the heart, and some heart muscle cells were able to contract. However, the organs were not functioning at the same level as before death.Researcher Dr Zvonimir Vrselja said: “Things are not as dead as we previously presumed – we have demonstrated that we can actually initiate cell-repair on a molecular level. We can persuade cells not to die.”At one point the pigs’ heads and necks began moving spontaneously. It could be a sign they were recovering some motor function, but that will need further investigation.Neuroscientist Dr David Andrijevic said it was a “quite startling moment”. However, he said it was “not indicative of any mental activity on the part of the pig”.Just like the experiment in 2019, there was evidence of repair in the brain. But there were no brainwaves or electrical activity that would suggest consciousness or awareness. Medical advance?It will take considerably more research before the technology could be adapted to be used on people. However, the initial aim is to preserve transplant organs for longer, so they can get to patients who need them. “I think the technology has a great deal of promise for our ability to preserve organs after they’re removed from a donor,” said Dr Stephen Latham, the director of Yale’s interdisciplinary centre for bioethics.More distant ambitions include making even more people suitable organ donors after death and even as a treatment.Commenting on the study, Dr Sam Parnia, director of critical care and resuscitation research at New York University, said the study was “truly remarkable and incredibly significant” and it could help explain reports of near-death experiences. He said the technology could also be used to buy more time for doctors to treat people whose bodies were starved of oxygen, such as those who died from drowning or heart attacks. He added that this could “bring such people back to life many hours after death”.Follow James on Twitter.

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This is how highly resistant strains of fungi emerge

An international research team has deciphered the mechanism by which the fungus Cryptococcus neoformans is resistant to fungus-specific drugs. It is a yeast-like fungus that can infect humans. Specific drugs, named antifungals, are available for treatment, but they don’t always work — a phenomenon similar to antibiotic resistance. A team from Duke University in the USA and Ruhr-Universität Bochum (RUB) has used genetic, bioinformatic and microbiological techniques to decipher the mechanism underlying this resistance. They describe it in the journal Nature Microbiology, published online on 2 August 2022.
“The results are highly relevant for combating fungal infections in clinical practice, veterinary medicine and agriculture,” says Professor Ulrich Kück, Senior Professor in General and Molecular Botany at RUB. He cooperated for the project with the Bochum researcher Dr. Tim Dahlmann and the team headed by Professor Dr. Joe Heitman, who is currently based at Duke University in North Carolina and has been a visiting professor at RUB on several occasions.
Number of fungal infections on the rise
“In the western hemisphere, the number of people with a lowered immune defence is increasing, because life expectancies are rising rapidly and treatment with immunosuppressants after organ transplants is becoming more common,” explains Ulrich Kück. “This is associated with an increase in fungal infections.” Cryptococcus neoformans is one of the most significant human pathogenic fungi responsible for so-called cryptococcosis. It triggers acute infections in immunocompromised patients; and the mortality rate may be as high as 70 per cent. This is because fungal strains that are resistant to the drugs often evolve in hospitals, which makes treatment more difficult. So far, it was unclear which cellular and genetic mechanisms lead to this resistance.
So-called transposons, however, were known to play a role in the resistances. Transposons are jumping genes, i.e. DNA segments that can change their position in the genome and thus affect the function of genes. If a transposon jumps into a gene that’s critical for susceptibility to a drug, it’s possible for resistance to emerge. The mobility of the transposons is controlled by regulatory RNAs, so-called small interfering RNA, or siRNA for short.
RNA mechanism causes resistance
In their current study, the researchers discovered gene mutations in resistant isolates that led to siRNA control being switched off. By introducing an intact copy of the gene, it was possible to restore siRNA control; as a result, the researchers were able to prevent the transposons from jumping and shed light on the cause of resistance. Due to their small size, the gene segments that code for siRNAs are not easy to find in the genome. Tim Dahlmann managed to locate them with special bioinformatic analyses. By identifying the resistance mechanisms, it will be possible to use them for the treatment of mycoses in humans in the future.
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Materials provided by Ruhr-University Bochum. Original written by Julia Weiler. Note: Content may be edited for style and length.

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