Culture

'DNA makes RNA makes protein' is a fundamental principle in molecular biology. The process of gene expression, namely creating RNA from a specific DNA sequence, is tightly regulated in different ways. The DNA itself carries a reversible chemical modification - called methylation - that can influence gene expression.

Scientists at EMBL Rome, in collaboration with Tim Bestor at Columbia University in New York and John Edwards at Washington University in St. Louis, Missouri, now show for the first time how DNA methylation instructs cells to repress parts of their genome by inducing the assembly of a silencing complex. Their work was published in Proceedings of the National Academy of Sciences (PNAS).

DNA methylation is the only epigenetic modification known to be inherited when cells divide, meaning once a specific DNA sequence is methylated it remains in that state throughout the lifespan of an organism. Methylation acts like a mark on the DNA that inactivates some genes in a manner that is dependent on the parental origin. DNA methylation also acts as a cellular defense mechanism against parasitic pieces of DNA that can move within the genome and threaten its integrity. The modification instructs cells to repress these so-called transposons.

Despite four decades of research, the precise mechanism by which DNA methylation represses gene expression has remained unknown. The scientists in Mathieu Boulard's group found that the protein TRIM28, which is a known silencing factor that had not been previously linked to DNA methylation, is required for the repression of methylated genes. However, TRIM28 does not directly interact with DNA, which meant that other proteins must be involved in the process.

Using a combination of genetic and biochemical analyses they showed that in the presence of DNA methylation, TRIM28 binds to the enzyme OGT, which modifies other proteins by adding sugar groups (a process known as glycosylation). They also show that methylation-directed glycosylation of specific DNA binding proteins prevents methylated genes from being expressed.

"Our study reveals that protein glycosylation plays a central role in DNA methylation, thereby unveiling the mechanism behind the most studied epigenetic modification," explains Matthieu Boulard, Group Leader at EMBL Rome.

The first evidence that glycosylation plays a major function in gene regulation came from another study at EMBL, which showed that glycosylation represses developmental genes in certain cells during the development of the fruit fly Drosophila. However, gene repression in this case does not involve DNA methylation.

Boulard says: "We show that DNA methylation in mammals induces gene silencing by activating a process that induces glycosylation of regulatory factors. These findings address one of the core questions in the field of epigenetics, which is the nature of the mechanism that represses methylated promoters."

Plastic products are durable. On one hand this is a great advantage, but on the other hand, if the plastic enters the environment, this advantage turns into a problem. According to current knowledge, natural degradation, as with organic matter, does not take place. It can only be estimated, how long plastic debris actually remains in the environment. Corresponding long-term experiments are lacking.

This applies particularly to the deep sea that is only poorly explored itself. Plastic objects that are found by chance with the help of deep-sea robots or other underwater vehicles are difficult to date. However, during an expedition with the German research vessel SONNE in 2015, researchers from the GEOMAR Helmholtz Centre for Ocean Research Kiel, the Max Planck Institute for Marine Microbiology in Bremen and the Kiel University were able to recover several pieces of waste from the seabed of the Eastern Pacific Ocean in a depth of more than 4000 metre. Conducting a little detective work allowed to constrain the age of deposition quite accurately. For the first time, this offered the opportunity to conduct a long-term study on plastic degradation in the deep sea. The study was published today in the international journal Scientific Reports.

In reality, in 2015 the team was out in the Pacific about 440 nautical miles (815 km) off the coast of Peru to investigate another long-term experiment in the so-called DISCOL area. There, German scientists had ploughed a piece of seafloor in 1989 in order to understand the environmental impacts arising from potential future mining of manganese nodules. They visited this site again in 1992, 1996 and in 2015 to study the recovery of the deep-sea ecosystem.

In 2015, the remotely operated deep-sea robot ROV KIEL 6000 observed almost incidentally some waste and recovered it from the seafloor. Among it was a plastic bag containing a Coke can, which was part of a special edition produced for the Davis Cup 1988. "The aluminum can itself would have corroded in the deep sea, if it was not wrapped tightly inside a plastic garbage bag that preserved it. This also indicates that the garbage bag must be of the same age", says Dr. Matthias Haeckel from GEOMAR, project manager on board back then and now co-author of the study.

A second recovered item was a curd box from a German manufacturer. The printed address shows a five-digit postal code. These were not introduced in Germany until 1990. However, the manufacturer was bought by a rival company in 1999, and the brand name disappeared.

"Since the DISCOL area is far away from important shipping routes, the plastic bag and the curd box could be attributed to the DISCOL expeditions in 1989 and 1992 or 1996," says Dr Haeckel. After all, this offered the extremely rare opportunity to examine in detail datable plastic objects from the deep sea. "It turned out that neither the bag nor the curd box showed signs of fragmentation or even degradation", says biochemist Dr. Stefan Krause from GEOMAR, lead author of the study. He led the onshore analyses in the home laboratories.

A scientifically most interesting finding was that the microbial community on the plastic surfaces differed from the one identified in the surrounding seafloor sediments. "All of the species can be found in the deep-sea sediment, but apparently, larger accumulations of plastics could locally cause a shift in the ratio of the predominant species," says Dr. Krause.

Overall, the study provides the first scientifically sound indication of the fate of plastic debris in the deep sea. "This study builds also an important basis for our new project HOTMIC, where we aim to trace the plastic waste entering the ocean from the continents to the large oceanic eddies and further to their final sink, the abyssal seafloor", says Dr Haeckel.

At the same time, the findings provide a good argument for him to pay even closer attention to compliance with regulations regarding waste on board. "Fortunately, the mentality has changed considerably since the 1990s. Today, both, the crews of the ships and the research teams on board take great care to ensure that no waste is disposed overboard," says Dr Haeckel.

Camelina sativa oil and fatty fish are rich in polyunsaturated omega-3 fatty acids, but their health benefits seem to differ. A new study from the University of Eastern Finland shows that Camelina sativa oil reduces the formation of fatty acid derivatives that may be harmful to cardiovascular health. Camelina sativa oil also seems to protect against oxidative stress. Fatty fish, on the other hand, increases the circulatory concentration of fatty acid derivatives that alleviate inflammation.

The study, conducted in collaboration between the University of Eastern Finland and Karolinska Institutet in Sweden, examined the associations of fatty and low-fat fish, and Camelina sativa oil, with lipid metabolism and low-grade inflammation. The study lasted for 12 weeks and it involved 79 men and women between 43 and 72 years of age and with impaired fasting glucose. The study participants were divided into four groups. One group replaced fats in their daily diet with Camelina sativa oil and reduced their intake of fish to one serving a week. Two of the groups ate fish four times a week: two servings of fatty fish, such as salmon or vendace, and two servings of low-fat fish, such as saithe or pike. The fourth group was a control group.

A high intake of omega-3 fatty acids from Camelina sativa oil and fatty fish reduced the circulatory proportions of arachidonic acid, which is a long-chain omega-6 fatty acid. Those using Camelina sativa oil also had lower concentrations of mediators derived from arachidonic acid, which may be harmful to cardiovascular health. Moreover, the intake of fatty fish increased the circulatory concentration of fatty acid derivatives that alleviate inflammation.

"Camelina sativa oil and fatty fish had a major effect on lipid metabolism. Our study shows that dietary fats can be used to target metabolic pathways that are linked to cardiovascular diseases and type 2 diabetes," Early Stage Researcher Topi Meuronen, the lead author of the article, from the University of Eastern Finland says.

In addition to its other beneficial effects, Camelina sativa oil was also observed to reduce the circulatory concentration of markers that are indicative of oxidative stress. Low-fat fish, however, did not have an effect on the metabolic pathways studied.

In addition to measuring traditional fatty acid concentrations from blood, the researchers were also interested in changes that occur in fatty acid metabolites, which serve as mediators. An examination of fatty acid metabolism on this level makes it possible to study the effects of dietary polyunsaturated fatty acid in more detail than before. These new results are promising and they support earlier findings on the health benefits of fatty fish. However, further research into fatty acid derived mediators, and especially into the effects of Camelina sativa oil's metabolites, is needed.

Patients with bipolar disorder who have multiple family members with severe mental disorders, are more difficult to treat and require more medicine. But if they receive an intensive course of treatment, the effect of this is just as good as for patients who do not have a family history of severe mental disorders.

Bipolar disorder is a serious mental disorder which affects >1 procent of the population during their lifetimes. Now, a new study from Aarhus University and Aarhus University Hospital Psychiatry - in collaboration with a number of American hospitals led by Massachusetts General Hospital in Boston - follows in the wake of previous studies in showing that patients with bipolar disorder have many family members who also suffer from severe mental disorders.

Treatment should be intensified

However, the new element in the study is that the course of the disorder is more complicated for patients who have e.g. a parent or sibling with a severe mental disorder. They had more depressive and manic episodes and more suicide attempts during their lifetime, while at the same time requiring a more intensive course of treatment with more medicine.

"The positive finding is that this extra effort in relation to treatment resulted in patients who both had and didn't have close relatives with severe mental disorders responding equally well to the treatment," explains one of the researchers behind the study, Medical Doctor and PhD Ole Köhler-Forsberg from Aarhus University and Aarhus University Hospital - Psychiatry.

The findings have just been published in the scientific journal Journal of Affective Disorders.

At the start of the study, patients with bipolar disorder self-reported the number of first-degree relatives with severe mental disorders. Of the participants, 85 per cent had at least one, and twenty per cent had five or more. Among the most frequent disorders were depression, alcohol abuse and bipolar disorder.

"We also found that a higher number of family relatives with severe mental disorders was linked to a lower level of education, lower income and earlier debut of the disorder. This suggests that mental disorders in the family also affect the lives of the patients in a very broad and general sense which goes beyond the disorder itself," says Ole Köhler-Forsberg.

The results are based on two large American randomised controlled trials with a total of 757 participants. The study is the first of its kind to include such a large group of patients and also to follow these patients over 24 weeks while they were treated with one of four different treatments.

"Future studies could take a closer look at how mental disorders in the family affect the patient, but also at the entire family and the lives of relatives, and whether efforts to help e.g. the children of people with mental disorders should begin earlier," says the researcher.

Three hours of weekly strength training combined with protein supplements leads to both bigger and stronger muscles in patients with cirrhosis. This is shown by a new study from Aarhus University and Aarhus University Hospital.

Patients with cirrhosis should be prescribed strength training. This is the opinion of the researchers behind a new study which shows that the loss of both muscle strength and size does not have to be permanent in patients with cirrhosis.

"Our training project has demonstrated that strength training and protein supplements can break the vicious circle and rebuild muscles so that their muscles become stronger and bigger," says Luise Aamann from Aarhus University and the Aarhus University Hospital. She is a member of the research group behind the study.

Everyday life became easier

A total of 39 people with cirrhosis took part in the trial which lasted twelve weeks. Half of the participants spent one hour three times a week doing strength training. Both the training group and the control group received dietary advice from a dietitian and also protein supplements throughout the twelve weeks. All physical activity and protein intake was recorded daily in a diary.

"The group who trained increased both muscle strength and size during the twelve weeks of strength training compared to the control group. Furthermore, we found that both functional capacity and quality of life were improved among the members of the training group, and all things being equal, this will make it easier to take care of everyday chores," says Luise Aamann.

The results have just been published in the scientific journal Clinical Gastroenterology and Hepatology.

It is well-known from other studies that strength training benefits the muscles with examples of this including emphysema and cardiovascular diseases. However, that strength training also can be effective for patients with cirrhosis, a disease which is particularly aggressive towards the body's muscles, is new.

"Frail and atrophied arms and legs due to malnutrition and weakened muscles are a characteristic of cirrhosis and are seen in seventy-five cent of hospitalised patients. Atrophying increases the risk of life-threatening conditions such as infections, kidney failure and impact on the brain," says the researcher.

And in everyday life, the weakening of the muscles is severely disabling for the individual and hampers ordinary activities such as shopping, climbing stairs and vacuuming.

"The inactivity creates a negative spiral with further loss of function and finally also social isolation," says Luise Aamann. The next phase of the study will look into whether the twelve weeks of training also affects mortality.

Background for the results:

The study is a randomised clinical trial with a training group and a control group carried out as an interdisciplinary project between the Department of Hepatology and Gastroenterology, the Department of Neurology, and the Department of Radiology at Aarhus University Hospital, together with Sport Science at the Department of Public Health at Aarhus University.

Adult patients in hospital intensive care units (ICUs) are often given rehabilitation therapy and urged to keep mobile from an early point in their hospital stays. This has been shown to improve muscle strength, physical functioning and cognitive health, along with reducing the risk of pressure ulcers ("bed sores"), blood clots and other short-term threats. However, the prevalence or lack of rehabilitation practices for critically ill children in pediatric intensive care units (PICUs) across the nation has been not been solidly researched.

Now, a multicenter study led by researchers at Johns Hopkins Medicine shows that 65% of the PICU patients examined did not get physical or occupational therapy, or adequate opportunities to be mobile, while hospitalized during the study period. Female patients and those with normal physical function prior to illness were the most likely to not receive this important care. The study team also found that 19% of critically ill PICU patients were completely immobile during the same time span.

The researchers reported their findings in the May 2020 issue of the journal Critical Care Medicine.

In the study, known as PARK-PICU (for "Prevalence of Acute Rehab for Kids in the PICU"), researchers gathered data on critically ill children in 82 PICUs in 65 hospitals across the United States. This represents one-third of all PICU beds in the country. There were 1,769 patient days in the PICUs reviewed, with the researchers also evaluating perceived barriers and potential safety events for patient mobility.

"Despite the evidence that early rehabilitative therapy and mobility provide benefits to adults in ICUs, and despite the fact that it is known to be safe and reliable for children, our findings reveal that patients in PICUs are not getting the rehabilitative care they need," says Sapna Kudchadkar, M.D., Ph.D., associate professor of anesthesiology and critical care medicine at the Johns Hopkins University School of Medicine and lead author of the study.

Kudchadkar and her colleagues also found that two-thirds of all children admitted to the PICU for three days or longer are under age 2.

"Pediatric survivors of critical illness commonly experience long-term physical, cognitive and psychological problems, and these issues are compounded by the fact that while children are in the PICU, they are undergoing intensive physical and mental development," she says.

Based on their study findings, the researchers urge hospitals to "systematically design and evaluate PICU rehabilitation interventions for a vulnerable patient population.

CABI scientist Dr Arne Witt has led an international team of researchers who have confirmed for the first time the presence of the date pest red palm weevil on Socotra Island, Yemen, putting the livelihoods of residents at risk.

The red palm weevil Rhynchophorus ferrugineus (Olivier) (Coleoptera: Curculionidae) has already proved its ability to devastate date crops around the world where in the Gulf Cooperation Council (GCC) countries, for example, annual losses associated with the removal of severely infested palms at 1 and 5% infestation levels have been estimated to range from $5.18 to $25.92 million.

Dr Witt and scientists from Mendel University in the Czech Republic, Senckenberg Research Institute and Natural History Museum in Germany and the Environmental Protection Agency in Socotra, fear that the red palm weevil - now well established on the island (a UNESCO World Heritage site) - is 'likely to have a significant negative impact on livelihoods as dates are the most important locally-produced food after milk and meat.'

The researchers, whose findings are outlined in a paper published in a Special Issue on Socotra in the journal Rendiconti Lincei, say more surveys are needed to determine the exact distribution of the palm pest on Socotra and what impact current invasions are having on date production.

However, their initial research and subsequent surveys confirm the presence of the pest in date palm plantations on the north-eastern coast, within 5km of the capital Hadiboh, as well as in at least 22 palm plantations on Socotra along the north coast, from west to east between Dihamd and Riy di Hamri, extending south in the Hadiboh Plain from Hadiboh to the mountain foothills towards the Qishn area. No infestations in the south (Noged area) and west (Qalansiyah area) of Socotra have been found.

They recommend that a specific strategy for the control of red palm weevil should be developed that may include cultural and sanitary methods, and the use of pheromone traps.

Dr Witt believes that the red palm weevil was accidentally introduced within the last few years as a contaminant of goods, including cuttings and potted plants, imported from mainland Yemen. "The red palm weevil is considered to be one of the most problematic pests of date palm in the world. There is a risk that reduced income from palms will result in additional pressure from communities on available natural resources contributing to further biodiversity loss."

"Poor management practices, such as the indiscriminate use of pesticides, will also impact negatively on endemic insects and other organisms."

Dr Witt outlines how the red palm weevil larvae bore into palm trees, and feed on the succulent plant material, especially in the main trunk or stem. Initial larval activity is very difficult to detect without specialized equipment. By the time the first symptoms are visible, it is most often too late, and so serious that any treatments are unlikely to be successful, resulting in the death of the affected plant.

Dr Witt added, "Surveys of incoming vessels at the port at Hadiboh, and local markets, have revealed that a large number of goods, especially fruits, vegetables, plant parts, and potted plants are imported from Yemen on a regular basis."

"However, we cannot exclude the possibility of the beetle being introduced from one of the other Arab States in the Persian Gulf that increasingly export goods, including live plants, to the island; date palm trees are known to be imported to Socotra frequently from other Gulf countries and this practice seems to have continued in recent years."

"One of the most vital issues is the much-needed establishment of quarantine facilities and phytosanitary measures for the island and adherence to these measures by different countries that deliver goods. This information will assist in the development and implementation of a management strategy, and determine if eradication is a possible viable option."

The scientists conclude that eradication of the beetle has been achieved on the Canary Islands, an indication of what can be done if management is well coordinated and it has the support of communities.

A good education system has long been linked with providing opportunity for people to get better jobs and escape poverty. However, less is known about the impact of education on youth violence. By analyzing data about the residents of 55 Baltimore, Maryland, neighborhoods from the City Health Department's 2017 Neighborhood Health Profile Reports, Johns Hopkins Medicine researchers recently showed that those urban areas with a larger number of third graders reading at grade level had lower rates of homicides among people age 25 or younger.

"Our findings fall in line with what we know about early childhood education, in that it helps form identities and a value system, and assists children with navigating dangerous situations more easily," says lead author Michael Bray, M.Sc., a medical student at the Johns Hopkins University School of Medicine. "Investing in kids at the third grade or elementary school levels could have a positive impact that ripples up through the community and could reduce risk of violence."

In the study, published online on June 8, 2020, in the journal Injury Epidemiology, the researchers found that for every 2% increase in the proportion of kids in a neighborhood who were proficient at reading in the third grade, there was one fewer homicide per 100,000 people a year in that area. On average overall, Baltimore has about 56 homicides per 100,000 people per year.

"Homicides are often the result of systemically inescapable poverty tied to a lack of options for upward mobility," says Paul Nestadt, M.D., senior author and assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine.

"Education has long been one of the few pathways out of this circular trap, fortified by racial and economic disparities," he says. "It's not surprising that when neighborhood schools are unable to provide comprehensive early education, the effects echo throughout the community imparting tragic outcomes."

PROVIDENCE, R.I. [Brown University] -- What doesn't kill you makes you stronger -- that claim is so universally accepted that it's a common truism in contexts from everyday conversations to Top 40 pop charts.

But new research led by a team of Brown University researchers finds that this is false.

In fact, the research suggests the opposite is true: Past stressors sensitize people to future traumas, thereby increasing their chances of developing a mental health disorder.

"We hope that this research will spur interest in the face of the increasing number of natural disasters per year -- a major consequence of climate change -- such as the devastating earthquake that affected Chile and neighboring countries," said Cristina Fernandez, a psychiatric epidemiologist and the study's lead author. "The immediate global impacts of these catastrophic events on disease, death and the economy are largely well-recognized. Unfortunately, despite a high disease burden, mental illness has thus far not achieved commensurate visibility, policy attention or funding."

The study, published in the British Journal of Psychiatry on Thursday, June 11, was a collaborative effort led by scientists at Brown and the University of Concepción in central Chile.

The team examined 1,160 Chileans in 2003 and 2011 -- both before and after the sixth-most-powerful earthquake on record and subsequent tsunami struck their country in 2010. When the study began in 2003, none of the participants had a history of post-traumatic stress disorder (PTSD) or major depressive disorder (MDD). After the 2010 earthquake, 9.1% of the survivors were diagnosed with PTSD and 14.4% with MDD­.

The risk of developing these disorders was particularly high among individuals who experienced multiple pre-disaster stressors, such as serious illness or injury, death of a loved one, divorce, unemployment or financial struggles, legal troubles or loss of a valuable possession. To be at increased risk for post-disaster PTSD (relative to those with zero stressors), individuals had to have crossed a "severity threshold" of four or more pre-disaster stressors.

MDD displayed a slightly different pattern: Every pre-disaster stressor -- even a single stressor -- increased a person's risk of developing post-disaster MDD, and each additional stressor further increased the risk.

The researchers say that overall, both findings suggest that the Chilean disaster survivors who had experienced multiple stressors and traumas were at a greater risk of developing a post-disaster mental health disorder compared to those who had experienced few or no prior stressors.

"Unfortunately, the same may well hold true with COVID-19," said Stephen Buka, a professor of epidemiology at Brown's School of Public Health and senior author of the paper. "We're already witnessing how black and Latino Americans are experiencing higher rates of [COVID-19] infections and fatalities. All evidence suggests that disadvantaged groups, who frequently have higher levels of prior life stresses -- such as limited finances and job instability -- will be most likely to suffer the most from serious mental health conditions following the pandemic."

The team hopes its research will help other countries understand the importance of accessible mental health care.

"Personal and national mental health preparedness kits, such as the ones utilized in Chile, help mitigate the negative effects of disasters and can serve as a model for other countries," said Benjamin Vicente, a principal investigator of the study from the University of Concepción. "Along with strict building codes, [Chile] has a national health care service, which includes integrated primary and mental health care centers, most of which have trained personnel to provide disaster coping strategies when needed."

A Turkish family from a village near the Black Sea first caught the attention of medical researchers in the early 1970s. A physician discovered that many members of this large family had both unusually short fingers and astronomically high blood pressure, sometimes twice as high as that of healthy people. Those affected die around the age of 50, usually due to a stroke.

Some twenty years later a group of researchers at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), led by Professor Friedrich Luft and Dr. Sylvia Bähring, began to study this mysterious phenomenon. It proved to be no easy task. Not until May 2015 were the researchers able to report in the journal Nature Genetics that they had found an altered gene in all patients who were affected by the hypertension and brachydactyly (HTNB) syndrome - i.e., high blood pressure and abnormally short digits. The genetic disorder is also known as Bilginturan syndrome, after its Turkish discoverer.

The genetic makeup encodes an enzyme called phosphodiesterase 3A, or PDE3A for short, that regulates both blood pressure and bone growth. The gene mutation that Luft and his team had discovered causes the enzyme to be more active than usual.

Researchers provide the missing evidence

Yet so far there has been no evidence that definitely shows that the mutated PDE3A causes Bilginturan syndrome, which has since been discovered in other families around the world. An international group of 40 researchers from Berlin, Bochum, Limburg, Toronto (Canada) and Auckland (New Zealand) has now supplied this evidence in the journal Circulation. Participating in the study were research groups from the MDC and Charité - Universitätsmedizin Berlin, including teams led by Professors Luft, Michael Bader, Maik Gollasch and Dominik N. Müller as well as Dr. Arndt Heuser and Dr. Sofia Forslund. The last author of the paper is Dr. Enno Klußmann, head of the MDC's Anchored Signaling Lab.

"We mainly worked with two animal models," reports Dr. Lajos Markó, the paper's co-lead author along with Maria Ercu. One of the models consisted of genetically modified mice in which the human enzyme PDE3A in the smooth muscle cells of the vessel walls was overactive due to the gene alteration. "These animals exhibited extremely high blood pressure as compared to the control animals," Markó says.

Genetically modified rats recapitulate the genetic disorder

But what proved more interesting to the scientists was a rat model created by the Bader Lab using CRISPR-Cas9 technology. With the help of the gene-editing tool, the team had altered nine base pairs in a region of the PDE3A gene that is mutated in the syndrome, a so-called mutation hot spot. The resulting enzyme differed from the normal variants with respect to three amino acids. "And just as in the patients, this tiny change increased the activity of the enzyme," Ercu says.

"The rats resembled human patients to a truly extraordinary degree," Ercu adds. "They not only suffered from high blood pressure, but the toes on their forefeet were significantly shortened - similar to the fingers of people with the syndrome." And using micro-computed tomography, the researchers discovered a prominent loop in the brain vessels of the rats that is also found in people with the syndrome. "Our rat model provides, in my view, definitive proof that the syndrome is caused by a mutation in the PDE3A gene," Klußmann says.

The goal is to treat hypertension more effectively

The researchers have even developed an approach for treating this inherited form of high blood pressure. "There is a drug called riociguat that is already approved as a therapeutic for pulmonary hypertension," Klußmann says. We know, he says, that it activates an enzyme that produces a signaling molecule, which in turn dampens down an overactive PDE3A. "The blood pressure of rats to which we administered a derivative of riociguat dropped to a normal level," Klußmann reports. There are already other PDE3A inhibitors on the market, according to him, but they are not suitable for long-term therapy due to their side effects.

Klußmann now wants to take a closer look at how the mutated PDE3A interacts with other protein molecules. Stronger interaction with certain adaptor proteins, he says, could cause cells of the vessel walls to replicate at an increased rate.

In fact, Klußmann has a big goal in his sights: "By learning more about the effects of the PDE3A's interactions with other proteins and understanding how they are involved in the regulation of blood pressure, we will hopefully find new and more effective therapeutic approaches for one of the most widespread diseases of all, hypertension."

Researchers at Karolinska Institutet in Sweden have discovered that excessive degradation of the power plants of our cells plays an important role in the onset of mitochondrial disease in children. These inherited metabolic disorders can have severe consequence such as brain dysfunction and neurological impairment. The study is published in EMBO Molecular Medicine.

"This is a completely new disease mechanism for mitochondrial disease which may provide a novel entry point for treating affected patients," says Nils-Göran Larsson, professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, who led the study.

Mitochondrial diseases are inherited metabolic disorders that affect about 1 in 4,300 individuals and are caused by dysfunctional mitochondria. Mitochondria are the power plants of our cells and are crucial for converting energy derived from our food into the energy currency that drives the cell's biochemical functions. Not surprisingly, organs that are mainly affected in patients are those with a high energy demand, such as the brain, heart, skeletal muscles, eyes and ears. In children, severe multisystem involvement and neurodegeneration are frequent manifestations.

FBXL4 is a gene that is implicated in controlling mitochondrial function, and mutations in this gene are one of the most common causes of mitochondrial diseases. FBXL4 mutations have been linked to encephalopathy, a form of brain dysfunction causing neurological impairment. The manifestations are impaired cognitive function, developmental regression, epileptic seizures and other types of neurological deficits. Despite the severe consequences of FBXL4 mutations in humans, the function of the protein that FBXL4 codes for has remained poorly understood.

In the current study, researchers generated mice that lack FBXL4 and showed that these mice recapitulate important characteristics present in patients with FBXL4 mutations. They were able to demonstrate that the reduced mitochondrial function is caused by increased degradation of mitochondria via a process called autophagy.

In the absence of FBXL4, mitochondria are more frequently delivered to the lysosome, the recycling station of the cell that contains enzymes that break down organic compounds. FBXL4 thus acts as a break on mitochondrial degradation. Patients who lack FBXL4 have too few mitochondria in their tissues which leads to disease.

"Further studies are needed to explore the therapeutic potential of these findings, in particular whether inhibition of the degradation of mitochondria may provide a new treatment strategy," says Nils-Göran Larsson.

The study was financed by several bodies, including the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the European Research Council, the Swedish Cancer Society, and the ALF agreement between the Swedish government and the regional councils.

DALLAS - June 11, 2020 - Dopamine, a chemical that sends messages between different parts of the brain and body, plays a key role in a variety of diseases and behaviors by interacting with receptors on cells. But despite their importance in physiology and pathology, the structure of these receptors embedded in a phospholipid membrane - their natural environment on the cell surface - was unknown. A new study led by UT Southwestern researchers reveals the structure of the active form of one type of dopamine receptor, known as D2, embedded in a phospholipid membrane.

These landmark findings, published today in Nature, could have implications for basic research and for designing drugs for treating conditions in which the D2 receptor plays a fundamental part, including Parkinson's disease, psychosis, and addiction.

Study leader Daniel Rosenbaum, Ph.D., an associate professor of biophysics and biochemistry at UT Southwestern Medical Center, explains that only one previous study had elucidated the structure of the D2 receptor. That research, published in 2018, examined this structure in its inactive form, bound to a drug often used to treat schizophrenia and other mental and mood disorders. It used a technique known as X-ray crystallography to determine the overall structure and detergent molecules to purify the receptor as an individual molecule. However, previous studies have shown that once D2 receptors are made soluble in detergent and left as free-floating constructs, their ability to bind target molecules such as dopamine and their analogs is compromised, leading to potential inaccuracies in the structure.

To avoid this drawback and take a closer look at the D2 receptor, Rosenbaum and his colleagues genetically engineered a form of the receptor that was significantly more stable than the native form. Then, after producing these receptors in cells, they allowed some to bind a compound called bromocriptine, a drug that activates D2 receptors and is used to treat a variety of conditions including Parkinson's disease, pituitary tumors, and hyperprolactinaemia. After purifying these activated receptors in detergent, they embedded them in small patches of phospholipid membrane, an environment akin to their native one in cell membranes. They then examined the D2 receptor using cryo-electron microscopy, a technique that uses beams of electrons delivered at very cold temperatures to decipher the structures of molecules and materials at the atomic scale.

Their results showed similar features to other receptors in the same class, a family of proteins known as G protein-coupled receptors. Like other similar receptors, the D2 receptor snakes through the phospholipid membrane, exposing domains to each side of the membrane. However, it also showed key differences, such as portions buried in the membrane's inner leaflet, ordered sidechains of amino acids in the membrane's interfacial regions, and lipid anchoring of the protein the receptor is coupled to within the membrane. Binding bromocriptine altered part of the receptor to accommodate this molecule, significantly changing its conformation.

Rosenbaum notes that future studies will be necessary to compare and contrast these findings with other types of dopamine receptors to better understand their commonalities and differences. Together, he says, these findings could be an enormous aid in drug design, where developing molecules that precisely fit one kind of receptor can maximize therapeutic effects while avoiding side effects. Specifically designed drugs could significantly improve current therapies for the wide variety of conditions in which dopamine plays a role, including cognitive dysfunction, multiple sclerosis, Parkinson's disease, drug addiction, psychosis, and attention deficit disorder.

"This is just the first structure of an activated dopamine receptor," says Rosenbaum, "but it could serve as a framework to design and tweak new classes of compounds that could change the activity of these types of receptors."

LA JOLLA--(June 11, 2020) A significant site of damage during COVID-19 infection is the lungs. Understanding how the lungs' immune cells are responding to viral infections could help scientists develop a vaccine.

Now, a team of researchers led by Salk Professor Susan Kaech has discovered that the cells responsible for long-term immunity in the lungs can be activated more easily than previously thought. The insight, published in the Journal of Experimental Medicine on June 11, 2020, could aid in the development of universal vaccines for influenza and the novel coronavirus.

"Inside our lungs exist long-lived killer T cells that recognize specific viruses and protect us against re-infection, should we encounter the virus again. Our results have elucidated the manner by which these cells 'see' the virus upon re-infection and provide rapid immunity," says Kaech, director of Salk's NOMIS Center for Immunobiology and Microbial Pathogenesis. "It also may help us understand long-term immunity as it relates to coronavirus."

When we are first exposed to bacteria or viruses, such as influenza, one type of our immune cells, known as killer T cells, destroy infected cells to prevent the spread of the disease. Once the pathogen is cleared, these experienced killer T cells (also called killer "memory" T cells) remain in our body long-term, and "remember" previous invaders. These killer memory T cells enable our immune systems to more rapidly respond to a second attack and effectively provide long-term protective immunity against the invader, a fundamental concept behind vaccination.

Scientists know a lot about how killer memory T cells get activated in lymphoid organs (such as lymph nodes). Immune messenger cells called dendritic cells present fragments of the virus to the killer memory T cell, similar to a handler presenting a scent to a hound, to license their killer function.

But prior studies had not examined this interaction in vital organs, such as the lung. The lung is a frequent entry site for pathogens such as influenza and coronavirus, so the team set out to confirm whether this long-held dogma applied to killer memory T cells that reside in the lungs.

Kaech and then-graduate student Jun Siong Low, first author of the paper, assumed that dendritic cells would be required to reactivate killer memory T cells to fight a second viral attack. So, they deleted various types of messenger cells one at a time in mice to see if the killer memory T cells would still recognize a second influenza infection. The researchers used a green florescent reporter protein to make the killer memory T cells glow if they recognized the virus. However, each time the researchers deleted a specific cell type, the killer memory T cells in the lungs continued to glow.

"At first, our results were disappointing because it didn't seem like our experiments were working; the killer memory T cells in the lungs continued to recognize the virus after the deletion of many different messenger cell types," says Low, now a postdoctoral fellow at the Institute for Research in Biomedicine (IRB) at the Università della Svizzera Italiana, in Switzerland. "Soon, we realized that these lung-resident killer memory T cells were special because they were not reliant on any single type of messenger cell. Instead, they could 'see' the second influenza infection through a variety of different messenger cells, including non-immune cells like lung epithelial cells, which was a remarkably exciting finding."

In contrast, when the researchers examined the killer memory T cells in the lymph nodes--glands that swell during infections--they found that the killer memory T cells needed dendritic cells to recognize the second viral attack. This suggests that the anatomical location of the killer memory T cells dictates how they get reactivated, challenging the long-held dogma that killer memory T cells require dendritic cells for reactivation. The results help to reshape the paradigm of killer memory T cell activation.

Because lung-resident killer memory T cells can be quickly reactivated by nearly any cell type at the site of pathogen entry, identifying vaccines that can create these lung-resident killer memory T cells will likely be critical for superior immunity to viral infections of the lungs.

"We will take this knowledge into our next study, where we will examine whether lung-resident killer memory T cells form after a coronavirus infection," says Kaech, holder of the NOMIS Chair. "Since not all infections induce killer memory T cells, we will determine if these cells form after a coronavirus infection and whether they can be protective against future coronavirus infections."

June 11, 2020-- A new paper published online in the Annals of the American Thoracic Society examines the nation's current shortage of vitally needed medications, and how this dangerous situation is being made worse by the COVID-19 pandemic. The authors provide recommendations on how clinicians and institutions might address potential scarcities of essential medications during the current public health crisis.

In "Preparing for COVID-19 Related Drug Shortages," Andrew G. Shuman, MD, and co-authors discuss how the federal and state governments, as well as health care providers, need to develop ethically sound policies that address already perilously low supplies of certain commonly-used medications, which are dwindling further due to resources needed to combat COVID-19.

"It is critical that these conversations occur now due to current shortages, as well as the necessary lead time to plan for future shortages," said Dr. Shuman, co-chief of the Clinical Ethics Service, Center for Bioethics and Social Sciences in Medicine, University of Michigan Medical School. "Drug shortages have been a national emergency for years and are currently exacerbated due to COVID-19. Issues related to supply chain and anticipated increased ICU needs over the course of the pandemic are worsening the problem."

Yoram Unguru, MD, MS, MA, a physician-ethicist at The Herman and Walter Samuelson Children's Hospital at Sinai and Johns Hopkins Berman Institute of Bioethics, who is a co-author of the paper, added, "As of today the American Society of Health-system Pharmacists (ASHP) reports 213 drugs shortages in the United States. It is not just patients with COVID-19 who are affected. One example of a current drug with a critically short supply is Erwinia asparaginase, a life-saving chemotherapeutic agent for both children and adults with cancer."

Among medical specialties severely affected are oncology, critical care and infectious disease.

The authors stated that regional communication among hospitals is an important first step -- helping determine how local drug supply chains are affected -- and that coordination and sharing mechanisms are also critical.

This information sharing would ideally occur via a central repository or clearinghouse. Both the FDA and ASHP also maintain databases of current drug shortages, and independent health care companies maintain their own databases that can provide invaluable information.

"Sharing information is an important first step," the authors stated. "The second and more difficult step involves actual sharing of medications among hospitals and health systems."

There are a number of barriers to this taking place, among others, the need for cooperation among competing health systems, concerns about potential liability, and legal regulations that affect the transfer of drugs.

Erin Fox, PharmD, a co-author who is director of drug information and support services for Utah Health noted, "Tantamount to this effort is facilitating communication between pharmacists -- those tasked with maintaining supplies, as well as those embedded within clinical teams -- in order to inform the clinical team how supply may impact care delivery."

She continued, "Pandemic-era strategies for conservation of commonly used critical care agents at risk of shortages should be noted, recognizing that these shortages are often regional and unpredictable, and intensive care protocols and strategies are highly individualized." A list of these commonly used drugs is included in the paper.

The authors noted that communication should not be limited to discussions among pharmacists, hospitals, and health systems. Open discussions with patients who are most affected by drug shortages are essential. In the spirit of openness, the authors recommended that hospitals consider publicly posting information about drug shortages.

Dr. Shuman and colleagues called upon stakeholders, from governments to clinicians, to refocus some of their efforts in managing shortages of ventilators during the COVID-19 crisis to develop workflows and rationing criteria for essential medicines. "Even if there are sufficient ventilators, a critical shortage of sedatives, paralytics and/or opioids will obviate the ability to keep patients safely intubated. Data suggest that these shortages have already been associated with inadvertent extubations."

The authors have also identified hoarding of drugs thought to be potential COVID treatments as a problem.

"Once effective treatments and/or vaccines for COVID-19 are available, prioritizing nascent supplies will present a formidable challenge," they predicted. "In the coming days and months, this matter demands global attention. Only with clear lines of communication and a proactive, collaborative approach can we weather this impending storm."

Researchers from Trinity College Dublin and the Royal College of Surgeons in Ireland (RCSI) have shown for the first time, the mental health significance of hallucinations in people with a history of seizures.

In a study published today (Thursday, June 11th, 2020), findings show that 8% of individuals with a history of seizures report hallucinations, including experiences of hearing or seeing things that are not based in reality. And, most importantly of that 8%, 65% also met criteria for one or more mental health disorders and 53% had one or more suicide attempt.

The study is published in leading journal Epilepsia.
As part of one of the longest running studies of mental health in the general population, researchers assessed a wide range of physical and mental health factors in 15,000 people living in the UK.
Hallucinations are known to occur in a proportion of adults with seizures but may be erroneously viewed as 'incidental' symptoms of abnormal electrical activity in the brain and nothing more. The findings of this study tell us that these symptoms are not just incidental in people with seizures; they are important markers of risk for mental ill health and for suicidal behaviour.

Dr Ian Kelleher, Research Associate Professor of Psychiatry, Trinity and Senior Author of the study said:

" People with epilepsy are known to be at increased risk of suicide. But among individuals with seizures, it's hard to pick out who is most at risk. What this research shows is that people with seizures who report hallucinations are a particularly high-risk group for suicidal behaviour - about half of these individuals had one or more suicide attempt. So, it's important in epilepsy clinics to ask about hallucinations - and where someone endorses these symptoms, to carefully examine their mental state."

In an Irish context, anecdotal evidence tells us that auditory and visual hallucinations are not routinely assessed in epilepsy clinics.

Kathryn Yates, RCSI, Study Author said:

"It's not surprising that individuals with seizures have a higher rate of hallucinations - almost any disease that affects the brain is likely to increase risk of hallucinations. However, it's important to recognise that hallucinations don't simply reflect abnormal electrical activity in individuals with epilepsy; they're important markers of risk for mental health problems and suicidal behaviour."

Dr Kelleher concluded:

"We'll need further research to fully understand the significance of hallucinations in people with seizures. But what's clear from this work is that, for clinicians working with people with seizures, asking about auditory and visual hallucinations should be a routine part of their assessment."