Culture

Scientists have identified a potential new treatment approach for Hutchinson-Gilford progeria syndrome (HGPS), a progressive genetic disorder that causes rapid and premature aging in children.

The findings in mice, published today in eLife, show that blocking a protein called ICMT can improve the condition of affected cells without reducing cell division and growth. ICMT is involved in modifying the structure of progerin, the mutant protein that causes HGPS.

These results suggest that ICMT could be a useful drug target to treat HGPS, especially as cell division and growth are important for development in children.

HGPS is caused by progerin, a mutant protein which undergoes two types of structural modifications called farnesylation and methylation. Progerin accumulates between the membranes that surround the cell nucleus, leading to damage that makes cells slow down their growth and die prematurely.

Current treatments for HGPS prevent the farnesylation of progerin, but although these drugs improve some symptoms in patients, they can stop cells from multiplying. Previous experiments have suggested that inactivating the gene for the protein ICMT, which normally causes the methylation of progerin, can also improve key symptoms while avoiding the effects on cell growth and division. However, these benefits have only been demonstrated in HGPS cells outside the body and in mice with a mimic of the disease.

"Previous research has raised the possibility that inhibiting ICMT activity could be an effective therapeutic strategy," explains first author Xue Chen, a PhD student at the Department of Biosciences and Nutrition, Karolinska Institutet, Sweden. "We wanted to determine if these therapeutic benefits would be seen in living mice with HGPS and whether we could use existing drugs to safely reproduce the effects of genetic inactivation on a cellular level."

To do this, the researchers used mice with HGPS that produced progerin and inactivated the ICMT gene, observing how it affected their health. They found that the mice which lacked ICMT survived significantly longer, and had higher body weights, compared to unmodified mice with progeria. They also had larger skeletal muscle fibres, and the muscle cells around their aorta - the large artery in the heart necessary for transporting oxygen-rich blood - resembled those of healthy mice. This result is particularly important as cardiovascular problems are the main cause of mortality in children with HGPS.

The team next treated HGPS cells and the HGPS-mimicking cells from mice with a synthetic chemical called C75 that strongly inhibited the ICMT protein. This treatment delayed the deterioration of the cells and stimulated cell division and growth. Importantly, when applied to healthy human cells and mouse cells that lacked the target ICMT protein, C75 had no significant unintended effects, meaning that it has good specificity for HGPS.

"We hope these findings will further incentivise the development of efficacious compounds targeting ICMT," says Mohamed Ibrahim at Sahlgrenska Center for Cancer Research, University of Gothenburg. "This approach would also likely lack the detrimental properties of current protocols treating already frail children with drugs originally developed to treat cancer."

Next, the team studied where the progerin protein accumulates in cells treated with C75. They found that progerin accumulates inside the centre of the cell - the cell nucleus. This suggests that blocking the methylation of progerin by ICMT redirects the proteins and reduces their ability to cause damage.

"Our study has taken important steps in validating ICMT as a potential drug target that could provide advantages over existing treatments for children with this fatal condition," concludes senior author Martin Bergo, Professor at the Department of Biosciences and Nutrition, Karolinska Institutet. "Further studies are now needed to find compounds that can target ICMT in living organisms, not just in cells."

Researchers have given new insights into why people would choose to donate Covid-19 plasma after recovering from the virus, which will be used to support the recruitment of convalescent plasma donors to help treat current Covid-19 patients and support ongoing trials.

Researchers from the University of Nottingham's School of Psychology, in collaboration with Australian Red Cross Lifeblood and the University of Queensland Australia have been the first in the world to examine the motivations and barriers to convalescent plasma donation in the UK. The findings published in Transfusion Medicine, showed that most people would choose to donate as they want to show their gratitude by giving something back after recovering.

Convalescent plasma is a treatment being trialled for Covid-19 and involves blood plasma from recovered Covid-19 patients being transfused into patients who are currently in hospital with the virus. This provides 'passive' immunity as the antibodies against Covid-19 are transferred from the recovered patient to the current patient to support their immune system to fight the virus.

Professor Eamonn Ferguson from the University of Nottingham's School of Psychology was one of the lead authors on the study, he said: "The use of convalescent plasma as a treatment relies on the generosity and 'altruism' of those who have recently recovered from the virus to help those currently ill. To enhance the recruitment of convalescent plasma donors - much as blood donors in general - we need to understand what would motivate, or even defer, those who are eligible to be convalescent plasma donors to donate."

The study involved 419 UK residents who indicated they had been infected with Covid-19 and were eligible to donate convalescent plasma. They were asked about their awareness of convalescent plasma, motivations, and barriers to donating.

The researchers identified six key motivations - Altruism from adversity, post-traumatic growth, moral and civic duty to help research, patriotism and control, reluctant altruism, and signalling reluctant altruism. They found the main motivation to donate from these was altruism from adversity - people being grateful to have survived with a sense of pay-it-back and pay-it-forwards reciprocity, and moral and civic duty- the morally right thing to do to help family, friends and support research.

Barriers to donating were also explored - not well enough, logistics, generic donation fears, lack of trust in institutions, fear of re-infection, infection and process risk to self and others and worry that others will know of COVID-19 infection. Of these, generic fears were the biggest barrier with a fear of needles being a particular deterrent.

Professor Ferguson continues: "These results highlight the extreme kindness, generosity, and cooperative spirit of human nature. Even under the adverse condition of a global pandemic, people are willing to help strangers and those who are in need which is borne out of adversity but also a moral sense of what is right. This is a real good news study about the human condition and how we are all there for each other. Indeed, little put people off donating convalescent plasma other than a general fear of needles.

The results also suggest several ways that transfusion services to develop recruitment campaigns to attract more convalescent plasma donors. These could focus on simple gratitude interventions, ideas of pay-it-back reciprocity, and moral imperatives.

We feel these new and novel findings have the potential to help in the fight against COVID-19 by providing evidence about ways to support the recruitment of convalescent plasma donors that are urgently needed to support ongoing research trials and treatment of patients."

Dr. Rachel Thorpe from Australian Red Cross Lifeblood said: "It's incredibly useful for transfusion services to understand that people are willing to donate plasma for research even during a pandemic, and that this willingness could be enhanced through increasing public awareness about convalescent plasma and about what is involved in donating plasma."

The immune system can be a mixed blessing: Usually it is highly effective in protecting the human organism against bacteria, viruses and mycosis and even cancer. But these defense cells can also turn against the body's own tissues and trigger autoimmune diseases, including for example rheumatoid arthritis and systemic lupus erythematosus, an illness involving chronic dermatitis and inflammation of the joints, the nervous system and internal organs or even become cancer cells themselves and develop into leukemias or lymphomas. But what causes these destructive immune system attacks?

"The question has yet to be finally resolved," says Prof. Juergen Ruland, Director of the TUM Institute for Clinical Chemistry and Pathobiochemistry. "B cells, a subgroup of white blood corpuscles produced in the bone marrow, play a central role in regulating immune responses. During a normal immune response, activated B cells produce antibodies which attack foreign substances. Defective activation can result in formation of antibodies which attack the body itself, triggering an autoimmune disease. The activity of B cells is controlled by a variety of signals, some of which we have yet to understand," observes Ruland. The immunologist and physician is also the winner of the 2021 German Research Foundation (DFG) Leibniz Prize, the most important German research award.

Ruland and his team have succeeded in identifying one decisive signal which influences B cell activity: "The objective of our research was to characterize the possible pathological roles of a protein located on the surface of the B cells. This receptor, the Receptor Activator of NF-κB, or RANK, exhibits increased activity in patients with systemic lupus erythematosus and in some B cell lymphomas. We wanted to find out if hyperactive RANK receptors actually trigger theseis illnesses."

Chronic signals lead to chronic illnesses

The RANK receptors work like switches within the cell: They generate a signal in the cell when activated by signal molecules. One such signal molecule is called RANKL, for Receptor Activator of NF-?B Ligand.

Working in the laboratory to determine the effects of hyperactive RANK receptors, the team compared healthy mice and genetically modified animals with modified RANK receptors. After only a few weeks a large portion of the mice with genetically modified receptors contracted systemic lupus erythematosus, while the animals in the control group remained healthy, proving that this autoimmune disease can be triggered by defective regulation of the RANK signals.

And that wasn't all: After about a year, the transgenic mice that survived systemic lupus erythematosus contracted chronic lymphatic leukemia or CLL. "This result was a surprise to us, since it shows that activated RANK proteins are also responsible for the degeneration of B cells to cancer of the lymphatic sytem nodes," says Maike Buchner, CLL specialist and junior group leaderyoung scientist at the Institute of Clinical Chemistry and Pathobiochemistry at the university hospital TUM Klinikum rechts der Isar.

Interrupting the cycle of self-destruction

These new findings will help treat autoimmune diseases and lymphatic leukemia in the future: Therapeutic antibodies which block the interaction of RANK receptors and RANKL ligands were originally developed and used to treat osteoporosis: Here the objective is to counteract the deterioration of bone tissue, which is also triggered by hyperactive RANK receptors. Scientists used these blocking antibodies to successfully treat mice suffering from chronic lymphatic leukemia. "Future clinical studies will have to determine whether or not this therapy is also suitable for humans," Ruland points out.

Raising kids can be tough, and sometimes you need all the help you can get. Biologists at the University of Bristol argue that some animals might be able to blackmail reluctant relatives into assisting with the rearing of young. The study is published today [2 February] in The American Naturalist.

In a Darwinian sense, family members are valuable as vehicles for shared genes. Whether helping evolves depends on a simple cost-benefit calculation known as 'Hamilton's rule': help if it will lead to a net increase in copies of your genes in the population.

Dr Patrick Kennedy, lead author and research associate in the School of Biological Sciences, said: "We explored a devious form of manipulation. An individual can threaten to harm its own survival or reproductive success if relatives withhold help."

Andy Radford, Professor of Behavioural Ecology and co-author, explained: "We considered an overlooked aspect of Hamilton's rule. Animals might increase their value to kin by acting in a way that puts shared genes in jeopardy if relatives fail to help."

The authors used simple kin-selection models to extend the theory of 'blackmail' -first suggested four decades ago by Israeli biologist Amotz Zahavi in relation to parental care - to the evolution of altruism between any relatives.

"The logic is similar to the 'Doomsday device' satirised in the film 'Dr Strangelove', added Dr Kennedy. A Doomsday device is a mechanism that will trigger a disastrous nuclear strike if a rival makes an unwelcome move. "If animals can tie more of their own survival or reproductive success to a partner's behaviour, they can make a threat of self-sabotage credible."

Professor Radford suggested: "Shrewd use of resources may be a promising focus to uncover blackmail among animals. For instance, a mother wasp could lay a large clutch and all but exhaust her energy reserves; unless relatives' step in to help, the babies may not leave the nest alive."

Dr Kennedy added: "Our paper looked at whether blackmail between kin is theoretically possible. We showed that, under the right conditions, it can indeed evolve. Underlying the illusion of harmonious co-operation, some animals could be making their families an offer you can't refuse."

Nearly 11 percent of people admitted to an intensive care unit in Sweden between 2010 and 2018 received opioid prescriptions on a regular basis for at least six months and up to two years after discharge. That is according to a study by researchers at Karolinska Institutet published in Critical Care Medicine. The findings suggest some may become chronic opioid users despite a lack of evidence of the drugs' long-term effectiveness and risks linked to increased mortality.

"We know that the sharp rise in opioid prescriptions in the U.S. has contributed to a deadly opioid crisis there," says first author Erik von Oelreich, PhD student in the Department of Physiology and Pharmacology at Karolinska Institutet. "Now, there are signs that opioid prescriptions have increased in parts of Europe and it is therefore important to find out to what extent opioid prescriptions during and after intensive care may contribute to long-term use and its consequences."

Opioids such as morphine and fentanyl are commonly used in critical care for sedation and pain management. There is, however, a lack of evidence to support the use of opioids as a long-term solution to dealing with chronic pain. In addition, misuse of prescription opioids has turned into major health problems in countries such as the U.S. where, on average, 130 Americans die per day from an opioid overdose.

In this study, the researchers found that nearly 11 percent (22,138) of 204,402 individuals continued to receive opioid prescriptions for at least six months and up to two years after critical care treatment in Sweden. The study included all adults who survived at least six months after being admitted to an ICU between 2010 and 2018.

Average opioid consumption peaked in the first quarter after admission and declined continuously during the 24-month follow-up period but never returned to the pre-admission level, according to the study.

Pre-admission opioid consumption was the main risk factor for chronic opioid use after discharge, which was defined as repeated prescriptions for at least six months following ICU treatment. A majority of those who continued to receive opioids had a pre-admission history of use. Women, older people, people with more than one illness and those who stayed longer than two days in ICU were also more likely to receive repeated opioid prescriptions.

The study also found that chronic opioid users had a 70 percent higher risk of death six to 18 months after critical care, also after adjustment for other risk factors. The same finding was seen in patients not using opioids before ICU admission.

Chronic opioid use has previously been linked to adverse health outcomes, including breathing difficulties, constipation, heart attack, stroke, blood clots and an inappropriate immune response.

"The care of the critically ill is complex and finding ways to alleviate pain are important for many patients," says Anders Oldner, adjunct professor in the Department of Physiology and Pharmacology at Karolinska Institutet and last author of the study. "However, it is important to be aware of the potential risks of long-term opioid use, including the risk of death. We hope that our findings contribute to increasing understanding about opioid use during and after critical care."

Study using surveys of more than 1.1 million 13-15-year-olds from 140 countries between 1999 and 2018, finds that the prevalence of smoking cigarettes on at least one day during the past 30 days decreased in 80 countries (57%) but was unchanged or increased in 60 countries (43%).

However, during the same time period, the prevalence of using other tobacco products, such as chewing tobacco, snuff, dip, cigars, cigarillos, pipe, or electronic cigarettes, levelled off or increased in 81 (59%) of 137 countries with available data.

Surveys of more than 530,000 adolescents from 143 countries between 2010 and 2018, finds that 17.9% of boys and 11.5% of girls used any tobacco product on at least one day during the past month.

Tokelau had the highest cigarette use (50.6%) and Kiribati had the highest use of tobacco products other than cigarettes (42.2%). Turkmenistan had the lowest cigarette use (0%) and the lowest use of tobacco products other than cigarettes (0.3%).

Researchers call for better tobacco control in adolescents and for policies to include non-cigarette tobacco products.

Despite an overall reduction in cigarette use over the last 20 years, nearly 1 in 5 boys (17.9%) and more than 1 in 10 girls (11.5%) around the world used tobacco at least once in the past month between 2010-2018, according to a new study published today in The Lancet Child & Adolescent Health journal.

Tobacco use kills more than 8 million around the world every year [1] and can lead to cancer, heart disease, lung disease, and chronic obstructive pulmonary disease, as well as affect fertility [2]. Tobacco use among adolescents and children is a crucial problem, given that most adult smokers start in adolescence or childhood.

In the new study, the authors looked at the Global Youth Tobacco Surveys data between 1999 and 2018 to assess trends in prevalence of tobacco use. All countries included did at least two surveys, resulting in 1.1 million 13-15-year-olds from 140 countries included between 1999-2018, and 530,000 adolescents from 143 countries between 2010-2018.

In the study, the prevalence between 2010 and 2018 of smoking cigarettes on at least one day in the past 30 days was approximately twice as high at age 15 years compared with age 13 years in both boys and girls (6.8% vs 15.4% in boys; 3.4% vs 8.7% in girls). The prevalence of cigarette smoking was highest in the Western Pacific region for boys (17·6%), with Tokelau having the highest prevalence of 49.3%. The European region had the highest prevalence of cigarette smoking for girls (9·0%), with a prevalence of 23.7% in Bulgaria and 23.6% in Italy.

The study also looked at the use of other tobacco products, such as chewing tobacco, snuff, dip, cigars, cigarillos, pipe, or electronic cigarettes.

Between 2010 and 2018, the prevalence of using these products was higher at age 15 years than at 13 years (8.4% vs. 13.9% in boys, 5.1% vs. 9.3% in girls), and there was a significant increase in using other tobacco products among boys aged 15 over the past 20 years, where it rose by an estimated 2.1%. The prevalence of using tobacco products other than cigarettes was highest in the Eastern Mediterranean region (16.7% in boys and 9.0% in girls). The Americas and European regions had the lowest prevalence (7.5% and 9.3% among boys and 5.4% and 5.5% among girls respectively), according to the study. The authors note that they could not distinguish between the different types of tobacco products in this category.

Prof Bo Xi, of Shandong University, China, and lead author of the study, said: "Cigarette use may have decreased in the majority of countries in the study, but there are still large numbers of young people smoking. The fact that in many countries the prevalence of using non-cigarette tobacco products is higher than, or as high as, the prevalence of cigarette use shows us there is still a lot of work to do. The need to strengthen tobacco control efforts, which include specific policies for different tobacco products and a focus on health education for adolescents globally is more important than ever." [3]

In the study there was varying prevalence of smoking cigarettes and using other tobacco products across different regions, which the researchers suggest was due to differences in how tobacco control measures are implemented and monitored. For example, Uruguay has been at the forefront of tobacco control, with a complete ban on tobacco promotion and advertising and strict pictorial health warnings. As a result, cigarette smoking reduced by 17% per 10 calendar years (from 20.1% in 2007 to 8% in 2014), the authors estimate.

The Western Pacific region showed improvement in the prevalence of smoking cigarettes and use of other tobacco between 1999 and 2018 where it reduced by 6.2% and 4.2%, respectively, per 10 calendar years. The prevalence of cigarette smoking also reduced in the European region by 5%. However, even though the region showed improvement, not all countries within the regions performed as well. For example, Bosnia and Herzegovina saw an increase of 10.6% every 10 years (from 11.7% in 2008 to 17% in 2013). The authors suggest that possible reasons for an increase in smoking in this country and some others could be due to the low cost of cigarettes, poor enforcement of smoking bans inside buildings, weak measures on tobacco advertising and promotion, or the sale of single cigarettes.

There were regions that showed an increase in prevalence of using other tobacco products. In the Eastern Mediterranean region, the prevalence increased by 3.5% and in the South-East Asia region it increased by 3.3% per 10 calendar years. For example, in Saudi Arabia in the Eastern Mediterranean region, the prevalence of using other tobacco products increased by 33.3% every 10 years (from 11.2% in 2007 to 21.2% in 2010). In Bhutan in South-East Asia it increased by 18% (from 7.2% in 2004 to 23.4% in 2013).

Professor Yajun Liang, of the Karolinska Institute, Sweden, said: "The largest reductions in tobacco use were seen in countries which had ratified the WHO Framework Convention on Tobacco Control, highlighting the importance of policy change to reduce tobacco smoking. But there is still a lot of work to be done especially with reducing the use of other tobacco products." [3]

"The prevalence of using any tobacco product was two or three times higher in adolescents aged 15 than aged 13 in most countries. Peer pressure, the desire to experience new things, and the ability to buy cigarettes could all explain this trend. Fortunately, many countries have implemented partial or total bans on tobacco advertising. However, it is challenging to address advertising or promotions on the internet and on social media. Health education from an early age about the dangers of tobacco remain crucial." [3]

In a linked Comment, co-authors Mohammed Jawad and Christopher Millett of Imperial College London, UK, and Rima Nakkash, of American University of Beirut, Lebanon, (who were not involved in the study) say that the study "portrays a somber situation" and "[the] findings uncovered a quietly growing phenomenon that has manifested into an urgent priority for the global tobacco-control agenda: the rise of non-cigarette tobacco products."

They discuss in depth the rise in the use of other tobacco products in the Eastern Mediterranean region and suggest this is due to the growing popularity of the waterpipe (known locally as shisha, hookah, or arghile) as a result of new flavoured tobacco, a thriving Middle Eastern café culture, and the misperception that waterpipe tobacco is less harmful than cigarettes. They agree with the study authors that different policies may be needed for different tobacco products and that existing tobacco control laws are based on reducing cigarette smoking and are less effective when applied to products such as waterpipe tobacco.

The authors write: "Simply extending existing laws to waterpipe tobacco seems reasonable in theory, but in practice is far from adequate and can be unenforceable. In the absence of an effective policy response to the emergence of a more nuanced tobacco-use landscape, tobacco consumption among adolescents will remain high... It is not yet certain whether plateaued trends in cigarette use among adolescents in the Eastern Mediterranean region were caused by increasing waterpipe tobacco use, but it is certainly plausible. At a minimum, rising non-cigarette tobacco use is likely to undermine the progress made in reducing cigarette smoking, and at worst could sizably exacerbate the tobacco epidemic."

The authors note some limitations. Not all countries around the world were included in the study because they had not completed a survey within the time period. The surveys were not carried out in the same year in every country and some countries (53 out of 140) had done only two surveys as opposed to more. This weakened the ability to assess how the prevalence changed over time. Additionally, the survey relies on self-reporting and so participants might have understood and interpreted the questions differently; and the survey did not distinguish between different non-tobacco products.

Researchers developing renewable plastics and exploring new processes for plastics upcycling and recycling technologies will now be able to easily baseline their efforts to current manufacturing practices to understand if their efforts will save energy and reduce greenhouse gas emissions.

Benchmark data calculated and compiled at the National Renewable Energy Laboratory (NREL) provide a measurement--at the supply chain level--of how much energy is required and the amount of greenhouse gases emitted from the production of a variety of plastics in the United States.

"Today, we employ a predominantly linear economy for many of the materials we use, including plastics," said Gregg Beckham, a senior research fellow at NREL. "Many people and organizations around the world are looking at ways to make our materials economy circular."

To that end, NREL leads the BOTTLE Consortium, a partnership involving research laboratories and universities to develop methods to upcycle today's waste plastics and redesign tomorrow's plastics to be recyclable by design. BOTTLE stands for Bio-Optimized Technologies to keep Thermoplastics out of Landfills and the Environment.

Beckham is the senior author of a newly published paper in the journal Joule. The article, titled "Manufacturing energy and greenhouse gas emissions associated with plastics consumption," reports on 18 plastics, each with a global consumption of more than 1 million metric tons per year. The co-authors of the study, all from NREL, are Scott Nicholson, Nicholas Rorrer, and Alberta Carpenter.

The estimates draw from a resource developed at NREL, the Materials Flows through Industry (MFI) tool, which tracks energy and material flows throughout the manufacturing supply chain to estimate energy requirements and greenhouse gas emissions.

"MFI is a publicly available tool that can be readily adapted for new technology options," Nicholson said. "We're constantly looking to add new production processes to the database. Researchers can request an MFI account and work with NREL to incorporate their own process data into the tool and calculate impacts for a proposed new supply chain."

Using the MFI tool, if a proposed manufacturing method is estimated to require more energy or produce more greenhouse gases than the status quo process, Nicholson said "a comparison of the sources and types of impacts can help us figure out what aspects of a new process could be targeted for improvement."

To give some context with respect to the broader industrial landscape, the polymers covered in this study represent approximately 95% of global production, a combined 360 million metric tons annually. According to the U.S. Energy Information Agency, plastics production accounted for about 11% of all manufacturing energy consumption in the United States as of 2014. The United States is responsible for generating the largest share of waste plastics in the world, according to a newly published analysis in Science Advances.

This MFI tool analysis reflects only U.S. consumption of plastics, considering where it is used on its own or incorporated into another material. Polyester fiber, for example, is not counted when it is used overseas to make clothes that are then imported to the United States. Future capabilities currently being developed by the MFI tool team will allow users to analyze global supply chains instead of just those based on U.S. manufacturing.

Two organizations within the Department of Energy--the Advanced Manufacturing Office and the Bioenergy Technologies Office--funded the research. The work was performed as part of the newly formed BOTTLE Consortium, which is part of the Department of Energy's Plastics Innovation Challenge.

An international research team from the Photobiotechnology Research Group at Ruhr-Universität Bochum (RUB) led by Professor Thomas Happe and the Laboratoire de Bioénergétique et Ingénierie des Protéines (CNRS) in Marseille has been able to get to the bottom of this unique feature. They describe the molecular mechanism in Nature Communications on 2 February 2021.

Enzyme repeatedly survives the attack unharmed

Representatives of the [FeFe]-hydrogenase enzyme group combine protons and electrons to form molecular hydrogen at particularly high turnover rates. Some of them even use sunlight as a primary energy source for this. However, even low oxygen concentrations quickly lead to the irreversible breakdown of the catalytic cofactor, called the H-cluster. "This has so far been observed in all representatives of this enzyme group - except for CbA5H. This enzyme has a molecular mechanism that allows it to repeatedly survive the oxygen attack unharmed," says Thomas Happe.

In collaboration with Professor Eckhard Hofmann, head of the Protein Crystallography group at RUB, the researchers discovered the enzyme's trick by analysing its crystal structure. "In the active enzyme, the open substrate binding site usually represents the primary point of attack for oxygen," explains Dr. Martin Winkler, one of the RUB researchers involved. In CbA5H, this normally accessible site is shielded under air: Under oxidative conditions the thiol group of a cysteine residue, which was already known for its involvement in proton mediation at the active site of [FeFe]-hydrogenases, binds directly to the free substrate coordination site of the catalytic 2FeH cluster. The point of access is thus blocked for oxygen as long as the ambient oxygen increases the redox potential.

As soon as oxygen is removed from the ambient gas mixture and the redox potential decreases, the thiol group is detached from the substrate binding site of the active site and the enzyme resumes its catalytic activity unharmed. "This hydrogenase can adopt the protected state repeatedly, unlike all other known [FeFe]-hydrogenases," explains Thomas Happe.

The difference from other enzymes

It was initially unclear why specifically CbA5H exhibits this protective function, while other very similar [FeFe]-hydrogenases, that also provide this cysteine residue in the same place as part of the proton mediation chain lack this important feature. A closer inspection of the crystal structure of CbA5H in the oxygen-protected state showed that the section of the protein chain carrying this cysteine is shifted towards the substrate binding site near the active cofactor. Compared with oxygen-sensitive [FeFe]-hydrogenases such as CpI from Clostridium pasteurianum, the researchers at RUB were able to identify three smaller amino acids in CbA5H near to the shifted section of polypeptide chain, which provide it with greater freedom of movement. Electrochemical and infrared spectroscopy examinations of protein variants with single and double exchanges in these positions confirmed the importance of these amino acids for the unique, potential-controlled molecular safety cap mechanism of CbA5H.

"As we now know the structural conditions of this protective mechanism, it should be possible to also transfer the advantageous property of oxygen resistance from CbA5H to other [FeFe]-hydrogenases," says Dr. Jifu Duan, another member of the Photobiotechnology Research Group. "If this is successful, we would be a major step towards using [FeFe]-hydrogenases as hydrogen biocatalysts," confirms Thomas Happe.

DANVILLE, Pa. and GAITHERSBURG, Md. - Researchers have discovered a strong link between genetic changes known to cause neurodevelopmental disabilities and cerebral palsy.

Cerebral palsy affects movement and posture and often co-occurs with other neurodevelopmental disorders, including intellectual disability, epilepsy and autism spectrum disorder. Individual cases of cerebral palsy are often attributed to birth asphyxia, although recent studies indicate that asphyxia accounts for less than 10% of cases. A growing body of research indicates that cerebral palsy may be caused by genetic changes, as is the case in other neurodevelopmental disorders.

The research team, which included investigators from Geisinger and GeneDx Inc., a wholly owned subsidiary of BioReference Laboratories Inc., an OPKO Health company and global leader in genetic diagnostics, studied the DNA sequence of 1,526 children and adults with cerebral palsy. The team found disease-causing changes in 229 genes, several of which have been previously identified in people with both cerebral palsy and other neurodevelopmental disorders. Disease-causing genetic changes were found in 32.7% of a primarily pediatric group of patients from GeneDx and in 10.5% of a primarily adult group from Geisinger.

"Finding a genetic cause for cerebral palsy not only provides an answer to the family, but also informs recurrence risk estimates for future children born to the same parents," said Christa Martin, Ph.D., senior co-author of the study and professor and director of Geisinger's Autism & Developmental Medicine Institute.

"Previous studies in families with children with CP have found a risk of recurrence of 1-2%. Identifying a genetic change that causes the CP in a child and is not present in either parent decreases the risk to less than 1% for future children born to the same parents. When the genetic change that causes CP is inherited from one or both of the parents, that risk increases to 50% and 25%, respectively," Martin said.

"At GeneDx, we were able to test three-fourths of patients along with both parents, allowing us to establish the inheritance of the genetic changes," said Francisca Millan, M.D., co-first author of the study and associate director of neurogenetics at GeneDx. "For approximately a third of the families where a causative genetic change was identified, the family recurrence risk increased to 25% to 50%."

The identification of these genetic changes in multiple patients and replication of these findings across different settings and cohort types provided strong evidence for their role in cerebral palsy, the research team wrote. The findings were published in the Journal of the American Medical Association (JAMA).

"DNA sequencing is recommended as a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders, which are known to co-occur with cerebral palsy," said Andres Moreno De Luca, M.D., physician-scientist and clinical neuroradiologist at Geisinger and co-first author of the study. "Since cerebral palsy can be identified earlier than other neurodevelopmental disorders, such as intellectual disability and autism spectrum disorder, genetic testing for individuals with cerebral palsy may allow for quicker identification of genetic changes and facilitate early interventions and treatment."

"This study re-iterates the value of genetic testing for neurodevelopmental disorders and highlights the utility of genetic testing for cerebral palsy patients," said Kyle Retterer, senior co-author of the study and senior vice president and chief technology officer at GeneDx. "Increasing utilization of and access to DNA sequencing for these patients will lead to earlier diagnoses and improved care in many cases."

BOSTON -- Genome-wide association studies (GWAS) have typically excluded diverse and minority individuals in the search for gene variants that confer risk of disease. Researchers at Massachusetts General Hospital (MGH), the Broad Institute of MIT and Harvard, and other institutions around the world have now developed a free-access software package called Tractor that increases the discovery power of genomics in understudied populations. A study of Tractor's performance and accuracy was published in Nature Genetics.

Researchers perform GWAS to identify where genetic variants responsible for causing disease are located in the genome. Recently, geneticists have begun creating models from published GWAS data to predict risks of disease in individuals. But the clinical utility of these models is currently limited, since most are based on genomic studies of people with European ancestry.

"If you build disease-risk models on available data and attempt to extrapolate them to diverse populations, the accuracy of predicting who will get sick is reduced," says Elizabeth Atkinson, PhD, lead author of the paper and an investigator in the Analytic and Translational Genetics Unit (ATGU) at MGH. "These errors exacerbate existing health disparities, in part because we aren't finding specific gene variants that may contribute to higher risk of a particular disease in diverse populations."

Another significant shortcoming of current GWAS is that "they leave many opportunities for genetic discovery on the table for all populations," says Atkinson. People of African descent, for example, have a million more genetic variations on average than someone who doesn't have African ancestry due to human migration patterns over the ages. Conducting a GWAS with diverse populations allows geneticists to pinpoint genetic associations to disease at many more spots across the genome, says Atkinson.

"Within these genomic regions identified in a GWAS, the genetic mutation that actually causes disease is shared across ancestries most of the time," she adds. By studying admixed populations -- people with recent ancestry from two or more previously isolated population groups, such as Africa and Europe -- "we can get more powerful and precise genetic association signals and do a better job at pinpointing where the causal mutation is, which improves our understanding of disease for everyone."

Until now, there was no fine-scale way to control for ancestry composition in mixed groups being studied in a GWAS. "Different ancestry groups have gene variants that occur at different frequencies due to the populations' demographic history," explains Atkinson. "Not taking ancestry into account in a GWAS can lead to false-positive hits or to gene variants cancelling themselves out and dismissed as not important. So, until now, it's been easier to exclude people with multiple ancestries from GWAS to avoid being confounded by different patterns of gene variants."

Tractor, however, allows researchers to account for ancestry in a precise manner so admixed individuals can be included in large-scale gene discovery efforts. The software colors pieces of each person's chromosomes according to its ancestry origin, which researchers can infer from reference genome sequences, and uses this information in a new GWAS model. "Tractor takes into account the ancestry backbone of each genetic variant so we can correctly calibrate the GWAS results to find causal variants in specific population groups," says Atkinson.

Tractor also provides estimates of ancestry-specific effect sizes, which isn't possible in a standard GWAS. "Instead of getting a weighted average of the disease-risk effect size for a particular gene variant, Tractor can determine how large or small the effect of a variant is in various ancestry groups," says Atkinson. "This will be informative for building genetic risk scores in diverse populations."
Another advantage of Tractor is its ability to improve the power of GWAS by detecting risk gene variants across multiple ancestries. "With Tractor, we can get stronger disease-association signals by leveraging ancestral genomic differences," says Atkinson.

"Tractor advances the existing methodologies for studying the genetics of complex disorders in diverse and minority populations," she adds. "We hope that this method increases the inclusion of admixed participants in large-scale association studies going forward."

GRAND RAPIDS, Mich. (Feb. 2, 2021) -- What does bile acid production in the digestive tract have to do with Parkinson's disease?

Quite a lot, according to a sweeping new analysis published in the journal Metabolites. The findings reveal that changes in the gut microbiome -- the rich population of helpful microbes that call the digestive tract home -- may in turn alter bile acid production by favoring synthesis of toxic forms of the acids.

These shifts were seen only in people with Parkinson's and not in healthy controls, a critical difference that suggests bile acids may be a viable biomarker for diagnosing Parkinson's early and tracking its progression. The insights also may provide new avenues for developing therapies that impede Parkinson's-related changes in the gut, thereby potentially slowing or stopping disease onset and progression.

The research was led by the late Viviane Labrie, Ph.D., of Van Andel Institute, in collaboration with colleagues at VAI, Beaumont Health, Michigan State University College of Human Medicine and Oregon Health & Science University.

"It's becoming increasingly clear that gut health is tightly linked to brain health," said Peipei Li, Ph.D., the study's first author and former postdoctoral fellow in the Labrie Lab. "Our findings provide exciting new opportunities for better understanding this relationship and possibly for developing new ways to diagnose -- and even treat -- Parkinson's."

To investigate differences in the microbiome, the team turned to the appendix, a frequently maligned bit of tissue that actually plays an important role in regulating gut microbes. Using a "multi-omics" approach, the team comprehensively analyzed and compared the microbiome composition of appendix samples from people with Parkinson's and healthy controls. They found significant differences, with the changes in microbial composition of the Parkinson's samples correlating with higher levels of toxic bile acids.

The findings track with a 2020 study led by scientists in Spain that suggest changes in bile acids in the plasma are associated with Parkinson's disease.

"My lab has grown increasingly interested in bile acids and Parkinson's disease following a study completed in collaboration with Dr. Patrik Brundin's group a few years ago," said Stewart Graham, Ph.D., director of Metabolomics Research at Beaumont Health. "We demonstrated that not only was there a significant shift in the bile acid metabolism due to changes we induced in the brain, but that these compounds have the potential to be used as early blood-based biomarkers of the disease. This is extremely important as this is when treatments are believed to be most effective."

In recent years, research has revealed a growing number of links between the gut and Parkinson's. For example, chronic constipation often is one of the earliest signs of Parkinson's disease and can occur years or even decades before the onset of the disease's hallmark motor symptoms. Other studies have shown that hepatitis C, which impacts the liver, increases the risk of developing Parkinson's.

Importantly, a 2018 study by Labrie and colleagues demonstrated that removal of the appendix is associated with a 19-25% reduction in Parkinson's risk when the surgery occurs early in life, before the start of the disease process. They also found that the appendix acts as a storehouse for Parkinson's-related proteins called alpha-synuclein, clumps of which are a key pathological sign of Parkinson's. However, alpha-synuclein was found in the appendixes of healthy controls as well as people with Parkinson's, implying that the presence of the protein alone isn't enough to trigger the disease.

Amsterdam, February 2, 2021 - The Canadian Neuromuscular Disease Registry (CNDR) was launched in 2010 to increase efficient patient access to cutting-edge research and clinical trials, to increase understanding of the natural history and epidemiology of neuromuscular disease across Canada, and to facilitate research collaboration. An assessment of CNDR's accomplishments, published in the Journal of Neuromuscular Diseases, found that it has been successful in securing funding and engaging the community over the past 10 years. With more than 4,000 enrolled patients, data from the registry have been used in over 125 research projects as of 2019, including clinical trial and research notifications, patient questionnaires, and data analyses around patient outcomes and care.

"I am very proud of the work that has been done by the registry team and all of our collaborators across Canada," says lead author Lawrence Korngut, MD, MSc, Department of Clinical Neurosciences, and Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada. "It takes a great deal of effort to enter high-quality data and it has been very fulfilling to provide use of the data currently more than 150 times in projects for researchers and organizations to benefit the neuromuscular community through positive impact on outcomes and advocacy."

Neuromuscular disease is a broad classification that includes numerous conditions that are individually rare, but collectively common, with a prevalence of 160 patients per 100,000 people. Canada is a very diverse country with a broad geographic spread and two national languages. With limited patient numbers in any individual clinic, the multi-disease methodology employed by the CNDR is an efficient and comprehensive way to facilitate collaboration across the country.

Diagnosis and contact information are collected from patients for all diseases. More detailed information, including a full disease-specific clinical dataset and patient demographics, is collected from individuals with one of five specific diseases: Amyotrophic Lateral Sclerosis (ALS); Duchenne Muscular Dystrophy (DMD); Myotonic Dystrophy (DM); Limb Girdle Muscular Dystrophy (LGMD); and Spinal Muscular Atrophy (SMA). For these indexed diseases, CNDR estimates that the registry has thus far ascertained variable percentages of the estimated total patient population in Canada, ranging from 9.0% for DM patients to 83.5% of DMD patients.

Among the projects facilitated by CNDR are more than 18 questionnaire studies, including quality of life studies for DMD and SMA patients, access to computer technology for DM patients, and a global study of risk factors for ALS. Organized to encourage companies to choose Canada for clinical trials and help recruit patients for clinical trials, it has also facilitated 37 clinical trial inquiries. Data have also been used to evaluate patients' access to care in different regions of the country and has helped the network of investigators advocate for their patients in access to therapy and care and support services.

As the current therapeutic landscape for neuromuscular disease is evolving, so too are the aims and scope of the CNDR. The registry has collected genetic test results ranging from 16.9% (of registered sporadic ALS patients) to 86.4% (of registered DM patients). Between 8.3% (LGMD) and 28.4% (DMD) of registrants have participated in clinical trials. The registry is now also being used to understand safety and effectiveness of new therapies.

"CNDR has been instrumental in encouraging clinics to assist registered patients in obtaining proper genetic testing," notes Dr. Korngut. "As there has been an increase in the number of disorders with available genetic testing and genetic-based therapies, awareness of and access to formal genetic counseling are essential components of clinician-patient discussions."

Dr. Korngut observes that in this new era of therapeutic discovery for rare neuromuscular diseases, national disease registries and their associated networks of affiliated clinics are essential. "Ultimately, the availability of comprehensive real-world data in Canada has been an asset to all stakeholders in the neuromuscular disease community and will likely become more so."

PROVIDENCE, R.I. [Brown University] -- Studies have shown that nearly half of all medical students in the U.S. report symptoms of burnout, a long-term reaction to stress characterized by emotional exhaustion, cynicism and feelings of decreased personal accomplishment. Beyond the personal toll, the implications for aspiring and practicing physicians can be severe, from reduced quality of care to increased risk of patient safety incidents.

According to a new study published on Tuesday, Feb. 2, in JAMA Network Open, students who identify as lesbian, gay or bisexual (LGB) are more likely than their heterosexual peers to experience burnout.

"The health and well-being of trainees is intimately linked to the quality of patient care, physician retention, and is key to reducing care inequities," said lead author Dr. Elizabeth Samuels, an assistant professor of emergency medicine at the Warren Alpert Medical School of Brown University. "Understanding how the current medical training environment impacts lesbian, gay and bisexual medical students is critical for improving their training experience, building and retaining a workforce of LGB physicians, and also delivering optimal care to all patients -- especially those who also identify as LGBTQI+."

Samuels, who is a practicing emergency physician at Rhode Island Hospital and The Miriam Hospital, has focused previous research on equity and diversity in the health care workforce and the care of transgender and gender non-conforming people. Data from Association of American Medical Colleges' annual survey of graduating medical school served as the basis for the new study.

"The impetus for this study came out of my own personal experiences as a medical trainee and as a mentor to medical students, as well as a person dedicated to addressing health inequities and improving care for LBGTQI+ patients," Samuels said. "When my collaborators and I learned that the AAMC had added questions about sexual orientation to their annual graduating medical student survey, we thought it would be a good opportunity to examine the experiences of LGB trainees generally, and more specifically, to examine whether medical student experiences of mistreatment and burnout varied by sexual orientation."

The study, conducted in collaboration with researchers from Yale University, is based on data from the 2016 and 2017 AAMC Medical School Graduation Questionnaire, a national survey that includes questions on everything from medical education to financial costs to clinical experiences. In the survey are questions about negative experiences (mistreatment, burnout) and identity, including sexual orientation. Response options include "heterosexual or straight," "gay or lesbian" and "bisexual." The study combined the former into the category of LGB. Information about the gender identity of students who identify as transgender or genderqueer was not provided to the researchers for analysis.

In the study's analysis of 26,123 total responses, 17% of LGB medical students reported high levels of burnout compared to 11.1% of heterosexual students.

Potential causes of burnout include the intensity of medical training, strained finances and unattainable expectations, the authors note in the study. Mistreatment is also a contributing factor, and there has been increased interest in examining its effects on trainees from racial and ethnic groups underrepresented in medicine. However, research has yet to focus specifically on LGB medical students.

"This is the first work that really looks at the relationship between sexual orientation and burnout and how that is mediated by mistreatment," Samuels said.

In the study, LGB students also reported a higher frequency of perceived mistreatment. For example, 27% of LGB students reported being publicly humiliated, compared with 20.7% of heterosexual students; 23.3% reported perceived mistreatment specific to their sexual orientation at least once during medical school, compared with 1% of heterosexual students.

Samuels notes that mistreatment didn't completely explain the emotional strain experienced by LGB medical students, who were 30% more likely to experience burnout even after adjusting for reported experiences of mistreatment.

The researchers found that LGB students reporting frequent experiences of mistreatment related to their sexual orientation had an 8 times higher likelihood of burnout compared to heterosexual students. This difference was dramatic when mistreatment occurred more frequently, Samuels said. But at lower levels of mistreatment, the differences weren't as extreme.

"I think this shows people's resiliency -- up to a point," Samuels said.

Samuels asserts that there are characteristics of medical training, separate from individual experiences of mistreatment, that leads to increased burnout among LGB trainees. After all, previous studies have shown that a high of LGB medical students report concealing their sexual identity during medical school for fear of discrimination. They also report more depression, anxiety, and low self-rated health compared with heterosexual students.

"Layering concerns about homophobia and discrimination on top of the general intensity of medical training can lead not just to burnout, but also to truly deleterious mental health effects," Samuels said.

This can have far-reaching consequences, she noted, as the well-being of the health care workforce is strongly linked to the kind of care that providers are able to offer patients. These findings, she said, underscore the need for continued, comprehensive support and mentorship for LGBTQ medical students, and the importance of institutional culture change to create healthy, diverse, inclusive medical school learning environments.

"Not only is that helpful for individual trainees, but building this workforce is a key strategy in addressing health inequities experienced by LGBTQI+ communities everywhere," Samuels said. "This study gives us a sense of where we are now, and how far we still need to go."

Period poverty, a lack of access to menstrual hygiene products, and other unmet menstrual health needs can have far-reaching consequences for women and girls in the United States and globally.

New research led by George Mason University's College of Health and Human Services found that more than 14% of college women experienced period poverty in the past year, and 10% experienced period poverty every month. Women who experienced period poverty every month (68%) or in the past year (61.2%) were more likely to experience moderate or severe depression than those who did not experience period poverty (43%).

Dr. Jhumka Gupta, an associate professor at George Mason University was senior author of the study published in BMC Women's Health. Lauren F. Cardoso, a graduate student in Social Welfare at University of Pennsylvania and a research assistant at George Mason University at the time of the study was lead author.

"Period poverty is a common yet hidden and stigmatized public health issue in the United States and globally," explains Gupta. "It can reduce women's participation in school and in the workplace. Our findings document the pervasiveness of period poverty among college-aged women and underscores the negative mental health implications. It is thus critical that we provide support to women and other menstruators in obtaining such basic necessities during menstruation."

For the current study, Gupta, Cardoso, and colleagues collected and analyzed data from 471 women enrolled in undergraduate programs who were part of a larger national, on-line survey on menstrual health, endometriosis, and related stigma.

The study's findings also point to inequities in period poverty experiences. Black and Latina women reported the highest levels of period poverty experiences in the past year (19% and 24.5% respectively). Similar patterns were also seen for immigrant and first-generation students. In order to address the unmet basic need for menstrual products, women who experienced period poverty reported borrowing products, using other non-menstrual products (e.g., toilet paper or fabric), using pads or tampons longer than recommended, or going without them entirely during menstruation.

Gupta, Cardoso, and colleagues cite promising examples of initiatives in schools, colleges, and cities that have started to offer free menstrual products in recognition of this need, as well as policy initiatives to remove a "luxury tax" from these products.

"The mental health of college students is of tremendous importance in the United States. Our study findings linking period poverty with increased vulnerability to depression suggest that addressing period poverty should be part of efforts to address well-being among college students," stated Cardoso.

Telehealth use has surged during the pandemic at clinics that serve lower-income Americans, which allowed the clinics to maintain access to care at a time when many other health care organizations saw significant declines in utilization, according to a new RAND Corporation study.

However, most of the telehealth appointments have been audio-only visits, which may pose challenges in the future if payers consider dropping reimbursement for such services.

Studying more than 500 clinic locations across California, researchers found that while overall visit volume remained stable during the pandemic, about half of primary care medical visits from March to August 2020 were done via telehealth. More than 77% percent of behavioral health visits were conducted via telehealth during the same period. Prior to the pandemic, there was minimal telehealth use.

The breakdown of telehealth visits by type greatly favored telephone-only service. Among primary care medical visits, 48.5% occurred via telephone, 3.4% occurred via video and 48.1% were in person. For behavioral health, 63.3% occurred via telephone, 13.9% occurred via video and 22.8% were in person.

The findings are published in the latest edition of the Journal of the American Medical Association.

Prior to the pandemic, many definitions of telehealth excluded audio-only visits and such services were seldom reimbursed by private insurers and government programs. In addition, some payers including the federal Centers for Medicare & Medicaid Services have signaled they may stop reimbursing for audio-only visits when the public health emergency ends.

"While there are important concerns about the quality of audio-only visits, eliminating coverage for telephone visits could disproportionately affect underserved populations and threaten the ability of clinics to meet patient needs," said Lori Uscher-Pines, the study's lead author and a senior policy researcher at RAND, a nonprofit research organization.

When the coronavirus pandemic struck in March 2020, federal officials agreed to reimburse federally qualified health centers to provide both video and audio-only telehealth services to their patients.

Federally qualified health centers are community-based organizations that provide comprehensive primary care and other health services to people of all ages, regardless of their ability to pay or whether they have health insurance. Such clinics are eligible for support from the federal government and are considered a linchpin of the nation's medical safety net.

Since the use of telehealth expanded, few studies have examined differences in the use of telehealth modalities. However, one federal agency estimated that 30% of telehealth visits have been audio-only during the pandemic.

The RAND study examined telehealth services provided by 41 health centers that operate 534 physical locations in California. The group included about 20% of the state's federally qualified health centers.

Researchers collected information from February 2019 to August 2020 about outpatient primary care and behavioral health visits, as well as demographic information about patients.

The total number of primary care visits dropped by 6.5% during the study period, while there was no significant change in total behavioral health visits.

The use of telehealth declined slightly during the study period after spiking at the start of the pandemic. Audio-only telehealth visits peaked in April 2020, comprising 65.4% of primary care medical visits and 71.6% of behavioral health visits.

"Lower-income patients may face unique barriers to accessing video visits, while federally qualified health centers may lack resources to develop the necessary infrastructure to conduct video telehealth," Uscher-Pines said. "These are important considerations for policymakers if telehealth continues to be widely embraced in the future."