Culture

ATLANTA -- New research presented at ACR Convergence, the American College of Rheumatology's annual meeting, shows that tuberculosis (TB) screening and ongoing clinical care is needed for people on methotrexate who live in areas where the highly infectious illness is common. Methotrexate users who also take corticosteroids or other immunosuppressant therapies are at particular risk and need adequate TB screening (ABSTRACT #0223).

Methotrexate is one of the most effective and commonly used medications in the treatment of rheumatoid arthritis and other forms of inflammatory arthritis in both adults and children. Methotrexate is part of a group of arthritis treatments called disease-modifying antirheumatic drugs (DMARDs).

Methotrexate effectively control rheumatic diseases and more people around the world are being prescribed this treatment. In many areas, TB is endemic and a serious health risk for local populations. Since methotrexate suppresses a person's immune system, the researchers wanted to know if they are at increased risk of TB infection. Current guidelines for the management of rheumatic diseases do not address TB risk for people who take methotrexate. To learn more, researchers in Canada conducted a systematic review of published literature on TB rates among people who take less than 30 milligrams of methotrexate per week.

"Methotrexate is the foundation medication for treatment of many rheumatic diseases, especially rheumatoid arthritis (RA). Our concern is that methotrexate can affect cell-mediated immunity, which may increase susceptibility to infections, including tuberculosis," says the study's co-author, Carol Hitchon, MD, Associate Professor of Medicine at the University of Manitoba. "TB is endemic across Africa and other parts of the world. Existing guidelines do not address the possible increased risk of TB in these areas. As one step in developing recommendations for the use of methotrexate intended for these areas, we wanted to review the literature on methotrexate use, and the incidence and new diagnosis of TB in people taking methotrexate."

The researchers reviewed published studies from January 1990 to May 2018 that contained the words methotrexate and tuberculosis, as well as citations from review articles. They identified titles, abstracts or full manuscripts from 4,707 different reports, which were then independently screened to pull out studies on TB in patients taking methotrexate. They collected data on TB incidence, or new TB diagnosis versus reactivation of latent TB infection; TB outcomes, such as pulmonary symptoms, dissemination and death; and the safety of isoniazid, the antibiotic used to treat TB. After removing duplicates and studies with insufficient information, 31 moderate-quality studies were used for the review. Only 27% reported data from low to moderate human development index countries.

Based on the case control studies, the review showed that there is a modest increased risk of TB for patients on methotrexate, and that rates of TB in people with rheumatic disease who are treated with either methotrexate or biologic drugs are generally higher than the general population. Two cohort studies reported TB incidence in Moldova and China, where the disease is endemic. They showed 12 TB cases in 44 patients in Moldova and nine cases in 114 patients in China. Based on other studies on TB infection rates in countries like Spain, South Africa and Canada, the researchers found that infection rates were higher if patients were prescribed methotrexate along with corticosteroids or other immunosuppressants. They also found that methotrexate users had higher rates of TB that was extra-pulmonary, or disease that spreads beyond a patient's lungs, compared to the general population.

Five studies from China, the U.S., Japan and Belgium all evaluated the safety of using methotrexate and isoniazid together. Based on this data, the researchers found that isoniazid-related liver toxicity and neutropenia, or low white blood cell count, were more common when people took the antibiotic along with methotrexate, but these effects were usually reversible.

"This work has important implications for physicians using methotrexate in areas of the world with high rates of TB and for travelers returning from regions with high TB rates," says Dr. Hitchon. "TB reactivation should be considered for anyone with possible prior TB exposure. This is especially true for patients who are also on steroids. Overlapping toxicity profiles, such as liver toxicity, for methotrexate with TB treatments indicate a need for close monitoring."

3D printing has seen great advancements in various aspects over the past few decades, and many industries have seen innovative breakthroughs in their respective fields. Amongst them, the water treatment industry has also reaped benefits off the prospects of 3D printing. High performance spacers and membranes can be fabricated by 3D printing, and they help increase permeate production while minimising energy consumption in purification processes.

Researchers from Nanyang Technological University (NTU) and the Singapore University of Technology and Design (SUTD) reviewed the recent efforts, shortcomings as well as the conflicting reports of 3D printing in membrane-based water treatment (refer to figure). Their research paper entitled 'A review on spacers and membranes: Conventional or hybrid additive manufacturing?' has been published in Water Research.

In the paper, they showed the potential of 3D printed spacers. The great freedom of design in 3D printing enables the fabrication of complex and innovative spacers, which was previously impossible with conventional heat extrusion methods. These spacers were able to reduce the number of dead zones within the flow channel, and help mitigate detrimental membrane fouling problems. Some spacer designs such as the helical spacer, turbospacer, and column spacer were even able to reduce energy consumption.

An interesting perspective was also presented in the paper regarding the feasibility of 3D printed membranes. Microfiltration membranes (MF) with pore sizes

In an attempt to resolve this confusion, the paper critically analyses these 3D printed membranes, especially on 3D printing's role in the overall fabrication process. Hybrid additive manufacturing, a process where 3D printing is used in conjunction with other established fabrication methods, is also introduced in the paper. It shows how 3D printing can still be a powerful tool in the fabrication of membranes when used together with other established processes despite its inadequate printing resolution.

"3D printing is gradually evolving from a single-standalone process to a multi-integrated process. The application continues to grow in the water treatment industry, especially the membrane-based technologies. Future focus is expected to shift from lab scale prototyping to large scale manufacturing," said principal investigator Associate Professor Chong Tzyy Haur from NTU.

"It will not be an easy challenge to overcome upscaling and material limitations, but consistent research efforts are already evident today. Potentially, 4D printing can even be a possibility in the future to fabricate smart spacers and membranes that adapt to its surrounding environment," explained co-author Professor Chua Chee Kai from SUTD.

An international team of scientists has used ancient DNA samples to elucidate the population history of dogs. The results show that dogs had already diverged into at least five distinct lineages by about 11,000 years ago and that their early population history only partially reflects that of human groups.
Dogs were the first species to be successfully domesticated by humans, and they have been our close companions for at least 15,000 years. In spite of the long and intimate relationship between the two species, little is known about how dog populations diversified and dispersed around the world - or to what extent these developments were linked to human migrations. A large-scale international collaboration now sheds new light on these issues. "With the aid of genetic and statistical analyses, we were able to reconstruct the population history of prehistoric dogs, and investigate its relationship to that of humans," says Laurent Frantz. Frantz (formerly at Queen Mary University of London) was recently appointed Professor of the Paleogenomics of Domesticated Animals at Ludwig-Maximilians-Universitaet (LMU) in Munich and is one of the lead authors of the new study. "Our results revealed that the migration patterns of humans and dogs did not always coincide," he adds.

Frantz and his colleagues sequenced a total of 27 ancient dog genomes from Europe, the Near East and Siberia, the oldest of which dates to 10,900 years ago. Their results demonstrate that dogs had already diversified into distinct populations prior to that time. Five separate lineages can be distinguished in the data: Arctic, American, Near Eastern/African, Asiatic and European. The European lineage, to which the great majority of today's most popular breeds belong, is the result of hybridization between the Arctic and Near Eastern/African lines.
"One of the biggest surprises for me was that we detected only a minor amount of gene flow from wolves to dogs," Frantz says. "In contrast to the case with many other domesticated pets, the genetic contribution of the wild ancestors of dogs left very little sign in their genomes following their initial domestication. He speculates that this might reflect strong selection on the part of humans against wolf hybrids - which were perhaps more aggressive.

In order to trace the relationships between the population histories of dogs and humans, the team compared the ancient dog genomes with genetic datasets for humans, obtained from DNA samples that were of comparable age, geographical origin and cultural context to those of the canine samples. This comparison revealed that certain aspects of the population history of the dog could indeed be correlated with that of their human contemporaries. For instance, the first farmers, who migrated to Europe and Africa from the Levant during the Neolithic period, were apparently accompanied by their dogs. These then interbred with dogs domesticated by the hunter-gatherer cultures that they encountered in their new homes. However, the resulting diversification of prehistoric dogs has left hardly any traces in the genomes of their modern European descendants. "A process of homogenization subsequently set in, the causes of which remain unknown. In fact, we found that the genome of a dog found at a 5000-year-old site in Southern Sweden can explain practically all of the genetic heritage of modern European dogs. This means that a single population with ancestry similar to that of this individual replaced all other populations on the continent," Frantz explains.

In other cases, however, the migratory patterns of humans and their hounds do not run in parallel with each other. For instance, the migration of peoples from the Eastern steppe zones during the Bronze Age not only led to a dramatic cultural transition, it also left a clear imprint on the genomes of the European populations of that era - but not on those of their dogs. In other words, the arrival of migrants from the steppes did not lead to large-scale and long-term shifts in the genetic heritage of European dogs. The researchers suspect that factors such as trading patterns, preferences for particular types of dog, variations in susceptibility to infectious diseases, or the adoption of local breeds by the incoming population could account for this striking finding.
When, where and how often wolves were domesticated by humans are issues that remain controversial. The fact that dogs had already diversified into several different lineages prior to 11,000 years ago points to a long prehistory during the Paleolithic period. "Our data support the idea that dogs were domesticated only once, and subsequently dispersed across the globe together with humans," says Frantz. In his view, the question of where the initial domestication took place is still an open one, which requires further investigation.

Ludwig-Maximilians-Universitaet (LMU) in Munich researchers have developed photoresponsive derivatives of the anticancer drug Taxol®, which allow light-based control of cytoskeleton dynamics in neurons. The agents can optically pattern cell division and may elucidate how Taxol acts.
The cells of higher organisms rely on three dynamically reconfigurable systems of protein filaments (collectively referred to as the cytoskeleton), which play crucial roles in all fundamental cellular processes involving motion and directionality. One of these systems consists of massive hollow polymer tubes called microtubules, which are in turn made up of globular subunits called tubulins. Microtubules serve as highways for intracellular transport of mitochondria, neurotransmitters and other biochemical cargos - and coordinated microtubule assemblies form the spindle apparatus that is responsible for the ordered segregation of chromosomes to the daughter cells during cell division (mitosis). Hence, compounds that bind specifically to microtubules and stabilize or destabilize them, provide vital tools for research on cellular cargo trafficking, regulation of mitosis and patterning of embryonic development. Such compounds also find application as powerful anticancer drugs that inhibit tumor-cell proliferation - and drugs such as paclitaxel (Taxol), vinca alkaloids, epothilones, auristatins and dolastatins have been used to treat millions of cancer patients worldwide.

"The problem with using these drugs as research tools is that they are not precise enough to tell us what we need to know," says Oliver Thorn-Seshold, who is in LMU's Department of Pharmacy. Biology is regulated at the subcellular level and with extreme temporal accuracy, but these drugs act on all the cells they reach, and it has not been possible to modulate their dynamics over time. Now, he and his colleagues have solved this problem. In cooperation with Dirk Trauner (New York University) and Anna Akhmanova (Utrecht University), he has developed light-responsive analogs of these drugs, which can be locally activated at specific times. This allows one to control their interactions with microtubules far more precisely. "These light-responsive reagents give us access to a range of powerful, high-precision biology studies," explains Thorn-Seshold. The researchers have used their light-responsive compounds to optically control cell division, cell survival, cytoskeleton structure and remodelling rates down to the level of individual cells, and even to subcellular regions in neurons.

By developing light-responsive analogs of one of the most powerful and clinically important anticancer drugs - paclitaxel, a taxane class drug that stabilizes microtubules - the team hopes also to impact applied research. These high-precision photoresponsive taxanes may be useful for decoding how the clinical drugs exert both their desirable antitumour activity, and their undesirable side-effects, which are primarily caused by damage to neurons. "Since our photoresponsive analogues are also powerfully active in neurons, but can uniquely be applied to selected neurons within a given sample for tightly controlled studies, we believe that our compounds will give us a better understanding of how these side-effects arise," Thorn-Seshold says.

The new compounds are the latest in a set of high-precision, light-responsive cytoskeleton research reagents developed by Dr. Thorn-Seshold and Prof. Trauner since 2013. Taxol is a difficult molecule to work on, because only a few modifications can be made easily. Most modifications could require months or years of effort to synthesize, before even a single compound can be tested. "Taxanes are also very water-insoluble compounds, which makes them tricky to apply reliably to cells or animals; we struggled to tune our compounds' polarity and solubility, and still cannot explain the patterns we observed," Thorn-Seshold explains. However, the researchers are confident that this new reagent approach brings significant benefits. "There are important differences in both the biological and therapeutic effects of microtubule destabilisers, such as those we previously developed, compared to the stabilisers we have now created." By bringing microtubule stabilisation under high-precision control, Thorn-Seshold and his colleagues are convinced that these new reagents will open up entirely new perspectives for cell biology research on topics where temporally or subcellularly specific roles of microtubules determine downstream biological effects, such as in cargo transport, cell migration, mitotic progression, and especially in neurobiology during neuron development or axonal regeneration.

Researchers at the University of São Paulo (USP) in Brazil have shown for the first time that stimulating expression of a protein naturally produced by the human body can be a strategy to combat loss of skeletal muscle mass, which happens normally with aging but can intensify in cases of neurodegenerative or inflammatory disease, or in patients who spend long periods in intensive care units (ICUs).

Ten days in an ICU are estimated to result in the loss of up to 20% of muscle mass in the legs and in important respiratory muscles such as the diaphragm. There are no drugs that can effectively treat these cases without severe side-effects. Only physiotherapy, breathing exercises, and electrostimulation can safely reverse ICU-acquired muscle atrophy.

“We were able to demonstrate that overexpression of protein kinase A [PKA] significantly improved muscle resistance to fatigue in mice. This is because PKA both suppresses FoxO proteins, which activate genes associated with atrophy and increases the formation of muscle fibers with augmented oxidative potential [respiratory capacity], thereby promoting hypertrophy and greater resistance to fatigue in specific muscles,” said Luiz Carlos Navegantes, a professor in the Physiology Department of the University of São Paulo’s Ribeirão Preto Medical School (FMRP-USP) and a co-author of the article on the research published in the journal FASEB J.

The study was supported by FAPESP and offers a new direction for the search for drugs that protect muscles from atrophy without severe adverse side-effects such as cardiac hypertrophy, tachycardia, heart attack, and even death.

“The beneficial role of PKA in muscles, which consists of stimulating anabolism and strength, is unique to all known proteins, making it a strategic target and object of study for the treatment of neuromuscular disease and pathological conditions that lead to weakness and muscle atrophy,” Navegantes told Agência FAPESP.

Metabolic relationship

The FMRP-USP research group, which is led by Professor Isis do Carmo Kettelhut, discovered 23 years ago that the hormone adrenalin not only breaks down energy sources such as lipids and carbohydrate but also inhibits degradation of the proteins in muscle fibers. “That was a paradigm shift,” Navegantes said. “Adrenalin had always been considered a hormone that mobilized energy, not one that prevented excessive breaking down of proteins, which would be catastrophic, especially if they maintain muscle contraction.”

Since they discovered that adrenalin protects muscles, the group has investigated the therapeutic potential of drugs similar to the hormone (sympathomimetics) but without managing to avoid adverse side-effects. “Everyone wants to preserve muscle proteins, from athletes who aim to increase muscle mass to patients who need their diaphragm to continue breathing normally,” Navegantes said. “However, these drugs can have effects that damage the organism and may even be deadly because of cardiac hypertrophy.”

The main problem with using synthetic adrenalin and sympathomimetics, he added, is that they have systemic effects and cannot be targeted to specific muscles. This was evidenced in another study conducted by the group in which the sympathomimetic formoterol was tested for chronic treatment of muscle mass loss and fatigue. In an article published in Cachexia, Sarcopenia and Muscle, the researchers described the effects of this drug, which is widely prescribed for asthma, and showed that it can also promote muscle growth and the strengthening of skeletal muscle.

“Muscles grew owing basically to two mechanisms: direct action of the drug inhibiting protein degradation, and increased secretion of insulin, a well-known anabolic hormone,” Navegantes said. “However, although sympathomimetics are extremely interesting to combat atrophy and have already been adopted in clinical practice, they can have adverse side-effects, especially cardiac hypertrophy, and chronic use of these drugs is therefore dangerous.”

Targeted action

The group decided to study PKA as a potential solution to the problem by means of selective gene transfer, targeting a specific muscle. “PKA was known to be activated by adrenalin and hence associated with lipid and carbohydrate breakdown for energy. However, PKA is located inside muscle cells and adrenalin is a circulating hormone. This difference enabled us to target the effect of PKA on a specific muscle in mice.”

In order for adrenalin to inhibit muscle degradation while also breaking down lipids and carbohydrates, PKA must be activated, Navegantes continued. The adrenalin attaches to a cell membrane receptor and sends a signal that leads to stimulation of PKA in the cytosol (intracellular fluid). Suppression of the genes associated with muscle atrophy is one of the final effects mediated by PKA in cell nuclei.

The researchers used electroporation to activate genes associated with PKA production not in all cells but in a single muscle. By this method, a plasmid was inserted in vivo by electric pulse into the muscle, where it modified the DNA of the muscle fiber. PhD candidate Dawit Albieiro Pinheiro Gonçalves learned the method during an internship in Italy with FAPESP’s support.

“It’s a technique used to prove hypotheses in live animals,” Navegantes explained. “You apply a pulse to the muscle you’re studying and introduce a plasmid that modifies the muscle’s genes [by genetic editing] so as to produce a protein of interest, in this case, PKA. In this manner, you can intervene selectively in a specific skeletal muscle without altering the animal’s other tissues.”

The intervention resulted in overexpression of PKA catalytic subunits (PKAcat) and growing oxidative fiber conversion, substantially improving resistance to muscle fatigue. “When we did the opposite, introducing a molecule called PKI that inhibited endogenous PKA, we observed activation of genes associated with atrophy and a reduction in muscle fiber area,” he said.

The discovery that PKA protects muscle fibers could lead to drug development. “We proved using electroporation that endogenous PKA inhibits loss of muscle mass. Next, we plan to study drugs that activate PKA, and to work with partners to conduct studies in clinical and experimental models, analyzing how it acts in aging and neurodegenerative diseases,” Navegantes said.

Solving the equations of general relativity for colliding black holes is no simple matter.

Physicists began using supercomputers to obtain solutions to this famously hard problem back in the 1960s. In 2000, with no solutions in sight, Kip Thorne, 2018 Nobel Laureate and one of the designers of LIGO, famously bet that there would be an observation of gravitational waves before a numerical solution was reached.

He lost that bet when, in 2005, Carlos Lousto, then at The University of Texas at Brownsville, and his team generated a solution using the Lonestar supercomputer at the Texas Advanced Computing Center. (Concurrently, groups at NASA and Caltech derived independent solutions.)

In 2015, when the Laser Interferometer Gravitational-Wave Observatory (LIGO) first observed such waves, Lousto was in shock.

"It took us two weeks to realize this was really from nature and not from inputting our simulation as a test," said Lousto, now a professor of mathematics at Rochester Institute of Technology (RIT). "The comparison with our simulations was so obvious. You could see with your bare eyes that it was the merger of two black holes."

Lousto is back again with a new numerical relativity milestone, this time simulating merging black holes where the ratio of the mass of the larger black hole to the smaller one is 128 to 1 -- a scientific problem at the very limit of what is computational possible. His secret weapon: the Frontera supercomputer at TACC, the eighth most powerful supercomputer in the world and the fastest at any university.

His research with collaborator James Healy, supported by the National Science Foundation (NSF), was published in Physical Review Letters [https://journals.aps.org/prl/abstract/10.1103/PhysRevLett.125.191102] this week. It may require decades to confirm the results experimentally, but nonetheless it serves as a computational achievement that will help drive the field of astrophysics forward.

"Modeling pairs of black holes with very different masses is very computational demanding because of the need to maintain accuracy in a wide range of grid resolutions," said Pedro Marronetti, program director for gravitational physics at NSF. "The RIT group has performed the world's most advanced simulations in this area, and each of them takes us closer to understanding observations that gravitational-wave detectors will provide in the near future."

LIGO is only able to detect gravitational waves caused by small and intermediate mass black holes of roughly equal size. It will take observatories 100 times more sensitive to detect the type of mergers Lousto and Healy have modeled. Their findings show not only what the gravitational waves caused by a 128:1 merger would look like to an observer on Earth, but also characteristics of the ultimate merged black hole including its final mass, spin, and recoil velocity. These led to some surprises.

"These merged black holes can have speeds much larger than previously known," Lousto said. "They can travel at 5,000 kilometers per second. They kick out from a galaxy and wander around the universe. That's another interesting prediction."

The researchers also computed the gravitational waveforms -- the signal that would be perceived near Earth -- for such mergers, including their peak frequency, amplitude, and luminosity. Comparing those values with predictions from existing scientific models, their simulations were within 2 percent of the expected results.

Previously, the largest mass ratio that had ever been solved with high-precision was 16 to 1 -- eight times less extreme than Lousto's simulation. The challenge of simulating larger mass ratios is that it requires resolving the dynamics of the interacting systems at additional scales.

Like computer models in many fields, Lousto uses a method called adaptive mesh refinement to get precise models of the dynamics of the interacting black holes. It involves putting the black holes, the space between them, and the distant observer (us) on a grid or mesh, and refining the areas of the mesh with greater detail where it is needed.

Lousto's team approached the problem with a methodology that he compares to Zeno's first paradox. By halving and halving the mass ratio while adding internal grid refinement levels, they were able to go from 32:1 black hole mass ratios to 128:1 binary systems that undergo 13 orbits before merger. On Frontera, it required seven months of constant computation.

"Frontera was the perfect tool for the job," Lousto said. "Our problem requires high performance processors, communication, and memory, and Frontera has all three."

The simulation isn't the end of the road. Black holes can have a variety of spins and configurations, which impact the amplitude and frequency of the gravitational waves their merger produces. Lousto would like to solve the equations 11 more times to get a good first range of possible "templates" to compare with future detections.

The results will help the designers of future Earth- and space-based gravitational wave detectors plan their instruments. These include advanced, third generation ground based gravitational wave detectors and the Laser Interferometer Space Antenna (LISA), which is targeted for launch in the mid-2030s.

The research may also help answer fundamental mysteries about black holes, such as how some can grow so big -- millions of times the mass of the Sun.

"Supercomputers help us answer these questions," Lousto said. "And the problems inspire new research and pass the torch to the next generation of students."

The incidence of dementia in patients with rheumatoid arthritis is lower in patients receiving biologic or targeted synthetic disease modifying antirheumatic drugs (DMARDs) than in patients who receive conventional synthetic DMARDs, according to a new study. The study was presented at the virtual annual meeting of the American College of Rheumatology.

"Being on a biologic or targeted synthetic DMARD actually decreased your risk of incidence of dementia by 17% compared to patients who were on a conventional synthetic DMARD only," said lead study author Sebastian Sattui, MD, MS, a rheumatology fellow at Hospital for Special Surgery (HSS) in New York City. The study was done in collaboration with investigators from Weill Cornell Medicine and the University of Alabama at Birmingham.

Dr. Sattui said that the treatment in patients with rheumatoid arthritis has become more complex based on the understanding that rheumatoid arthritis has an impact well beyond what are thought of as the classical manifestations. Previous studies have suggested that inflammatory diseases such as rheumatoid arthritis can increase the risk for dementia and that TNF agents may have a role in preventing the incidence of dementia.

In the new study, researchers identified a cohort of patients with rheumatoid arthritis in Medicare claims data from 2006 to 2017. To be eligible, patients had to have continuous enrollment of at least 12 months in Medicare Part A, B and D, be at least 40 years of age and have no prior diagnosis of dementia.

In the sample of 141,326 eligible patients with rheumatoid arthritis, the crude incident rate of dementia was 2.0 per 100 person-years for patients on conventional synthetic DMARDs and 1.3 for patients on any biological DMARD. After adjusting for factors such as age, sex and other comorbidities, patients on biologic or targeted synthetic DMARDs had an adjusted 17% lower risk for dementia than patients on conventional synthetic DMARDs. No significant differences were observed between the different classes of biologic or targeted synthetic DMARDs, suggesting that decreased risk is possibly explained by the overall decrease in inflammation rather than a specific mechanism of action.

The researchers say clinicians should factor this new information into treatment decisions, but prospective studies are needed. "Our work shows yet another dimension in which treatment of rheumatoid arthritis can impact the overall health and quality of life of our patients," said Dr. Sattui. "Rheumatoid arthritis is a systemic disease and it can have cognitive implications. However, these complications seem to share similar pathways to those of articular disease, and the medications that we use to treat rheumatoid arthritis could be effective in the prevention of dementia in patients with rheumatoid arthritis. Future studies need to assess the impact of the interventions, such as the treat-to-target strategy, on the incidence of dementia in patients with rheumatoid arthritis."

In a current opinion article "Reduction of environmental pollutants for prevention of cardiovascular disease: it's time to act", published in the European Heart Journal this week, a group of international environmental researchers from the University Medical Center of Mainz (Thomas Münzel and Andreas Daiber), from the University/BHF Centre for Cardiovascular Sciences, University of Edinburgh, United Kingdom (Mar Miller), the Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark (Mette Sørensen), the Max Planck Institute for Chemistry, Atmospheric Chemistry Department, Mainz, Germany (Jos Lelieveld) and the Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center and School of Medicine, Cleveland, OH, USA (Sanjay Rajagopalan) summarized the epidemiologic and mechanistic evidence in support of an association between noise and air pollution with cardiovascular and metabolic disease, and recommended comprehensive mitigation measures.

Environmental risk factors are increasingly recognized as important determinants of cardiovascular disease (CVD). While the contribution of high cholesterol, diabetes, arterial hypertension, obesity and smoking are well established, the contribution by factors such as noise and air pollution to cardiovascular disease are often not acknowledged, despite the recognition that they represent the two most common and pervasive environmental risk factors globally.

Recent data indicate that air pollution attributable premature deaths approach 9 million per year globally (mostly cardiovascular causes), accounting for a loss of life expectancy that rivals that of tobacco smoking. The health burden due to noise pollution is mostly based on loss of healthy life years, amounting to several 100 Mio. of disability adjusted life years per year.

In particular with respect to air pollution, 90% of the world population lives in an environment with air pollution levels higher than 10μg/m3, being recommended by the WHO.

"The European levels air pollution limits for PM 25 μg/m3 is 2.5 fold higher than the WHO limit and a reduction of the air pollution limits down to the WHO recommendation mainly due to a phase out of fossil fuel use could prevent around 400.000 to 500.000 thousand excess deaths of Europeans. Thus, we urgently need to reduce these limits" urges Thomas Münzel.

The environmental stressors such as air pollution and noise pollution cause primarily cardiovascular disease such as chronic coronary artery disease, stroke diabetes mellitus, arterial hypertension but also neurological diseases and thus represent per se cardiovascular risk factors that can be positively influenced not by doctors or patients themselves but rather by politicians by introducing noise and air pollution limits that protect us from adverse health effects caused by these environmental stressors, "the lead author Münzel comments.

The author team proposes mitigation maneuvers for to protect from air pollution induced health side effects such as active personal exposure mitigation with home air cleaning and personal equipment such as N95 respirators while face masks are not effective in ?ltering PM2.5, Modification of human behavior to reduce passive exposures such as advising patients with pre-established cardiovascular disease to continue to remain >400 m away from major roadways to avoid exposure to traffic pollutants is a reasonable measure, despite the current lack of strong evidentiary support. Although a variety of over the counter drugs and medications have been shown to mitigate association between air pollution and surrogates, almost none can be recommended to protect against air pollution mediated adverse health effects at this time.

With respect to noise pollution the team suggests for road traffic noise that the sound generated by the contact between the tires and the pavement is the dominant noise source, at speeds above 35 km/h for cars and above 60 km/h for trucks. Therefore, changing to electric cars will result in only minor reductions in road traffic noise. Generally applied strategies for reducing road traffic noise include noise barriers in densely populated areas, applying quiet road surfaces, and reducing speed, especially during nighttime. Furthermore, there is a great potential in developing and using low-noise tires. As many of these mitigation methods result in only relatively small changes in noise a combination of different methods is important in highly exposed areas. For aircraft noise, mitigation strategies include to minimizing overlapping of air traffic routes and housing zones, introduction of night bans, and implementation of continuous descent arrivals, which require the aircraft to approach on steeper descents with lower, less variable throttle settings. For railway noise, replacing cast-iron block breaks with composite material, grinding of railway tracks and night bans, are among the preferred strategies for reducing noise. Lastly, installing sound-reducing windows and/or orientation of the bedroom towards the quiet side of the residence can reduce noise exposure.To this end Münzel further proposes that "increased awareness of the health burden posed by the risk factors such as noise and air pollution and their incorporation in traditional medical guidelines will help propel legislation to reduce them and significantly improve cardiovascular health."

MISSOULA - Warmer winters, earlier springs, shrinking ice and increased human development - the Arctic is undergoing dramatic changes impacting native animals. And now, scientists can track the movements of thousands of Arctic and sub-Arctic animals over three decades with the new global Arctic Animal Movement Archive.

Researchers from around the world, including the University of Montana, have long observed the movements and behavior of animals in the Arctic, but have had difficulty discovering and accessing data. To solve the problem, an international team led by Sarah Davidson, data curator at the Max Planck Institute of Animal Behavior in Radolfzell, Germany, and Gil Bohrer, professor at Ohio State University, established the global data archive for studies of animal migration in the Arctic and sub-Arctic. It currently contains over 200 projects and movement data of more than 8,000 marine and terrestrial animals from 1991 to the present.

The archive, hosted on the Max Planck Institute's Movebank platform and funded by NASA, helps scientists share their knowledge and collaborate on questions on how animals are responding to a changing Arctic - particularly important because the Arctic region extends around the world. Researchers from more 100 universities, government agencies and conservation groups across 17 countries are involved in the archive.

UM contributors include Professor Mark Hebblewhite, graduate student Stephen Lewis and former postdoctoral researcher Eliezer Gurarie. Their research is part of Hebblewhite's funded NASA Arctic Boreal Vulnerability Experiment project that studies the effects of rapid climate change on wildlife in the Arctic, with a focus on caribou.

"UM has a long history, pioneered by researcher Steve Running, of understanding consequences of climate change to ecosystems, and this work builds on this important legacy in a region of the world undergoing some of the fastest rates of climate change, fires and impacts on people and nature," said Hebblewhite, who studies ungulate habitat ecology.

Three recent studies from the archive reveal large-scale patterns in the behaviors of golden eagles, bears, caribou, moose and wolves in the region and illustrate how the archive can be used to recognize larger ecosystem changes. The results were published Nov. 6 in an article in Science, one of world's premier scientific journals.

First, by comparing movements of more than 100 golden eagles from 1993 to 2017, researchers found that immature birds migrating north in the spring arrived earlier following mild winters. However, the arrival time of adults has remained rather constant, regardless of conditions at their breeding grounds, with consequences for nesting and chick survival.

The archive uses data from UM doctoral student Lewis, who is a wildlife biologist with the U.S. Fish and Wildlife Service Alaska Region, Division of Migratory Bird management. Lewis began studying the movements of golden eagles in 2012 to understand the costs of migration and carry-over effects of wintering in the contiguous U.S. for eagles born in Alaska. His data fit perfectly into the Arctic Animal Migration Archive and NASA's Arctic Boreal Vulnerability Experiment project, and he will continue to analyze eagle movement ecology at UM.

A second study of more than 900 female caribou from 2000 to 2017 found that more northern herds are giving birth earlier in the spring, while the calving dates of more southern populations have not shown the same change.

"Caribou are the Arctic's dominant large herbivore - an iconic symbol and crucial to Indigenous peoples for their food security and culture," Hebblewhite said. "Yet they are declining across the Arctic, and an obvious question is the role of climate change."

Hebblewhite said the research, which brought together an unparalleled dataset of nearly 1,000 GPS radio-collared caribou, showed a strong shift in calving dates across most of the region - and a potential contribution toward declining trends in the population.

A third analysis looking at the movement speeds of bears, caribou, moose and wolves from 1998 to 2019 showed that species respond differently to seasonal temperatures and winter snow conditions.

"Movement is central to animal survival in the harsh Arctic environment. Yet movement is costly, especially in the stark Arctic landscapes," Hebblewhite said. "Our work showed that increasing temperatures, especially in summer, were affecting movement rates of these large mammals, which could have energetic costs that stress these species. And changes in snow in the winter were also influencing wildlife movements - also in ways that could have population impacts."

In addition to the UM research and hundreds of studies already included in the archive, the resource is continually growing, as data are transmitted from animals in the field and more researchers join. Results should help detect changes in the behavior of animals and ultimately in the entire Arctic ecosystem.

"The Arctic is undergoing some of the most rapid climate change on the planet - upward of double the rates we are seeing here in Montana," Hebblewhite said. "We hope our collective work shows that the changes underway in the Arctic are real and strong and affecting almost all Arctic wildlife species, as well as the ecosystems and people who depend on them."

November 6, 2020 - Botulinum toxin - best known by the brand name Botox - is a popular treatment to reduce facial lines and wrinkles. Over the years, plastic surgeons have explored alternative approaches to maximize effectiveness while minimizing side effects of botulinum toxin injection, including smaller doses and more-diluted concentrations.

Now a team of plastic surgeons is developing an innovative, less-invasive "Microbotulinum" injection technique - using many tiny doses of botulinum toxin injected in a grid pattern just under the surface of the facial skin. In a preliminary report, this micro-dose technique provides objective improvement in skin texture and roughness, backed up by a high patient satisfaction rate.

The Microbotulinum technique is a safe and effective method of facial rejuvenation, yielding objective improvements of about 20 percent in skin texture, microroughness and pore size, according to the report by Alberto Diaspro, MD, MSc, of the Rigeneralab Centre for Regenerative Medicine in Turin, Italy, and colleagues. The researchers present a description and initial evaluation of their approach in the November issue of Plastic and Reconstructive Surgery®, the official medical journal of the American Society of Plastic Surgeons (ASPS).

Cosmetic botulinum toxin injection is by far the most common cosmetic procedure, performed about 7.7 million times in US patients in 2019, according to ASPS statistics. In the standard technique, a few injections are made to treat common problems such as frown lines, forehead creases and crow's feet around the eyes.

The new, less-invasive technique uses a series of tiny "blebs" of botulinum toxin A injected just under the skin surface. The injections follow a one-centimeter grid pattern, extending from the forehead to the cheek and down to the jawline. "This targets the superficial fibers of the facial muscles and weakens their insertion into the undersurface of the skin, which is responsible for the fine lines and wrinkles on the face and neck," Dr. Diaspro and colleagues write.

The researchers used a specialized, high-resolution "skin scanner" system to provide objective data on how the Microbotulinum procedure performed in improving the skin appearance. Graded on a 10-point scale (0 being best, 10 being worst), average skin texture improved from 6.0 to 4.0, while scores for skin "micro-roughness" improved from 7.5 to 5.0. There was a similar and significant reduction in enlarged pore size.

The improvements were backed up by subjective ratings: 90 days after micro-dose treatment, 95 percent of patients were satisfied or very satisfied with their results. As in any botulinum toxin procedure, the effects were temporary, lasting up to 120 days. After that, treatment would need to be reported in order to maintain the improvement.

The results of the Microbotulinum technique appeared best in middle-aged patients. Dr. Diaspro and colleagues believe it will be most appropriate for patients ranging from their mid-thirties to early fifties. The researchers emphasize the need for further studies to determine the optimal dose of botulinum toxin to produce a longer-lasting effect at the dilution used.

Click here to read "Microbotulinum: A Quantitative Evaluation of Aesthetic Skin Improvement in 62 Patients."
DOI: 10.1097/PRS.0000000000007248

For our cells to assemble into tissues and whole organs, the extracellular ma-trix (ECM) as well as the integrins are required. The ECM forms a kind of extra-cellular protein meshwork, the integrins are surface proteins, which our cells use to attach to this extracellular support structure. How human cells balance attachment to versus detachment from the ECM is a yet unsolved question. The research team led by Professor Christof Hauck in the Department of Biolo-gy at the University of Konstanz, now identified a key enzyme, PPM1F, which regulates the integrins' detachment from the ECM. The results have been pub-lished in the online edition of the Journal of Cell Biology https://doi.org/10.1083/jcb.202001057.

The ECM mainly consists of a network of protein fibres such as collagen and other filamentous extracellular proteins. In order to adhere to this meshwork, nearly every human cell possesses surface proteins termed integrins. Integrins operate like mo-lecular carabiners that lock the cells to the network of collagen fibres or other ECM proteins and thus provide a strong focal point of attachment for the cell. However, cells in our body do not always stay in place, but sometimes need to migrate over long distances to their final destination - just think of immune cells that have to travel from the lymph node to a skin wound. As a solution, nature provided integrins with special features.

Like a sailor in the ship's rigging

Integrins are peculiar, because they can be repeatedly folded over and extended: When folded over, integrins cannot connect to the ECM, as the carabiner is buried. Upon extension of the integrin, the carabiner is exposed and can lock the cell to the ECM. Interestingly, cells can extend integrins at the front end of the cell, while they fold over their integrins at the rear and detach from the ECM at these positions. Cy-cles of integrin-mediated "gripping and let loose" allow cells to move in the protein meshwork of the extracellular matrix like a sailor climbs in the ship's rigging. Integrins consist of two parts, the α- and the β-subunit. Both subunits traverse the cell mem-brane, so that a small part of the protein is inside the cell, but the larger portion, the actual carabiner, is outside of the cell. It has been known for some time that the ex-tension of the integrin is initiated by the integrin β-subunit: In particular, the protein talin initially binds to the intracellular part of the β-subunit and triggers integrin exten-sion and thus the activation of the carabiner.

Without phosphorylation the carabiner hook remains buried

Tanja Grimm and Nina Dierdorf, doctoral researchers at the Konstanz Research School Chemical Biology have discovered that the β-subunit is being marked for talin binding by a small chemical modification, a so-called phosphorylation. This phos-phorylation works like a switch: Upon phosphorylation, talin can bind and the integrin is extended. If phosphorylation does not take place or if this position in the integrin is mutated, talin does not associate and the carabiner remains buried. Consequently, the cells lose their grip. Moreover, the doctoral researchers now showed for the first time that a single enzyme is responsible for reversing the phosphorylation of the integrin β-subunit: the protein phosphatase PPM1F. This enzyme can remove the phosphorylation and thus trigger the integrins to fold over. The PPM1F-regulated "phosphorylation switch" in the integrin seems to be essential, because in the absence of PPM1F, embryonic development, when different cell types have to arrange themselves into functioning tissues, terminates prematurely. Isolated cells, in which the PPM1F gene is disrupted, show enhanced attachment to the extracellular matrix and can hardly move, as they are unable to release integrin-based matrix contacts.

Does less cell adhesion allow uncontrolled migration?

The researchers now hope that this knowledge can be used in the future to specifi-cally control PPM1F activity and thus the functionality of integrins. In some tumour cells, this phosphatase appears to be particularly abundant, and the resulting reduced adhesion of such tumour cells could be one of the reasons, why they are able to leave the primary tumour and form metastases at distant body sites.

"In the next step, we want to learn how to manipulate the phosphorylation switch and thus the function of integrins," says Tanja Grimm, first author of the study. "We might be able to specifically influence integrin-dependent processes in our body, from im-mune cell movement to tumour metastasis. With these novel findings we might help our cells to firmly stay in touch with their surrounding and prevent them straying away for the worse".

Key facts:

Original publication: Grimm, T.M., Dierdorf, N.I., Betz, K., Paone, C., Hauck, C.R. (2020): PPM1F controls integrin activity via a conserved phospho-switch, Journal of Cell Biology (2020) 219 (12): e202001057; published online on 29 November 2020. doi: https://doi.org/10.1083/jcb.202001057

The team led by Professor Christof Hauck, cell biologist at the Department of Biology, University of Konstanz, discovered new details about the regulation of cell adhesion and cell migration

The phosphatase PPM1F is key for releasing integrin-based contacts between human cells and the extracellular matrix

Research was conducted in the context of the Collaborative Research Centre (SFB 969) "Chemical and Biological Principles of Cellular Proteostasis", which is funded by the German Research Foundation (DFG)

Tanja Grimm and Nina Dierdorf, the lead authors of the study, received schol-arships of the Konstanz Research School Chemical Biology (KoRS-CB).

ITHACA, N.Y. - In emerging renewable energy industries, are producers' decisions to shut down or upgrade aging equipment influenced more by technology improvements or government policies?

It's an important long-term question for policymakers seeking to increase renewable electricity production, cost-effectiveness and efficiency with limited budgets, says C.-Y. Cynthia Lin Lawell, associate professor in the Charles H. Dyson School of Applied Economics and Management at Cornell University.

In a new study focused on Denmark, a global leader in wind energy - a relatively mature and low-cost renewable technology - Lin Lawell found that government policies have been the primary driver of that industry's growth and development.

"Technological progress alone wouldn't have led to that widespread development of wind energy in Denmark," said Lin Lawell, the Robert Dyson Sesquicentennial Chair in Environmental, Energy and Resource Economics. "Well-designed policy may be an important contributor for nascent industries like renewables, which need to develop technology and which have broader societal benefits in terms of the environment."

Lin Lawell is the co-author with Jonathan Cook, an associate in her DEEP-GREEN-RADAR research group, of "Wind Turbine Shutdowns and Upgrades in Denmark: Timing Decisions and the Impact of Government Policy," published in a recent issue of The Energy Journal.

Wind turbines in many countries are approaching the end of their useful lives of roughly 20 years, Cook and Lin Lawell note, making decisions about whether to scrap or upgrade them increasingly relevant.

Denmark is ahead of that curve, having promoted wind energy since the oil crisis in the late 1970s. The country produces over 40% of its electricity from wind power and dominates other countries, the authors said, in wind deployment per capita and per gross domestic product. The Danish wind industry is highly decentralized, with 88% of the nearly 3,000 producers included in the 32-year study period from 1980-2011 operating no more than two turbines.

The researchers built a dynamic structural econometric model that incorporated the capacity, age and location of every turbine operated by small producers during that period. The model's "bottom-up" approach enabled analysis of individual owners' decisions to shut down, upgrade or add turbines over time, and simulated outcomes if government policies had been scaled back or were not implemented.

"Understanding the factors that influence individual decisions to invest in wind energy and how different policies can affect the timing of these decisions is important for policies both in countries that already have mature wind industries," the researchers wrote, "as well as in regions of the world that are earlier in the process of increasing renewable electricity generation (e.g. most of the U.S.)."

Denmark since the late 1970s has offered a feed-in tariff that guaranteed producers a fixed price per amount of wind energy generated, whether turbines were new or old. Since 1999, replacement certificates have incentivized upgrades.

Both policies significantly impacted small producers' shutdown and upgrade decisions and accelerated the development of Denmark's wind industry, the scholars concluded. Without them, the model showed most small-scale wind producers would have left the industry by 2011, concentrating production in larger wind farms.

However, the analysis determined that replacement certificates were far more cost-effective than the feed-in tariff in encouraging small producers to add or upgrade turbines, helping Denmark reduce its carbon emissions.

The study estimated the Danish government spent $3.5 billion on the feed-in tariff program over the study period, and as much as $114 million on the replacement certificates. Together, the two programs reduced carbon emissions by 57.4 million metric tons of carbon dioxide.

"One was just really expensive at doing it," Lin Lawell said. "Both the cost per metric ton of carbon dioxide avoided, and the cost per percentage point increase in payoff to the turbine owner, are much lower for the replacement certificate program."

For every million metric tons of carbon dioxide avoided, the researchers estimated the feed-in tariff cost Danish taxpayers $61.8 million, compared to $2.2 million or less for the replacement certificates.

Cook and Lin Lawell said their analysis offers lessons about the role of government policy in incentivizing the development of renewables and about which policies generate the most bang for the buck.

"Our application to the Danish wind industry," they wrote, "has important implications for the design of renewable energy policies worldwide."

TAMPA, Fla (Nov. 6, 2020) -- SARS-CoV-2, the respiratory virus that causes COVID-19, attacks the body in multiple steps. Gaining entry into cells deep within the lungs and hijacking the human host cell's machinery to churn out copies of itself are two of the earliest steps -- both essential for viral infection.

A new study offers insight into designing antiviral drugs against COVID-19 by showing that some existing compounds can inhibit both the main protease (Mpro), a key viral protein required for SARS-CoV-2 replication inside human cells, and the lysosomal protease cathepsin L, a human protein important for viral entry into host cells. The study, led by researchers at the University of South Florida Health (USF Health) Morsani College of Medicine and the University of Arizona College of Pharmacy, was published today in Science Advances.

"If we can develop compounds to shut down or significantly reduce both processes - viral entry and viral replication - such dual inhibition may enhance the potency of these compounds in treating the coronavirus infection," said study co-principal investigator Yu Chen, PhD, a USF Health associate professor of molecular medicine with expertise in structure-based drug design. "Metaphorically, it's like killing two birds with one stone."

The USF Health-University of Arizona (UA) collaborators built upon their previous work, which identified and analyzed several promising, existing antiviral drugs as candidates to treat COVID-19. All the candidates chosen to pursue target Mpro to block the replication of SARS-CoV-2 within human cells grown in the laboratory.

Two of the compounds, calpain inhibitors II and XII, did not show as much activity against Mpro as another drug candidate called GC-376 in biochemical tests. However, the calpain inhibitors, especially XII, actually worked better than GC-376 at killing SARS-CoV-2 in cell cultures, said lead author Michael Sacco, a doctoral student in Dr. Chen's laboratory.

"We figured if these calpain inhibitors were less effective at inhibiting the virus's main protease, they must be doing something else to explain their antiviral activity," Sacco said. They learned from research done by other groups, including collaborator and study co-principal investigator Jun Wang, PhD, of UA, that calpain inhibitors can block other proteases, including cathepsin L, a critical human host protease involved in mediating SARS-CoV-2 entry into cells.

In this latest study, the USF Health researchers used advanced techniques, particularly X-ray crystallography, to visualize how calpain inhibitors II and XII interacted with viral protein Mpro. They observed that the calpain II inhibitor fit as expected into the targeted binding sites on the surface of the SARS-CoV-2 main protease. Unexpectedly, they also discovered that the calpain XII inhibitor adopted a unique configuration - referred to as "an inverted binding pose" -- to tightly fit into Mpro active binding sites. (A snug fit optimizes the inhibitor's interaction with the targeted viral protein, decreasing the enzyme activity that helps SARS-CoV-2 proliferate.)

"Our findings provide useful structural information on how we can design better inhibitors to target this key viral protein in the future," Dr. Chen said.

Besides the increased potency (desired drug effect at a lower dose) of targeting both viral protease Mpro and human protease cathepsin L, another benefit of dual inhibitors is their potential to suppress drug resistance, Dr. Chen said.

SARS-CoV-2 can mutate, or change its targeted genetic sequence. These viral mutations trick the human cell into allowing the virus to attach to the cell's surface membrane and insert its genetic material, and can alter the shape of viral proteins and how they interact with other molecules (including inhibitors) inside the cell.

When the virus mutates so it can continue reproducing, it can become resistant to a particular inhibitor, reducing that compound's effectiveness. In other words, if the genetic sequence of the viral target (lock) changes, the key (inhibitor) no longer fits that specific lock. But let's say the same key can open two locks to help prevent COVID-19 infection; in this case the two locks are Mpro, the viral target protein, and cathepsin L, the human target protein.

"It's harder for the virus to change both locks (two drug targets) at the same time," Dr. Chen said. "So a dual inhibitor makes it more difficult for antiviral drug resistance to develop, because even if the viral protein changes, this type of compound remains effective against the human host protein that has not changed."

The USF Health-University of Arizona research team continues to fine-tune existing antiviral drug candidates to iMprove their stability and performance, and hopes to apply what they've learned to help design new COVID-19 drugs. Their next steps will include solving how calpain inhibitors interact chemically and structurally with cathepsin L.

JUPITER, FL--A new strategy for treating a variety of diseases known as RNA-repeat expansion disorders, which affect millions of people, has shown promise in proof-of-principle tests conducted by scientists at Scripps Research.

The results suggest that someday, a handful of well-targeted drugs might be able to treat the more than 40 human disorders--including Huntington's disease and variants of amyotrophic lateral sclerosis (ALS)--that arise from RNA-repeat expansions.

"This study lays a foundation for the development of drugs that can address multiple repeat-expansion diseases by targeting shared abnormal structures on their RNAs," says the study's principal investigator Matthew Disney, PhD, professor of chemistry at Scripps Research.

In RNA-repeat expansion diseases, mutant genes contain excess DNA in the form of dozens or even hundreds of repeating short strings of DNA "letters." In cells where these mutant genes are active, that DNA is copied out into RNA molecules on the way to being translated into proteins. The resulting abnormal RNAs can cause trouble in a variety of ways, such as by folding up into structures that are toxic to cells.

In the study, published in Cell Chemical Biology, the scientists showed that a potential drug molecule they developed can neutralize the toxic RNA that causes two distinct repeat-expansion disorders, myotonic dystrophy 1 (DM1) and Fuchs endothelial corneal dystrophy (FECD). In the latter case, it can do so by an unexpected but powerful mechanism.

Genetic diseases in dire need of a treatment

DM1 is estimated to affect about 140,000 people in the United States. It can manifest anywhere from infancy to adulthood. And while it doesn't always shorten lifespan, it often brings a debilitating set of symptoms including muscle weakness and pain, cataracts, and respiratory and gastrointestinal problems. The disorder is caused by a mutant copy of a gene called DMPK, whose RNAs contain dozens to hundreds of repeats of the RNA letters "CUG."

FECD, which causes progressive damage to the cornea of the eye that often necessitates corneal transplantation, has a relatively high prevalence; studies suggest it manifests in at least several percent of Caucasian people older than 50. The disorder is caused by a mutant version of a gene called TCF4, whose RNAs also contain abnormally long CUG repeats.

These disorders arise from different mutant genes, and consequently appear in different cell types, but involve virtually the same toxic mechanism: In each case, the inclusion of an abnormally long sequence of CUG repeats causes the RNA copied from the gene to form structures that are "sticky" to certain other proteins in the cell, and effectively capture them--preventing them from doing their jobs in the cell. The depletion of one of these captured proteins, MBNL1, is a particularly important cause of cell damage and symptoms in DM1 and FECD.

Encouraging results in pre-clinical tests

For the new study, Disney and his team used advanced computational methods to design a small organic molecule that selectively binds to the abnormal CUG-expansion RNAs found in MD1- and FECD-affected cells, preventing these RNAs from capturing MBNL1.

To evaluate and improve the molecule, the team used a unique tool they had developed previously, Competitive Chem-CLIP, which allowed them to test their molecule's ability to selectively recognize toxic CUG-expansion structures.

The team showed that in cultured cells derived from patients with DM1, as well as in an animal model of the disease, their improved designer molecule successfully reduced the depletion of MBNL1 and the loss of its function.

In FECD cells, the drug molecule also worked to prevent signs of disease, but this time by a different and potentially more powerful mechanism. In FECD cells, the disease-causing gene mutation occurs in a non-coding part of the gene called an intron. Normally, introns when copied into RNA are cut out of the RNA almost immediately and degraded by disposal systems in the cell. In FECD, the presence of the CUG-repeat expansion prevents the affected intron from being excised. However, Disney and his team found that their molecule allows that excision to take place, so that the abnormal RNA element is not just blocked but destroyed.

Targeting toxic RNAs with small organic molecules that can be put into pill form has generally been very challenging, so far, Disney notes, but the finding in this study points to the promising possibility of using such molecules not just to block bad RNAs but to trigger their destruction.

"If a drug causes a toxic RNA to be destroyed instead of merely blocking it, then the effect should be longer lasting," he says.

Having performed their proof-of-principle demonstration, he and his team, which includes a startup biotech company, Expansion Therapeutics, are continuing to develop the molecule tested in the study as a potential drug treatment for DM1 and FECD.

The researchers also are taking a similar approach in developing potential drug treatments for RNA repeat-expansion diseases involving CAG repeats, which include the progressive and fatal neurological disorder known as Huntington's disease.

Disney notes that his group's computational approach to drug discovery, versus traditional methods involving the screening of large sets, or libraries, of molecules, gives them a big advantage: "Our ability to do computation-aided design allows us to get initial compounds quickly, and quickly test them," Disney says.

High deductible health plans (HDHPs) have become much more common among all racial/ethnic and income groups, but the health savings accounts (HSAs) that make these plans potentially workable are far less common among Black, Hispanic, and lower-income enrollees--and the gap is growing.

That's according to a new Boston University School of Public Health (BUSPH) study published in the November issue of the journal Health Affairs, the first to examine these trends.

"This is a deeply concerning inequity that is getting worse and worse with each passing year," says study senior and corresponding author Dr. Megan B. Cole, assistant professor of health law, policy & management at BUSPH.

HDHPs offer lower premiums but leave patients potentially paying thousands of dollars out-of-pocket for healthcare before insurance kicks in, making it difficult or even impossible to afford needed care. So, HDHPs are often coupled with an HSA, where enrollees and their employers may contribute tax-exempt dollars to help pay for those out-of-pocket healthcare costs.

The first-of-its-kind study delves into the racial/ethnic and income-level trends in HDHP enrollment with and without HSAs, something missed by just looking at whether people have insurance or not.

"The ACA effectively reduced income and racial disparities in insurance coverage, but we don't know very much about disparities in underinsurance, or having coverage and not being able to pay for care," says study lead author Dr. Jacqueline Ellison, a postdoctoral researcher at Brown University School of Public Health.

According to the study's findings, "patients who would be the most likely to benefit from the financial protection of an HSA are increasingly the least likely to have an HSA, which further exacerbates the health inequities already faced by Black, Hispanic, and low-income adults," Cole says.

In a previous study, Cole and Ellison found that Black cancer survivors on HDHPs face more cost-related barriers to care than white cancer survivors on the same plans, including needing to skip a medication or delay a refill to save money, and not being able to see a specialist. The new study suggests racial disparities in having an HSA may be a big part of the reason.

"These consumer-oriented approaches to cost containment are disproportionately impacting marginalized populations that already experience financial barriers to care," Ellison says.

For the new study, Cole, Ellison, and co-author Paul Shafer, assistant professor of health law, policy & management at BUSPH, used data from the National Health Interview Survey from 2007-2018.

They found that HDHP enrollment skyrocketed during that time period, with similar rates of increase for all racial/ethnic and income groups. For example, among the lowest-income privately-insured adults, HDHP enrollment increased from 17% in 2007 to 40% by 2018.

"This means that by 2018, two in five low-income privately-insured adults often had to pay thousands of dollars in out of pocket costs before their health insurance would cover most of the cost, despite the fact that this represents a really substantial portion of their total income," Cole says. "While these lower-income patients may technically be insured, when they need any type of health care that is not otherwise exempt from cost-sharing, it is effectively like being uninsured."

HSAs were more common among high- and middle-income HDHP enrollees than low-income enrollees, and among white enrollees than Black and Hispanic enrollees--and these gaps widened between 2007 and 2018.

"In the short term, it's critical that we implement policies that not only tackle uninsurance but that also tackle underinsurance, particularly for low-income and racial/ethnic minority groups," Cole says. "This may include expanding Medicaid in current non-expansion states, expanding Marketplace cost-sharing subsidies to persons under the federal poverty line, and creating more substantial tax incentives for employers to subsidize cost-sharing for their lower-income employees."

But most importantly, Cole says, "we need policies that address the root causes of these inequities--namely, racism and structural inequalities, which lead to differential employment opportunities (meaning employers that are more versus less likely to contribute to an HSA), wealth, and abilities to save."