Culture

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."

A new Boston University School of Public Health study of the first four months of America's coronavirus epidemic, published in the journal Nature Human Behaviour, shows that physical distancing (also called "social distancing") policies had little effect on lower income people still needing to leave their homes to go to work--but does show them staying home when they could.

"If lower-income people were simply ignoring the trend towards physical distancing, we would have expected them to continue going to places like supermarkets, liquor stores, and parks at the same rates as before. Instead, their visits dropped at almost the same rates as the very highest-income group," says study lead author Dr. Jonathan Jay, assistant professor of community health sciences at BUSPH.

"This indicates that lower income people were just as aware and motivated as higher-income people to protect themselves from COVID-19, but simply couldn't stay home as much because they needed to go to work," he says.

Jay and colleagues used anonymized mobility data from smartphones in over 210,000 neighborhoods (census block groups) across the country, each neighborhood categorized by average income. They were able to see whether people from these neighborhoods stayed home, left home and appeared to be at work--staying at another location for at least three hours during typical working hours, or making multiple stops that looked like delivery work. The researchers also tracked movement to "points of interest": beer, wine and liquor stores; carryout restaurants; convenience stores; hospitals; parks and playgrounds; places of worship; and supermarkets.

"The difference in physical distancing between low- and high-income neighborhoods during the lockdown was just staggering," says study co-author Dr. Jacob Bor, assistant professor of global health and epidemiology at BUSPH.

"While people in high-income neighborhoods retreated to home offices, people in low-income neighborhoods had to continue to go to work--and their friends, family, and neighbors had to do the same," he says. "Living in a low-income neighborhood is likely a key risk factor for COVID-19 infection."

To analyze the role that policies played in these mobility patterns, the researcher used the COVID-19 U.S. State Policy Database (CUSP), a project led by study co-author Dr. Julia Raifman, assistant professor of health law, policy & management at BUSPH.

They found that the huge drop in mobility early in March had little to do with state policy, following similar patterns in different states regardless of when their orders went into effect. When state policies did go into effect, they modestly decreased mobility further--but did nothing to close the gap between low- and high-income neighborhoods.

"The orders did not have the effect of making it easier for lower-income people to stay home," Jay says. But they did stay home to the degree possible, visiting non-work non-home locations less--which counters a major narrative about how different groups of people have responded to COVID, Jay says. "Early in the pandemic, there was a lot of talk about 'non-compliance,' and it was rarely directed at the people with the most power and privilege," he says.

"We found strong evidence of compliance among the people who are most economically marginalized, which because of structural racism disproportionately includes people of color. As the pandemic has played out, the evidence of poor safety practices at the very highest levels of power has become more clear.

"Still, it's deeply troubling that throughout the pandemic, staying home has been a choice for some people and not for others."

The researchers say that closures are an important tool for states and cities to prevent the spread of the coronavirus, but that they need to be accompanied by other policies that make it easier for frontline workers to protect themselves.

"That people living in low-income households are more likely to face exposure to COVID-19 at work increases the importance of complementary policies, such as mask requirements in indoor spaces, that protect essential workers from COVID-19," Raifman says.

"One of the most important arguments for mask mandates is that they protect the folks who are in public spaces not because they want to be, but because showing up is how they make ends meet," Jay says. He also points to "policies that make it easier to work from home, stay home sick, and not to take a risky new job just to put food on the table."

However, Jay says, policies that make it easier to stay home only help if people have homes. As a wave of evictions and foreclosures sweeps the country, he says extending moratoriums and enacting other housing policies continue to be an important part of the picture.

MIAMI--A new study by researchers at the University of Miami (UM) Rosenstiel School of Marine and Atmospheric Science projects an increase in Florida's late summertime rainfall with rising Atlantic Ocean temperatures.

Scientists have known for years that Florida receives more rainfall in decades when North Atlantic waters are warmer than average, but the UM research team wanted to learn more about this interaction to help communities prepare for a wetter future. This study showed that ocean temperatures are most influential on Florida precipitation in late summer, during the region's highest high tide events.

The researchers used a suite of climate models to show that the link between ocean temperatures and rainfall only develops as a result of human influences on the climate system, such as greenhouse gas emissions and industrial pollution.

"We know that humans are continuing to make North Atlantic waters warmer, so we expect an increase in late summer rainfall in Florida in the future," said Jeremy Klavans, a PhD student at the UM Rosenstiel School and lead author of the study.

The study, titled "Identifying the Externally?forced Atlantic Multidecadal Variability Signal through Florida Rainfall" was published in the early online edition of the American Geophysical Union's journal Geophysical Research Letters. The study's coauthors include: Jeremy Klavans, Amy Clement and Lisa Murphy from the UM Rosenstiel School; and Honghai Zhang, a UM Rosenstiel School alumni currently at Columbia University's Lamont?Doherty Earth Observatory.

AMHERST, Mass. - In a new paper with results that senior author Eric Strieter at the University of Massachusetts Amherst calls "incredibly surprising," he and his chemistry lab group report that they have discovered how an enzyme known as UCH37 regulates a cell's waste management system.

Strieter says, "It took us eight years to figure it out, and I'm very proud of this work. We had to develop a lot of new methods and tools to understand what this enzyme is doing."

As he explains, a very large protease called a proteasome is responsible for degrading the vast majority of proteins in a cell; it may be made up of as many as 40 proteins. It has been known for more than 20 years that UCH37 is one of the regulatory enzymes that associates with the proteasome, he adds, "but no one understood what it was doing."

It turns out that the crux of the whole process, he adds, is how complicated modifications in a small protein called ubiquitin can be. "In addition to modifying other proteins, ubiquitin modifies itself resulting in a wide array of chains. Some of these chains can have extensive branching. We found that UCH37 removes branchpoints from chains, allowing degradation to proceed."

Writing this week in Molecular Cell, he and first author and Ph.D. candidate Kirandeep Deol, who led and conducted the experiments, with co-authors Sean Crowe, Jiale Du, Heather Bisbee and Robert Guenette, discuss how they answered the question. The work was supported by the NIH's National Institute of General Medical Sciences.

This advance could eventually lead to a new cancer treatment, Strieter says, because cancer cells need the proteasome to grow and proliferate. "Many cancer cells are essentially addicted to proteasome function," he points out. "Its cells produce proteins at such a fast rate that mistakes are made, and if these are not cleared out, cells can't function. Since UCH37 aids in clearing out proteins, it could be a useful therapeutic target to add to the proteasome inhibitors that have already been successful in the clinic."

To begin their years-long process, Strieter says, "we had to come up with a way to generate a wide variety of ubiquitin chains that would represent the potential diversity in a cell. Using that new library of ubiquitin chains allowed us to interrogate the activity of UCH37 in a controlled setting. That series of experiments gave us the first clue that this enzyme was doing something unique."

Another new method they developed uses mass spectrometry to characterize the architecture of ubiquitin chains in complex mixtures. "This allowed us to see that the activity we discovered with our library of substrates was also present in a more heterogenous mixture," Strieter says. Finally, the chemists used the CRISPR gene editing tool to remove UCH37 from cells to measure the impact of UCH37 on proteasome-mediated degradation in vitro and in cells.

This technique led to one more surprise. "Instead of acting as expected and opposing the degradation process, it turned out that UCH37 was removing branchpoints from ubiquitin chains to help degrade proteins," Strieter says. "You would think that by removing the signal for degradation that degradation would be impaired," he adds, "but it didn't work that way."

In future experiments, Strieter and colleagues hope to further explore the degradation process and learn in more detail how UCH37 manages to regulate cellular function.

The effect of dopaminergic medication on the learning abilities of patients with Parkinson's disease turns out to be linked to the presence of tremor symptoms. In patients who do not experience tremor, dopaminergic medication improves the ability to learn from rewards (reinforcement learning). Remarkably, the medication brings no benefit in reward learning to patients who do exhibit tremor. These were the results from a new study by brain researchers at the Donders Institute of Radboud University and Radboud university medical center, published on 6 November in the scientific journal Brain.

"It is somewhat surprising that until now, studies of cognition in Parkinson's disease never assessed the distinction between patients who exhibit tremor and those who do not", says Hanneke den Ouden, brain researcher at Radboud University. "Our study shows that there is a link between problems with motor skills and problems with cognition in patients with Parkinson's disease."

Learning abilities and Parkinson's disease
Most patients with Parkinson's disease experience tremor -shaking in an arm or leg. Only one in four patients does not experience these symptoms. In addition, many patients experience mental issues. Due to a decrease in dopamine, a chemical messenger molecule that occurs in the brain, patients with Parkinson's disease become less sensitive to learning through rewards.

A large number of prior studies have shown that this learning disorder can be remedied by administering dopaminergic medication. It remained a mystery, however, why medication had no effect in many patients. The study of the Radboud researchers reveals that this improvement through medication only occurs in patients who do not experience tremor.

Presence and absence of tremor

"We observed that, with medication, patients without tremor got better at a task in which they had to learn to push a button in order to receive a reward (points). This result fully agrees with prior research. However, remarkably enough, patients with tremor would exhibit an opposite effect", Den Ouden says. "Importantly, patients without tremor generally exhibit a faster deterioration of the cognitive abilities and are more likely to develop dementia, for example."

"The fact that we only observe results from earlier studies in patients without tremor suggests that prior studies only included these patients. This would make sense, as it is easier for patients without tremor to participate in an experiment. However, it is important to realise that three out of four patients actually do experience tremor, and our study shows that the medication has a different effect on these patients. We see this as a major warning: Always be aware of the diversity of patients in your study, as you might otherwise draw the wrong conclusions."

Predictive value

According to the researchers, it is crucial to improve our understanding of such patient diversity. "This study tells us that the dopamine systems of Parkinson's disease patients with and without tremor are affected in different ways, and that this goes beyond the level of just motor problems, affecting cognition as well", according to co-author Rick Helmich, neurologist at Radboud university medical center. "Whether someone experiences tremor or not might therefore potentially have a significant predictive value regarding the effectiveness of medication in the cognitive domain. However, more and larger studies are needed before this can be confirmed."

Subarachnoid haemorrhage (SAH), the most fatal of all cerebrovascular disturbances, results in death for 40-50% of patients suffering from the condition in the first months after the haemorrhage.

The annual incidence of SAH is considered to be six to seven cases per 100,000 people globally. Due to its rarity, the effects of this cerebral haemorrhage type have been considered very minor on the population level. Furthermore, it has been previously estimated that no more than 4% of all deaths caused by strokes are caused by SAH.

Although the disease has been known to be most prevalent among the middle-aged population, it has been impossible to reliably determine the share of deaths among the working-age population caused by subarachnoid haemorrhage: As many as a quarter of SAH patients die before reaching the hospital, and many countries record the deaths of such SAH patients according to more likely causes, for example, as sudden cardiac deaths. If an autopsy is not conducted in the case of sudden death, the cause of death and the possibility of SAH remain undetermined.

In Finland, autopsies are mandated by law to be conducted to determine the cause of death in cases of sudden death. This has enabled Finnish researchers to determine, for the first time, the share of deaths caused by subarachnoid haemorrhage in all deaths of middle-aged people.

The registry study, which was recently published in the Journal of Neurology, Neurosurgery and Psychiatry (JNNP), included precise details on the cause of death for almost 200,000 individuals between the ages of 40 and 65 who have died in Finland in the past 20 years.

The results indicate that, in middle-aged women, subarachnoid haemorrhage was the 12th most common cause of death from among all deaths and the most common type of stroke death throughout the entire 20-year study period.

More middle-aged women die from subarachnoid haemorrhage than in car crashes or from cerebral infarctions

According to Ilari Rautalin, the principal investigator, the finding is a surprise in the light of previous literature.

"In middle-aged women in particular, the number of SAH deaths clearly exceeds that of deaths caused by cerebral infarctions, deaths from several cancers and, for example, car crashes and other accidents," says Rautalin, Bachelor of Medicine, who is also a PhD student.

As SAH is a disease primarily caused by smoking and high blood pressure, it is largely preventable.

"Investment in healthy lifestyles would cut down significantly the share of premature deaths among the working-age population," says Rautalin.

The other two members of the research group and authors of the article, Miikka Korja, docent and neurosurgeon at Helsinki University Hospital, and Jaakko Kaprio, professor of genetic epidemiology at the University of Helsinki, also emphasise the importance of a healthy lifestyle.

According to them, premature deaths among the working-age population could be effectively prevented, for example, by encouraging people to not smoke and by preventing hypertension as well as by providing them with good care.

Extensive registers provide information on fatal cerebral haemorrhage

The study of deaths among Finnish middle-aged people is based on population-level registers maintained by Statistics Finland and the Finnish Institute for Health and Welfare. The registers make it possible to carry out comprehensive studies on subarachnoid haemorrhage in Finland.

"There have been digital health registers in use in Finland from the 1960s. Finland's high-quality healthcare system and a number of related top-level registers that cover the entire population are the reason why Finland has produced so many groundbreaking studies on subarachnoid haemorrhage," says Docent Korja, who heads the group.

Recently, the group published a finding on the effect of smoking on subarachnoid haemorrhage, and they have now uncovered new information on the share of SAH deaths among middle-aged people. However, the significance of several risk factors potentially associated with SAH remains unknown.

"The topic is in urgent need of high-quality research evidence based on the health records of hundreds of thousands of individuals and decades-long monitoring periods," Rautalin says.

What The Study Did: The association between patient demographic characteristics and socioeconomic status and engagement in telemedicine during the COVID-19 pandemic is examined in this observational study.

Authors: Samantha Tam, M.D., M.P.H., of the Henry Ford Health System and Henry Ford Cancer Institute in Detroit, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamaoto.2020.3052)

Editor's Note: The article includes conflict of interest disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

What The Study Did: National health record data were used to examine whether the rate of positive tests for variants of the BRCA gene that increase the risk for certain cancers changed among older women in the United States between 2008 and 2018.

Authors: Fangjian Guo, M.D., Ph.D., of the University of Texas Medical Branch at Galveston, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2020.24358)

Editor's Note: The article includes funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.