Culture

When it wants to promote democracy in other countries, the US has several options, ranging from foreign democracy aid and economic sanctions to military intervention. But, what do North Americans think about these different strategies for promoting democracy? What features of authoritarian countries determine their preferences when wanting one or another form of intervention?

The opinion of US citizens on foreign policy is very important because it often influences the type of tools that their leaders end up using when it comes to promoting democracy abroad and the type of state in which they are applied. This subject has been little studied, and often leads to major dilemmas within the US government and public controversy surrounding whether to intervene or not, and if so, how.

"In our work, we examine in what kind of autocracies North Americans are most likely to support the use of military force or economic sanctions and in what kind of regimes they are more likely to provide economic aid for democracy".

Research conducted by the researchers Abel Escribà-Folch and Toni Rodon, at the UPF Department of Political and Social Sciences, together with Laia H. Muradova, of the Catholic University of Leuven (Belgium), sheds light on these questions. "In our work, we examine in what kind of autocracies North Americans are most likely to support the use of military force or economic sanctions and in what kind of regimes they are more likely to provide economic aid for democracy", they explain.

The study by the authors who recently signed an article in the blog American Politics and Policy (USCenter, London School of Economics), based on their article published last August in Foreign Policy Analysis (Oxford University Press), was carried out based on a conjoint experimental survey. Its goal is to help determine what shapes these preferences of the North Americans and they conclude that the citizens of this country give greater support to coercive measures (military interventions and sanctions) in highly personalistic and consolidated autocratic, mostly Muslim countries, that do not hold elections and are not US allies. However, support for giving foreign aid is greater for autocracies with (strategic or financial) ties with the US and that hold multi-party elections.

However, the authors add that "experience shows that intervening in countries with these characteristics often leads to the growth and progress of democracy". In addition, the authors note that although the US has punished some countries after human rights abuse, by invading countries and imposing sanctions (e.g., Haiti, Iraq, Cuba), it has refrained from doing so in others, despite the presence of similar violence against human rights (e.g., Saudi Arabia, Turkey, Russia).

A survey to determine North Americans' foreign policy preferences

The survey, conducted on a sample of nearly 1,500 US citizens, includes an experiment that randomly varies nine different characteristics of the potential targets and estimates the effects of each of these characteristics on people's opinions about the instruments for promoting democracy abroad. This design allows the authors to test the effect of an institutional feature (for example, a regime governed by a personalistic leader, such as the former leader of Iraq, Saddam Hussein or Russian president, Vladimir Putin).

It was shown that these countries, whose regimes are a far cry from those that have civilian governments, elected by the citizens and with institutional balances (such as the US) are perceived as more threatening by US citizens, and would lead to adopting more coercive foreign policy instruments (military intervention and sanctions). And the opposite is true; countries that seem more legitimate, that hold elections with more than one party and have ties with the US, would be rewarded with a positive incentives, such as foreign democracy aid.

In addition to the institutional characteristics, the target country's alliance with the US and military force are important drivers of public support for war. US respondents responded that they would support a war when the regime is not an ally of the United States; and this support decreases significantly when the country is militarily strong.

The cases of Saudi Arabia and Egypt illustrate that despite having certain characteristics which, in theory, would push citizens to favour more coercive measures, both are US allies, which is an important attribute that, in itself, is capable of reducing support for punitive measures against these regimes.

"Our results show that people are more likely to support tough measures against personalistic autocratic regimes that do not hold elections and do not have ties to the US, such as Iraq and Libya. However, as we know from experience, these measures have proved ineffective, and have often not led to democracy but to civil war or state failure", the researchers conclude.

HOUSTON - (Nov. 17, 2020) - A new study from researchers at Rice University found that Americans' attitudes about gun ownership are impacted by the gender and race of firearms' potential owners.

"Race-gender bias in white Americans' preferences for gun availability" will appear in an upcoming edition of the Journal of Public Policy. The study is the first to examine how race and gender together shape attitudes toward gun availability.

The study was conducted by Matthew Hayes, an assistant professor of political science at Rice; David Fortunato, an associate professor at the University of California, San Diego's School of Global Policy and Strategy; and Matthew Hibbing, an associate professor of political science at the University of California, Merced.

The researchers randomly assigned racially and gender-distinct names to study participants who were categorized by race, gender and political affiliation. Then they asked the survey subjects if they would support that person's right to own firearms to protect themselves and their family.

The survey not only found evidence of both racial and gender bias, it also showed Republicans were more likely to support gun rights than Democrats. White Democrats were much more willing to support a white woman's right to own a firearm than they were any other group. Republicans showed less support for a Black man owning a firearm than they did any other racial or gender group.

Hayes said he and fellow political scientists have long believed that gender and race should be considered together when evaluating opinions about gun ownership. The overall findings were not unexpected, he said, but there were some surprises, including how Democrats felt about white women owning guns, the first time those feelings have been conveyed in a scientific study.

Hayes and his fellow researchers also hope the study will shed light on biases among elected officials.

"I think these findings might help us get public policies that are better crafted for people who might be vulnerable or might tend not to get represented," he said. "The Republican Party, which has historically been stronger in protecting Second Amendment rights, needs to be aware of the racial and gender biases that exist regarding gun rights -- in theory, they should be just as willing to support the rights of African Americans as anyone else. As for Democratic lawmakers who are more likely to support gun control, they should be aware of how the restrictions they support will impact groups, such as women, who might want to be able to protect themselves.

"We know that a lot of firearm homicides in this country are related to domestic violence," Hayes continued. "The safety of women, who are much more likely to be victims of domestic violence, should factor into our gun control policymaking as well, absolutely."

A small drone takes a test flight through a space filled with randomly placed cardboard cylinders acting as stand-ins for trees, people or structures. The algorithm controlling the drone has been trained on a thousand simulated obstacle-laden courses, but it's never seen one like this. Still, nine times out of 10, the pint-sized plane dodges all the obstacles in its path.

This experiment is a proving ground for a pivotal challenge in modern robotics: the ability to guarantee the safety and success of automated robots operating in novel environments. As engineers increasingly turn to machine learning methods to develop adaptable robots, new work by Princeton University researchers makes progress on such guarantees for robots in contexts with diverse types of obstacles and constraints.

"Over the last decade or so, there's been a tremendous amount of excitement and progress around machine learning in the context of robotics, primarily because it allows you to handle rich sensory inputs," like those from a robot's camera, and map these complex inputs to actions, said Anirudha Majumdar, an assistant professor of mechanical and aerospace engineering at Princeton.

However, robot control algorithms based on machine learning run the risk of overfitting to their training data, which can make algorithms less effective when they encounter inputs that differ from those they were trained on. Majumdar's Intelligent Robot Motion Lab addressed this challenge by expanding the suite of available tools for training robot control policies, and quantifying the likely success and safety of robots performing in novel environments.

In three new papers, the researchers adapted machine learning frameworks from other arenas to the field of robot locomotion and manipulation. They turned to generalization theory, which is typically used in contexts that map a single input onto a single output, such as automated image tagging. The new methods are among the first to apply generalization theory to the more complex task of making guarantees on robots' performance in unfamiliar settings. While other approaches have provided such guarantees under more restrictive assumptions, the team's methods offer more broadly applicable guarantees on performance in novel environments, said Majumdar.

In the first paper, a proof of principle for applying the machine learning frameworks, the team tested their approach in simulations that included a wheeled vehicle driving through a space filled with obstacles, and a robotic arm grasping objects on a table. They also validated the technique by assessing the obstacle avoidance of a small drone called a Parrot Swing (a combination quadcopter and fixed-wing airplane) as it flew down a 60-foot-long corridor dotted with cardboard cylinders. The guaranteed success rate of the drone's control policy was 88.4%, and it avoided obstacles in 18 of 20 trials (90%).

The work, published Oct. 3 in the International Journal of Robotics Research, was coauthored by Majumdar; Alec Farid, a graduate student in mechanical and aerospace engineering; and Anoopkumar Sonar, a computer science concentrator from Princeton's Class of 2021.

When applying machine learning techniques from other areas to robotics, said Farid, "there are a lot of special assumptions you need to satisfy, and one of them is saying how similar the environments you're expecting to see are to the environments your policy was trained on. In addition to showing that we can do this in the robotic setting, we also focused on trying to expand the types of environments that we could provide a guarantee for."

"The kinds of guarantees we're able to give range from about 80% to 95% success rates on new environments, depending on the specific task, but if you're deploying [an unmanned aerial vehicle] in a real environment, then 95% probably isn't good enough," said Majumdar. "I see that as one of the biggest challenges, and one that we are actively working on."

Still, the team's approaches represent much-needed progress on generalization guarantees for robots operating in unseen environments, said Hongkai Dai, a senior research scientist at the Toyota Research Institute in Los Altos, California.

"These guarantees are paramount to many safety-critical applications, such as self-driving cars and autonomous drones, where the training set cannot cover every possible scenario," said Dai, who was not involved in the research. "The guarantee tells us how likely it is that a policy can still perform reasonably well on unseen cases, and hence establishes confidence on the policy, where the stake of failure is too high."

In two other papers, to be presented Nov. 18 at the virtual Conference on Robot Learning, the researchers examined additional refinements to bring robot control policies closer to the guarantees that would be needed for real-world deployment. One paper used imitation learning, in which a human "expert" provides training data by manually guiding a simulated robot to pick up various objects or move through different spaces with obstacles. This approach can improve the success of machine learning-based control policies.

To provide the training data, lead author Allen Ren, a graduate student in mechanical and aerospace engineering, used a 3D computer mouse to control a simulated robotic arm tasked with grasping and lifting drinking mugs of various sizes, shapes and materials. Other imitation learning experiments involved the arm pushing a box across a table, and a simulation of a wheeled robot navigating around furniture in a home-like environment.

The researchers deployed the policies learned from the mug-grasping and box-pushing tasks on a robotic arm in the laboratory, which was able to pick up 25 different mugs by grasping their rims between its two finger-like grippers -- not holding the handle as a human would. In the box-pushing example, the policy achieved 93% success on easier tasks and 80% on harder tasks.

"We have a camera on top of the table that sees the environment and takes a picture five times per second," said Ren. "Our policy training simulation takes this image and outputs what kind of action the robot should take, and then we have a controller that moves the arm to the desired locations based on the output of the model."

A third paper demonstrated the development of vision-based planners that provide guarantees for flying or walking robots to carry out planned sequences of movements through diverse environments. Generating control policies for planned movements brought a new problem of scale -- a need to optimize vision-based policies with thousands, rather than hundreds, of dimensions.

"That required coming up with some new algorithmic tools for being able to tackle that dimensionality and still be able to give strong generalization guarantees," said lead author Sushant Veer, a postdoctoral research associate in mechanical and aerospace engineering.

A key aspect of Veer's strategy was the use of motion primitives, in which a policy directs a robot to go straight or turn, for example, rather than specifying a torque or velocity for each movement. Narrowing the space of possible actions makes the planning process more computationally tractable, said Majumdar.

Veer and Majumdar evaluated the vision-based planners on simulations of a drone navigating around obstacles and a four-legged robot traversing rough terrain with slopes as high as 35 degrees -- "a very challenging problem that a lot of people in robotics are still trying to solve," said Veer.

In the study, the legged robot achieved an 80% success rate on unseen test environments. The researchers are working to further improve their policies' guarantees, as well as assessing the policies' performance on real robots in the laboratory.

Some pharmaceutical companies have received criticism for engaging in illegal activities, such as providing kickbacks and bribes, knowingly shipping adulterated or contaminated drugs to pharmacies, and marketing drugs for unapproved uses. This study examined financial penalties for illegal activities among large pharmaceutical firms in relation to annual revenues.

Methods

We collected data on financial penalties for pharmaceutical firms listed on the Global 500 or Fortune 1000 lists using procedures similar to Almashat et al.1 Consistent with prior research,2 we analyzed all firms that met inclusion criteria and appeared on the list for 7 years or more. All instances of financial penalties from state and federal settlements between January 2003 and December 2016 were obtained from the US Department of Justice, the US Securities and Exchange Commission, the US Environmental Protection Agency, and states' attorneys general. Each settlement included the penalty amount and described the scope, type, and duration of the associated illegal activity. We secured missing data through Freedom of Information Act requests. Financial penalties were attributed to the settlement year.

To adjust for inflation, we calculated the cumulative dollar value of each firm's financial penalties for each year and applied the Bureau of Economic Analysis' Gross Domestic Product Deflator to convert the cumulative amount to 2016 dollars. When firms merged with or were acquired by other firms during the study period, we attributed all penalty settlements, both before and after acquisition, to the firm that engaged in the illegal activity. We calculated the mean penalty amount by dividing the total dollar value of each company's financial penalties by the total number of penalties levied during the study period. We calculated the total dollar value of each company's financial penalties as a percentage of their total revenues during the study period using data from Compustat, Mergent Online, Edgar Direct, and annual reports filed with the Securities and Exchange Commission. We provided the mean duration of illegal activity for penalties settled during the study period. We used content analysis to classify each settlement into 1 or more types of illegal activity and summarized the frequency by firm and illegal activity type.

Results

Among 26 firms in our sample, 22 (85%) had financial penalties for illegal activities. The combined dollar value of financial penalties totaled $33 billion for 2003 to 2016. Eleven firms with financial penalties exceeding $1 billion in inflation-adjusted dollars accounted for $28.8 billion (88%) of the total penalties (Table 1). The firms with the highest penalties as a percentage of revenues (ie, >1%) were Schering-Plough, GlaxoSmithKline, Allergan, and Wyeth; the number of penalties for these firms varied between 1 (Allergan) and 27 (GlaxoSmithKline). Four firms had financial penalties that totaled less than $80 million and no more than 2 penalty settlements (Actavis [Watson], Roche Group, Genzyme, and Perrigo). All but 1 firm (Perrigo) engaged in illegal activities associated with penalties for 4 or more years. An additional 4 firms received no financial penalties for illegal activities during this period. The most common types of illegal activity involving penalties (Table 2) were pricing violations, off-label marketing, and kickbacks. The firms with the greatest variety in the types of illegal activities involving penalties were GlaxoSmithKline, Bristol Myers Squibb, and Merck. Three firms (Actavis, Allergan, and Perrigo) had penalties limited to a single violation type.

Discussion

Among the large pharmaceutical companies included in this study, 85% had evidence of financial penalties for illegal activities. Given the scope and nature of the illegal activities involving financial penalties, physicians and regulators should exhibit vigilance over the activities of large pharmaceutical firms. Four firms were not found to have penalties for illegal activities during the sample period. This may indicate an ability for illegal activity to be undetected, although these firms may instead have effective ethics and compliance programs.3,4

Limitations of the study include focus on the largest firms, exclusion of class-action settlements and penalties by non-US governments, and the possibility that some settlements were missed. Also, only settlements from a limited time period were examined; whether these data reflect current activities of pharmaceutical companies or whether financial penalties for illegal activities have increased or decreased more recently could not be determined. Other industries also engage in illegal activities, but a comparative analysis is beyond the scope of this study.

Oil droplets can be made to act like predators, chasing down other droplets that flee like prey. The behavior, which is controlled by chemical signaling produced by the droplets, mimics behavior seen among living organisms but, until now, had not been recreated in synthetic systems. This tunable chemical system could potentially serve a model to help understand interactions in many-body systems such as schools of fish, bacterial colonies, or swarms of insects.

An international team of researchers led by Penn State scientists describe the system in a paper published November 16, 2020 in the journal Nature Chemistry.

"By controlling the chemistry of the oil droplets, we can create a system in which the droplets behave actively and communicate with each other through chemical gradients," said Lauren Zarzar, assistant professor of chemistry at Penn State and the leader of the research team. "The exciting thing that we found is that you can design a system of droplets that exhibit 'non-reciprocal' interactions. One droplet is attracted to the other, while the other is repelled, similar to the behavior of predator and prey."

The researchers place microscale droplets of the two different oils into a solution of water and a surfactant--a compound commonly found in soaps that lowers the surface tension of liquids. One of the oils dissolves more easily in the surfactant solution causing those droplets to emit a chemical gradient of oil molecules into its surroundings. Droplets are repelled by the dissolved oil.

"Initially this cloud of oil around the droplets is basically symmetrical and the droplets don't move," said Caleb Meredith, a graduate student at Penn State and co-first author of the paper. "But what we discovered is that the prey droplets can actually uptake some of the oil released by the predator droplets, setting up a source-sink exchange of oil between the droplets. When the droplets get close enough, it creates an asymmetry in the chemical gradient between the two droplets and causes the predator droplet to move towards the prey, setting up a chase."

The asymmetry of the oil chemical gradient generated by the source and sink causes a difference in the surface tension across the surface of both the predator and prey droplets. The gradient causes the predator droplet (source) to move toward the prey droplet (sink). Similarly, due to the effect of the predator's emitted chemical gradient, the prey is repelled by the approaching predator.

"One of the surprising results is that the two oil droplets don't need to be very different chemically from each other to elicit this behavior," said Zarzar. "We looked at a wide variety of chemical compositions for the oils and surfactant, which allowed us to establish a set of rules that govern these interactions. We can use these rules to tune the strength of the interactions by controlling the compositions of the droplet oils or surfactant."

The research team also developed a model, which based on measurements of the speeds of chasing between individual pairs of droplets, was able to accurately simulate the motion of many droplets and show how they organize into larger clusters that move in a variety of fashions.

"They really look to me like they're alive sometimes," said Meredith. "When multiple droplets get together into clusters they can start to rotate, stop-and-go, move in spirals, and even split apart into smaller clusters."

The researchers say that by understanding the types of rules that govern these interactions, their system could eventually be used for experimentally modeling many-body systems ranging from the behavior of large numbers of animals to the interactions that might have played a role in the evolution of early life.

"What we are doing is really basic, fundamental research where the motivation is to understand the processes at work that can control the activity of inanimate things like the oil droplets," said Zarzar. "But, these ideas could find application in other areas, like self-assembly, group behaviors, and even in thinking about the origins of life on Earth where mixtures of simple chemical components had to somehow organize into non-equilibrium structures. Clearly, we are not looking at the same chemicals, but we may be able to establish parameters or conditions that, for example, give rise to similar types of interactions that occurred."

KANSAS CITY, MO--In a new study, researchers at the Stowers Institute for Medical Research have identified a handful of variations in an amino acid sequence critical for retaining the ancestral function of a gene over the course of 600 million years of evolution.

The breakthrough discovery detailed in an article published online November 12, 2020, in Genes and Development, offers important insight into the evolution of the gene regulatory networks that drive diversity among organisms, and shows that small differences in key protein sequences can lead to important evolutionary changes.

"It's generally understood that gene duplication and divergence allow genes to take on new functions, while essential genes are conserved and remain unchanged during evolution," says Stowers Investigator Robb Krumlauf, PhD. "But how variation in proteins, the building blocks of life, affects this process has been unclear."

The Krumlauf Lab at the Stowers Institute used a cross-species functional analysis of the labial Hox gene in the fruit fly and related genes in the mouse to explore this question.

The study used modern gene editing technologies, including CRISPR/CAS9, to replace the labial Hox gene in the fruit fly with the three related genes in the mouse--HOXA1, B1, and D1. The researchers found that replacing labial function with HOXA1 in fruit flies restores its original function, but B1 and D1 do not, suggesting that A1 retains an ancestral function, while B1 and D1 have diverged.

"In 600 million years of evolutionary time, only one gene has retained the ancestral activity," says Narendra Pratap Singh, PhD, a senior research associate in the Krumlauf Lab and first author of the article. "The other genes evolved and have taken on a new function. This was a great surprise."

The researchers pinpointed a six amino acid sequence critical for the ancestral function of A1, which is important for modulating interactions with other proteins. Also surprising was the fact that the sequence makes up only 2% of total amino acids in the protein, suggesting that tiny differences in certain key regions can have a big impact on protein function.

"Subtle and seemingly innocuous differences in protein sequence can profoundly impact the course of evolution," says Stowers Investigator Kausik Si, PhD, an author on the study. "Also, in the evolution of protein function, we tend to focus on what is conserved. This study suggests we should start paying attention to small differences, because some of the most interesting biology is hidden in the tiny differences."

In mice, HOXB1 appears to have evolved to have a new function in vertebrates to allow for greater diversity in facial expression and feeding behavior not found in invertebrates. Mutations in B1 in mice and humans affect facial morphology, neuronal development, and nerve function. In humans, Mobius syndrome, a neurological condition that results in lack of facial expressions, is sometimes associated with B1 mutations.

The study builds on more than three decades of work on Hox genes, a family of "master planner" genes that control the layout of the developing embryo from head to tail. Krumlauf's seminal discovery that Hox genes are essentially the same in mice and fruit flies helped establish the idea that there is a common genetic tool kit and that many organisms have surprisingly similar genes. The lab's comparative studies in mouse, chick, and zebrafish, and more recently sea lamprey, continue to provide critical information on how different species use the same genetic toolkit to form diverse structures. Hox transcription factors are well-suited for investigations into gene duplication and divergence because of their expansion from invertebrates to mammals.

The work paves the way for additional studies on the evolution of protein activity as well as further exploration into the role of conserved toolkit genes following gene duplication and divergence.

"I think we are poised to exploit the emerging strengths of structural biology, functional analyses, and genome engineering," Krumlauf says. "We can really ask, 'Is this role preserved in other invertebrates? Is this gene or protein really doing the same thing or has it evolved completely new functions?' I think there's a new era of analysis now feasible because of the power of gene editing."

Additional contributors to the study include Bony De Kumar, PhD, Ariel Paulson, Mark E. Parrish, PhD, Ying Zhang, PhD, Laurence Florens, PhD, and Joan Conaway, PhD. This work was funded by the Stowers Institute for Medical Research.

Lay Summary of Findings

In a new study, researchers at the Stowers Institute for Medical Research have identified tiny differences in a key protein sequence that can have an important impact on how species evolve. The breakthrough discovery, detailed in an article published online November 12, 2020, in Genes and Development, sheds light on the evolution of the gene regulatory networks that drive diversity among organisms.

The study from the laboratory of Robb Krumlauf, PhD, used modern gene editing technologies to replace the labial Hox gene in the fruit fly with the three related genes in the mouse--HOXA1, B1, and D1. The researchers found replacing labial function with HOXA1 in fruit flies restores its original function, but B1 and D1 do not, suggesting that A1 retains an ancestral function that has survived 600 million years of evolution, while B1 and D1 have diverged. The researchers pinpointed a six amino acid sequence critical for the ancestral function of A1, which is important for modulating interactions with other proteins. The work paves the way for additional studies on the evolution of protein activity as well as further exploration into the role of toolkit genes in gene duplication and divergence.

AMHERST, Mass. - Among seismologists, the geology of Alaska's earthquake- and volcano-rich coast from the Aleutian Islands to the southeast is fascinating, but not well understood. Now, with more sophisticated tools than before, a University of Massachusetts Amherst team reports unexpected new details about the area's tectonic plates and their relationships to volcanoes.

Plate tectonics - the constant underground movement of continental and ocean shelves, is often characterized by "subduction zones" where plates clash, one usually sliding under another. Many are prime earthquake- and volcano-prone regions.

Lead author Xiaotao Yang says, "For a long time, the whole central Alaska region was thought to have one simple subduction plate. What we discovered is that there are actually two major subduction slabs. It's a surprise that we see differences between these two slabs and the associate mantle materials." Overall, Yang says the new research shows, "there are many more subtleties and variations that we had not seen before."

Yang, who did this work at UMass Amherst with co-author Haiying Gao, is now on the faculty at Purdue University. Writing in the Journal of Geophysical Research: Solid Earth, they point out that central Alaska is "an ideal place to investigate subduction segmentation and its correlation with volcano distribution" because "it is not clearly understood what controls the distribution of arc volcanoes."

Yang says their study highlights how complex a subduction zone can be and how this complexity may control volcano distribution. It also helps to clarify a long-standing question in seismology: what determines whether volcanoes are present and whether they are in a linear arc, or in clusters. Yang says it depends in part on whether rocks deep in the mantle above the subducting slab melt into magma, and how magma is stored in the crust.

For their investigations, Yang and Gao used a powerful seismic imaging technique that Yang says is similar to a medical CAT scan of the Earth. With it, they constructed a detailed seismic velocity model of the Aleutian-Alaska margin from crust to the uppermost mantle. Seismic velocity refers to the rate at which a seismic wave travels through a material such as magma or crust. Waves travel more slowly through low-density, low-velocity material compared to surrounding rocks, for example, he says.

The researchers' new model reveals multiple downgoing slabs, with various seismic velocities, thicknesses and dip angles, they write. Yang adds, "Once we got to look at the two central Alaska volcanoes for the first time in a really precise way, what we see is a much more complicated subduction system than we knew before. This new information about the complexity helps us to understand the distribution of volcanoes in Alaska. It's all more complicated than the tools could show us before," he adds.

Their findings help to explain why there is a break in the arc of volcanoes called the Denali Volcanic Gap, Yang says. Below it is a wedge-shaped region of high seismic velocity material above the subduction plate but below the mantle. It is relatively cold and dry with no melting, which explains why there is no volcano in the region.

By contrast, the cluster of volcanoes in the Wrangell Volcanic Field do not have the same signature, he adds. The Wrangell volcanoes have distinctly low seismic velocity material in the crust. It's a rather large magma reservoir that may explain why they're in a cluster instead of an arc, Yang says, though "the fact that it's there helps to explain where the magma came from for past eruptions."

This study was made possible by the National Science Foundation's (NSF) array of seismic sensors in Alaska, part of its EarthScope Transportable Array program (http://www.usarray.org), Yang notes. His co-author Gao had startup funding from UMass Amherst and an NSF CAREER grant. They also used computational resources at the Massachusetts Green High Performance Computing Center in Holyoke.

Yang says that their work adds to seismologists' understanding of volcano distribution in the Cascades in the Pacific Northwest, South America and the south Pacific. He hopes to follow up with more detailed analyses of magma reservoirs in the crust, how volcanoes are fed and particularly, whether Aleutian volcanoes have magma in the crust.

Nov. 17, 2020 - The latest clinical practice guideline on home oxygen therapy addresses long-term and ambulatory oxygen therapy for adults with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) and includes the most comprehensive review of the evidence of any oxygen guideline to date.

The guideline from the American Thoracic Society was posted online, ahead of print in the Nov.15 issue of the American Journal of Respiratory and Critical Care Medicine.

The new guideline was borne out of the 2017 ATS workshop on Optimizing Home Oxygen Therapy data, which "identified the lack of evidence-based clinical practice guidelines for appropriate use of home oxygen as a critical gap," wrote the guideline panel.

Further rationale for new guidance came out of "a summary of results from an online survey of almost 2,000 oxygen users in the U.S. describing the multiple problems they had in accessing and using their oxygen," said Susan S. Jacobs, MS, RN, co-chair of the guideline committee and a research nurse manager in Pulmonary, Allergy, and Critical Care Medicine at Stanford University.

"Oxygen is a common, yet burdensome, equipment-laden therapy, so if we are going to prescribe it, there should be enough evidence that we can tell our patients what they should expect in terms of improving their symptoms, and the quality and quantity of their lives," noted Jacobs.

To that end, the multidisciplinary panel used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to formulate their recommendations summarized below:

COPD Recommendations

In adults with COPD who have severe chronic resting room air hypoxemia, we recommend prescribing Long Term Oxygen Therapy (LTOT) at least 15 hours per day (strong recommendation, moderate quality evidence).

In adults with COPD who have moderate chronic resting room air hypoxemia, we suggest not prescribing LTOT (conditional recommendation, low quality evidence).

In adults with COPD who have severe exertional room air hypoxemia we suggest prescribing ambulatory oxygen (conditional recommendation, moderate quality evidence).

ILD Recommendations

For adults with ILD who have severe chronic resting room air hypoxemia we recommend prescribing LTOT at least 15 hours per day (strong recommendation, very low quality evidence).

For adults with ILD who have severe exertional room air hypoxemia we suggest prescribing ambulatory oxygen (conditional recommendation, low quality evidence).

Liquid Oxygen Recommendation

In patients with chronic lung disease who are mobile outside of the home and require continuous oxygen flow rates of >3L/minute during exertion, we suggest prescribing portable liquid oxygen (conditional recommendation, very low quality evidence).

The guidelines also include a 'best-practice statement' that describes a minimum standard of oxygen education and training for all oxygen users.

The ATS has published nearly 20 clinical practice guidelines on various conditions, ranging from allergy and asthma to TB and other pulmonary infections. For ATS guideline implementation tools and derivatives, go here.

OAK BROOK, Ill. - Racket sports like tennis and racquetball appear to accelerate knee joint degeneration in overweight people with osteoarthritis, according to a study being presented at the annual meeting of the Radiological Society of North America (RSNA).

Knee joint osteoarthritis, a gradual wearing down of the protective cartilage that cushions the ends of the bones, is a major cause of pain and disability worldwide, affecting approximately 14 million people in the U.S. alone. Excess body weight is a major risk factor.

Physical activity offers a host of benefits for people who are overweight, but the wrong type of exercise could potentially damage knee joints and hasten the need for knee replacement surgery. The effects of different types of exercise on overweight people have seldom been studied with MRI, the most sensitive imaging method for assessing structural changes to the knee joint.

For the new study, researchers used high-powered MRI to assess the rate of degeneration of the knee joint in 415 overweight and/or obese patients, average age 59, drawn from the Osteoarthritis Initiative, a National Institutes of Health-supported study of individuals with mild to moderate osteoarthritis.

Study participants kept detailed records of their participation in six different types of physical activity, including ball sports, bicycling, jogging/running, elliptical trainer, racket sports and swimming. The researchers performed baseline MRIs and then measured changes in the patients' knees over four years using the modified Whole-Organ Magnetic Resonance Imaging Score (WORMS). A higher score indicates more degeneration.

Patients regularly participating in racket sports saw their overall WORMS score increase significantly, compared to patients regularly using the elliptical trainer over the study period. Surprisingly, the overall WORMS score also increased significantly in the racket sports group compared to the jogging/running group. Racket sports participants saw significantly greater degeneration in the medial tibial cartilage compartment, the compartment on the inside of the knee where arthritis often first appears.

Participants using the elliptical trainer showed the smallest changes in structural degeneration over four years.

"In our study, progression of overall knee joint degeneration was consistently higher in overweight and/or obese patients engaging in racket sports," said the study's lead author Silvia Schirò, M.D., from the University of California San Francisco and the University of Parma in Parma, Italy. "We also found that workouts using an elliptical trainer were associated with reduced progression of overall knee joint and cartilage defects. Moreover, our findings showed that when comparing different low impact activities with each other, such as bicycling, elliptical trainer and swimming, the elliptical trainer was associated with the lowest increase in WORMS sub-scores over 48 months."

The more rapid degeneration of the knee joints in people who participated in racket sports is likely due to the high-speed lateral movements inherent to such sports, Dr. Schirò said. These movements can affect the femoral-tibia compartment, a structure in the knee made up of the femur condyle, the rounded end of the thighbone that helps it slide over the tibia, or shinbone, and the meniscus, the rubbery, C-shaped cartilage between the thighbone and the shinbone.

"A large lateral force imparted at the foot during side-to-side movements may be driving large knee adduction moments, a key feature in medial compartment disease, which imparts high compressive loads on the medial tibia and femoral condyle," she said. "In support of this premise, the racket sports group showed elevated cartilage degeneration in the medial tibia."

The researchers theorize that joint mechanics are impaired in overweight and obese individuals, with a harmful joint overload triggering increased contact stress on the meniscus. Damage to the meniscus compromises the protective cushion on the cartilage of the knee.

"High impact physical activity with elevated load and high shear forces may trigger and accelerate this process," Dr. Schirò said. "Moreover, participants who played racket sports showed significantly more meniscal degeneration when compared to the remainder of the study group."

The data suggests that overweight individuals who continue to play racket sports could slow degeneration in their knees by making modifications to their activities, such as switching to sports with less fast-paced and high shear loads like badminton or doubles tennis.

However, Dr. Schirò emphasized that the degenerative process is complex and individual joint mechanics are highly variable.

"It is possible that some individuals with sufficient strength and motor control may be able to safely play these sports," she said. "Our data suggests that as a group, though, overweight and obese individuals who play racket sports are at higher risk for disease progression."

BOSTON - Findings from a team led by investigators at Massachusetts General Hospital (MGH), reported in the online journal mBio, may help scientists develop a more effective vaccine for cholera, a bacterial disease that causes severe diarrhea and dehydration and is usually spread through contaminated water.

The bacterium that causes cholera, called Vibrio cholerae, settles within the intestines after ingestion. There, it secretes a toxin that causes intestinal cells to secrete massive amounts of fluid, eventually leading to death from dehydration and shock if untreated. The disease is a significant problem in many impoverished regions of the world.

Interestingly, immune responses to the toxin do not protect against cholera, but previous research led by investigator Edward Ryan, MD, director of Global Infectious Diseases at MGH, has shown antibodies that bind V. cholerae's sugar coating--called O-specific polysaccharide (OSP)--do offer protection.

"A big question is: How do these antibodies protect? The answer would help develop better vaccines," says Ryan, who is also a professor of Medicine at Harvard Medical School and a professor of Immunology and Infectious Diseases at the Harvard T.H. Chan School of Public Health. He notes current vaccines for cholera are not very protective in young children, who bear much of the global burden of cholera, and induce relatively short-term protection in recipients.

To investigate, Ryan and his colleagues analyzed antibodies recovered from humans who survived cholera. Experiments showed the antibodies block V. cholerae bacteria's motility. "V. cholerae are very mobile, and swimming is critical to their ability to cause disease," Ryan explains. "Interestingly, the tail-like flagellum in V. cholerae that propels swimming is coated with the OSP sugar." More detailed analyses demonstrated the human antibodies attached to this OSP coating to block the ability of V. cholerae to swim and cause disease.

"Our results support a unique mechanism of protection against a human pathogen. We are not aware of previous work demonstrating a comparable direct anti-motility effect of human antibodies," says Ryan.

BUFFALO, N.Y. -- In the TV series, "How It's Made," viewers often discover that common objects like pencils or rubber bands are quite complicated to make. The show walks people through complex production processes that lie behind familiar items.

A new paper in the journal Cell Reports does the same for saliva.

The study, which will be published on Nov. 17, breaks down, in detail, where the multitude of proteins floating in our saliva originate.

The research traces these vital proteins back to their source, showing which proteins are produced by each of the three major types of human salivary glands, and showing how individual cells within a single gland can secrete different proteins. The project also identifies proteins in the mouth that seem to be coming from outside of salivary glands, from places such as epithelial tissues or blood plasma.

"Saliva is important for tasting, for digesting, for swallowing, for defending us from the pathogens that we are constantly inhaling and consuming. The proteins in our mouth form an army, if you will, that's working constantly to protect us. Before this, scientists had an idea of the proteins that are found in the mouth, but we didn't have a complete picture of where they were coming from. We're addressing this gap," says Omer Gokcumen, PhD, associate professor of biological sciences in the University at Buffalo College of Arts and Sciences.

"From a biomedical perspective, our research opens the door for further studies into the functions of saliva and salivary glands, and the use of saliva as a diagnostic fluid. Our study takes a snapshot of how healthy salivary glands should function. Deviations from this healthy expectation can indicate disease," says Stefan Ruhl, PhD, DDS, professor of oral biology in the UB School of Dental Medicine.

The study's first author is Marie Saitou, PhD, a tenure-track researcher in biosciences at Norwegian University of Life Sciences, and a former postdoctoral researcher at the University of Chicago and UB. Saitou, Gokcumen and Ruhl led the study with Sarah Knox, PhD, associate professor of cell and tissue biology in the University of California, San Francisco (UCSF) School of Dentistry.

The biological factories that churn out our saliva

To explain how our bodies make saliva, the scientists first sought to understand which proteins are produced by each major type of salivary gland -- the parotid, submandibular and sublingual glands (humans have a pair of each).

To do this, the team used a method called transcriptomics to measure gene activity in each kind of gland. Gene activity provides insight into protein production, because each gene provides instructions for making a specific protein.

This endeavor enabled the scientists to understand the proteins that each gland generates, and how the glands differ from one another in terms of what they produce.

For instance, the study finds that the parotid and submandibular glands create a lot of salivary amylase, an enzyme that helps to digest starch, while the sublingual gland makes almost none. Meanwhile, the sublingual gland produces relatively large quantities of certain GalNAc transferases, a family of enzymes that's important in initiating a process called O-glycosylation that attaches a sugar to certain salivary mucin proteins. These are just a couple of examples.

"We show how the actions of different glands collectively help to produce a complex bodily fluid -- our saliva," Saitou says.

"Our work reveals that even a gland type itself is not homogenous: the saliva-producing acinar cells, which were once thought to produce the same proteins, and thus be the same cells, actually synthesize distinct saliva proteins, thus indicating a new level of cellular diversity," Knox says.

Gokcumen says the research is one step toward understanding the immense complexity of saliva. Beyond parsing out the origins of proteins made by salivary glands, the team also concluded that some proteins drifting in saliva likely don't originate from salivary glands, and that some important proteins that help to regulate gene expression are predominantly active in salivary glands, but not in a litany of other tissues.

"Salivary proteins are a gateway to our body," Gokcumen says. "When they do not function properly, we suffer. Our work brings us one step closer to understanding their complex origins and the intricate interplay between them."

"Long wished-for diagnostic applications of saliva for monitoring systemic well-being and disease will need to measure quantitative differences of biomarkers in saliva," Ruhl says. "One obstacle always hampering progress in this arena was that we did not know exactly which proteins were intrinsically produced by the salivary glands, and which proteins diffused into saliva from surrounding tissue leakage. Also, we were lacking a reliable baseline, a standard, if you will, that tells us what are normal and healthy values for the protein components in saliva. Our paper helps resolve these conflicts, providing information that I expect will propel salivary diagnostic applications forward."

WASHINGTON, November 17, 2020 -- Monitoring how patients with multiple sclerosis or other degenerative diseases use their smartphones could provide valuable information to help get them better treatment.

In an article published in Chaos, by AIP Publishing, researchers used a mobile app to record the keystroke dynamics of a control group and those of subjects in various stages of multiple sclerosis treatment over the course of a year.

Keystroke dynamics show how quickly or slowly someone is typing on a touch screen, the amount of time between letters typed, the number of mistakes made and corrected while typing, and other behaviors. As part of the study, researchers at Amsterdam University Medical Center used a mobile app that tracks how a user is typing on their phone's keyboard.

In doing so, they observed changes over time in the way people with MS typed that were not seen in subjects who did not have the disease.

"The clinically relevant changes in keystroke dynamics can be seen as early warning signals for changes in disease activity of the patient prior to the change occurring," the authors wrote.

James Twose, one of the authors, called the study's findings a "first promising step" toward using keystrokes to help diagnose changes in patients with chronic diseases like MS.

"The dream is prediction," said Twose. "If there is some semblance of predictability, the joy would be to forecast the disease in a similar way you do with weather."

Multiple sclerosis patients generally make clinical visits every 3-12 months, according to the authors, and MRIs are the best way to measure changes in damage to the brain from the disease.

If doctors were able to use something like keystrokes to monitor patients on a more ongoing basis, they could better predict when new treatments are needed.

"In chronic diseases like MS and Alzheimer's disease and Parkinson's disease, there is inherent worsening over time," Twose said. "When it comes to typing, you need all your faculties to do this well. We notice when you have problems with that."

Such a system would be helpful to chronic disease sufferers for a variety of reasons. Consistent monitoring would give doctors a fuller picture of their condition than occasional clinic visits, which can only provide a snapshot of how they are doing at that moment. It also would be a boon for patients whose conditions make traveling to and from doctor appointments difficult.

Effector regulatory T cells (eTreg cells) are a specialized subset of white blood cells that keep the immune system in check. St. Jude Children's Research Hospital scientists have revealed the metabolic signaling mechanisms that regulate function of eTreg cells. The work may aid efforts to better understand and treat inflammatory diseases. The findings were published online today in Cell Metabolism.

"This process is quite fascinating to us, and helps explain how metabolites can drive selective signaling pathways to enforce the differentiation, persistence and function of eTreg cells," said corresponding author Hongbo Chi, Ph.D., of St. Jude Immunology. "We were looking specifically at suppression of autoimmunity that can develop spontaneously in our models, but we also know Treg cells play a role in multiple diseases."

Although eTreg cells are involved in prevention of autoimmune diseases, including lupus and rheumatoid arthritis, they are detrimental in other diseases, such as cancer. Understanding how metabolic signaling regulates Treg cell heterogeneity or function may help scientists develop more specific drugs to target these pathways to help treat disease. How metabolic pathways regulate the differentiation and persistence of eTreg cells, especially at the level of intracellular signaling, has been unclear until now.

Metabolic pathways exert control

The researchers showed that two-way metabolic signaling that intersects with T cell receptor signaling is critical to regulating eTreg cell function.

Investigators identified a class of metabolites called isoprenoids that are essential for the suppressive activity of activated Treg cells such as eTreg cells. Isoprenoids are required for cellular processes called posttranslational lipid modifications, specifically protein farnesylation and geranylgeranylation. These processes are mediated by Fntb and Pggt1b, respectively. Disruption of these processes by Treg cell-specific deletion of Fntb or Pggt1b causes mice to develop autoimmunity.

Further research into the metabolic signaling mechanisms revealed the discrete details of Treg cell-mediated immune suppression downstream of T cell receptor signaling. Fntb acts through two parallel pathways to promote eTreg cell persistence: the protein kinase mTORC1, which regulates metabolic reprogramming of Treg cells, and the immune receptor ICOS. Pggt1b enforces signaling through the small G protein Rac to support eTreg cell differentiation.

"We were able to dissect how metabolic regulation controls eTreg cell differentiation and maintenance," said first author and graduate student Wei Su of St. Jude Immunology. "This bidirectional interplay between intracellular signaling and metabolism allows eTreg cells to maintain the self-tolerance in our body."

"These pathways have been of long-standing interest outside of the immune system for a way to inhibit inflammatory responses," said study author Nicole Chapman, Ph.D., of St. Jude Immunology. "Our study provides a deeper understanding of the molecular interplay between signaling and metabolism and could allow for more potent and selective targeting of downstream metabolic functions in Treg cells."

Oak Brook, IL - The December edition of SLAS Discovery, "Drug Discovery Targeting COVID-19" is a special collection assembled by Associate Editor Timothy Spicer (Scripps, FL, USA), focusing on drug discovery efforts toward the current global pandemic of COVID-19caused by the novel coronavirus, SARS-CoV-2.

In this Special Issue, you will find seven papers published as open access articles.
The issue includes four reviews that cover the commonly utilized approach of repurposing drugs to rapidly treat COVID-19, as well as targeting the virus using new vaccines and clinical drugs.

The articles of original research focus on novel proteins necessary for virus replication. The article, "High-Throughput Screening for Drugs that Inhibit Papain-Like Protease in SARS-CoV-2," explores how an ultra-high throughput screening platform targeting PLPro was used to investigate over 13,000 clinically applicable drugs. The article, "Discovery of Drug-Like Ligands for the Mac1 Domain of SARS-CoV-2 Nsp3" tests drug-like ligands for their efficacy against the MAC domain of SARS2 Nsp3, a novel approach. In addition to these two articles, the December special issue contains an additional two articles of original research.

Articles of Original Research include:

Method Development and Application of an Accelerated Solution Stability Screen for Drug Discovery

Comparative Analysis of Multiple Immunoassays for Cytokine Profiling in Drug Discovery

Other articles include:

Potential Repurposed Therapeutics and New Vaccines against COVID-19 and Their Clinical Status

A Review of the Preclinical and Clinical Efficacy of Remdesivir, Hydroxychloroquine, and Lopinavir-Ritonavir Treatments Against COVID-19

Based on Principles and Insights of COVID-19 Epidemiology, Genome Sequencing, and Pathogenesis: Retrospective Analysis of Sinigrin and Prolixin RX (Fluphenazine) Provides Off-Label Drug Candidates

RNA-Dependent RNA Polymerase as a Target for COVID-19 Drug Discovery

Repurposing Nimesulide, a Potent Inhibitor of the B0AT1 Subunit of the SARS-CoV2 Receptor, as a Therapeutic Adjuvant of COVID-19

Recommended Guidelines for Developing, Qualifying, and Implementing Complex In Vitro Models (CIVMs) for Drug Discovery

Drug Discovery Targeting COVID-19

PULLMAN, Wash. -- Studies conducted in yeast show that exposure to ultraviolet light (UV) induces new types of DNA damage that may cause the deadliest form of skin cancer, malignant melanoma.

That's according to research conducted by a team featuring undergraduate students from Washington State University's School of Molecular Biosciences. The work, led by WSU researchers John Wyrick and Steven Roberts of the College of Veterinary Medicine, was published today, Nov. 17, in Cell Reports.

While melanoma has been associated with UV light, this study directly links UV exposure to the atypical mutations known to spread the disease. The results also indicate that UV light can induce a more diverse spectrum of mutations than previously suspected.

"There's been this debate: how much does UV light cause the mutations that actually cause the cancer?" Wyrick said. "Our research supports that UV light plays a major role in producing mutations specific to the growth and spread of melanoma."

As in humans, UV light damages DNA and produces mutations in baker's yeast, making it an excellent model to study how dangerous the resulting mutations can be.

Researchers irradiated yeast cells from 150 yeast colonies with UV lamps 15 times for 8-second intervals over the course of a month. They used UV-C radiation, the strongest form or ultraviolet light. The team then used whole-genome sequencing to identify an estimated 50,000 mutations that occurred in cells due to the UV irradiation.

The team found about half of all the mutations found in the irradiated cells were rare mutations linked to melanoma.

Until now, UV damage in DNA was thought to be confined to two of the DNA bases: C (cytosine) or T (thymine). However, this new research indicates that UV damage also occurs at low frequency at A (adenine) DNA bases, a surprising finding.

WSU students and researchers also showed that a single intense exposure of ultraviolet-B radiation, which is present in sunlight, could also induce the atypical mutations.

Haley Morris, an undergraduate biochemistry major, began working on the research as a first-year student.

"This has a lot of real-world applications and could help identify causes of severe skin cancers," Morris said. "It's cool that something I enjoy and am a part of has the potential to help a lot of people."