Culture

Philadelphia, July 28, 2020 - Imagine a young girl with a peanut allergy, so stricken by fear of anaphylaxis that she no longer takes part in everyday activities many children take for granted. She's stopped playing with her siblings, worried that residue from their peanut butter crackers may trigger an allergic reaction. She obsessively washes her hands to make sure there is no trace of peanut on them. She worries that every stomachache could mean she accidently ate something she was allergic to.

This story is becoming more familiar to families across the country. While most children with food allergies maintain a healthy level of caution, there is a small percentage whose anxiety is excessive and impairing. The hallmark of excessive anxiety is going to extreme, medically unnecessary lengths to avoid the allergen, such as no longer visiting extended family or refusing to eat any allergen-free food that isn't familiar. While these coping mechanisms may relieve anxiety in the short term, they may ultimately cause more harm by negatively reinforcing the idea that the world is a dangerous place and that children are helpless to keep themselves safe.

Now, Children's Hospital of Philadelphia (CHOP) has launched the Food Allergy Bravery (FAB) Clinic to help children with a phobia of anaphylaxis. This revolutionary clinic, housed within the Food Allergy Center, is the first in the world to bring together psychologists and food allergy experts to treat food allergic children with severe phobia of anaphylaxis.

The three Founders of the FAB Clinic published a set of best practices in the Journal of Allergy and Clinical Immunology, providing guidance to allergists and pediatricians on how to address allergy-related phobias through Cognitive Behavioral Therapy (CBT).

"CBT works by gradually encouraging anxious children to take part in 'brave practices,' like eating with the rest of their family, playing with siblings, and trying new foods that don't contain allergens," said Katherine Dahlsgaard, PhD, ABPP, Director of the FAB Clinic at CHOP. "As a child's confidence grows, we gradually introduce them to more challenging brave practices. This could include sitting in the same room with the food they're allergic to, or even touching the food and then washing their hands thoroughly. The aim is to help children realize, through safe, structured practices in the FAB Clinic, that the world is much safer than they think and that they are capable of keeping themselves safe within it."

The FAB clinic enthusiastically employs the help of family members, coaching parents or caregivers to repeat brave practices at home.

"We want these children and their families to know they're safe and capable," said Dr. Dahlsgaard. "Our ultimate goal is to equip families with practical skills and confidence via focused treatment sessions, so that their child can safely navigate a world that can't always be allergen-free."

About Children's Hospital of Philadelphia: Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 564-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu

Journal

Journal of Allergy and Clinical Immunology

According to new research, the failure to protect tropical rain forests has cost trillions of dollars stemming from the coronavirus pandemic, which has wreaked economic havoc and caused historic levels of unemployment in the United States and around the world.

For decades, scientists and environmental activists have been trying to draw the world's attention to the many harms caused by the rapid destruction of tropical forests. One of these harms is the emergence of new diseases that are transmitted between wild animals and humans, either through direct contact or through contact with livestock that is then eaten by humans. The SARS-CoV-2 virus--which has so far infected more than 15 million people worldwide--appears to have been transmitted from bats to humans in China.

"Much of this traces back to our indifference about what has been occurring at the edges of tropical forests," says Les Kaufman, a Boston University professor of biology.

He recently brought together 18 experts from Princeton University, Duke University, Conservation International, and other institutions, to better understand the economic costs of reducing transmission of viruses like the novel coronavirus. Looking at existing research, they made a startling realization.

They discovered that significantly reducing transmission of new diseases from tropical forests would cost, globally, between $22.2 and $30.7 billion each year. In stark contrast, they found that the COVID-19 pandemic will likely end up costing between $8.1 and $15.8 trillion globally--roughly 500 times as costly as what it would take to invest in proposed preventive measures. To estimate the total financial cost of COVID-19, researchers included both the lost gross domestic product and the economic and workforce cost of hundreds of thousands of deaths worldwide. They published their findings in a policy brief in Science.

The researchers say disease transmission from wild animals to humans occurs frequently near the edges of tropical forests, where human incursions increase the likelihood of contact with animals. These incursions take the form of logging, cattle ranching, and other livestock businesses, and the exotic animal trade, among others. Tropical forests are often cut down in a patchwork or checkerboard pattern, increasing the amount of land that lies at the edges of the forest and thus increasing the risk for disease transmission between species that would normally live in different ecosystems.

To reduce disease transmission, Kaufman and his collaborators propose expanding wildlife trade monitoring programs, investing in efforts to end the wild meat trade in China, investing in policies to reduce deforestation by 40 percent, and fighting the transmission of disease from wild animals to livestock.

In China alone, wildlife farming (a government-monitored effort to sustainably hunt wild animals without overhunting them) is an approximately $20 billion industry, employing 15 million people, say Kaufman and his peers. In many China communities, the purchase of wildlife and bushmeat--meat from wildlife species--is a status symbol.

The researchers also propose to increase funding for creating an open source library of the unique genetic signatures of known viruses, which could help quickly pinpoint the source of emerging diseases and catch them more quickly, before they can spread.

Every year, two new viruses are estimated to transfer from animals to humans, the researchers say. Historically, these have included HIV, MERS, SARS-CoV-1, H1N1, and most recently, the SARS-CoV-2 virus that causes COVID-19. Kaufman and his colleagues hope that their report will spur governments around the world, including the US government, to help fund these preventive measures.

There are some signs of hope, they say, including the February announcement by the Standing Committee of the National People's Congress that wildlife consumption for food or related trade would be banned in China.

"The pandemic gives an incentive to do something addressing concerns that are immediate and threatening to individuals, and that's what moves people," says Kaufman. "There are many people who might object to the United States fronting money, but it's in our own best interest. Nothing seems more prudent than to give ourselves time to deal with this pandemic before the next one comes."

AMES, Iowa - Exposure to the chemical glyphosate changed the level of some ovarian proteins in mice but did not impact ovarian steroid production, an indication glyphosate may not adversely affect reproduction, according to a new study.

Two studies, published in the peer-reviewed academic journals Toxicology and Applied Pharmacology and Reproductive Toxicology, analyzed how ovarian function in mice responded to various levels of exposure to glyphosate, a chemical extensively used to kill weeds. The research found the highest exposure levels included in the experiments resulted in increased ovarian weight and follicle number, but Aileen Keating, an associate professor of animal science at Iowa State University and lead author, said the research did not uncover evidence that glyphosate affects the healthy functioning of ovaries.

"The big takeaway is that while we did find some changes in ovarian proteins, many of the endpoints we examined were not altered by glyphosate exposure," Keating said.

Keating, whose research focuses on reproductive health, said it's unclear if the increased ovarian size or altered protein abundance that resulted from the highest exposure level could cause changes in the ability of mice to reproduce. Answering that question will require further study, she said. The study found glyphosate exposure did not affect heart, liver, spleen, kidney or uterus weights. Keating said the study's conclusions largely agreed with findings published years ago meant to determine how the chemical can be used safely.

The researchers introduced glyphosate to groups of mice orally, mimicking how humans could be exposed to glyphosate residue in water or in crops used for food production. Groups of mice were exposed to different glyphosate levels and for periods of 5, 10 or 20 weeks. The researchers chose the doses, measured in milligrams per kilogram of bodyweight, to approximate potential glyphosate levels that humans could be exposed to.

However, Keating noted that it remains unclear how much glyphosate humans are exposed to regularly, which made it difficult to judge what levels were appropriate for the experiments. Additionally, they used only the active compound contained in weed treatments, not the additional ingredients.

The use of glyphosate has sparked controversy regarding its proposed health effects. Accordingly, Keating said the researchers designed the study to be as unbiased as possible. For instance, the scientists didn't know the glyphosate treatment of individual samples as they conducted their analysis, which meant perceived expectations or biases could not affect the results.

"It's a commonly used chemical, and there's been some alarm in the media about its use," she said. "We need more well designed, independent studies to see if this is something we should be concerned about."

Fossil remains of a novel species of lizard that lived more than 130 million years ago have been found in the north of Minas Gerais, Brazil. It has been named Neokotus sanfranciscanus and is the oldest representative of the order Squamata ever found in South America.

Squamates are the largest reptile group, comprising lizards, snakes and amphisbaenians (worm lizards).

The discovery shows that scaled lizards were present on the continent at least 20 million years earlier than previously recorded and suggests that early South American squamates were part of a much broader global distribution, in contrast with the high levels of endemism (confinement to certain geographic regions) characteristic of modern species.

The fossil is described in an article published in Communications Biology.

The study was led by Jonathas Bittencourt, who was formerly awarded a postdoctoral research scholarship by FAPESP and is currently a professor at the Federal University of Minas Gerais (UFMG). The last author of the article is Max Langer, a professor in the Biology Department of the University of São Paulo’s Ribeirão Preto School of Philosophy, Science and Letters (FFCLRP-USP). The study was supported by the Minas Gerais Research Foundation (FAPEMIG) via a grant awarded to Bittencourt and by FAPESP via a Thematic Project led by Langer.

“This was a small lizard, approximately 10 cm long,” Langer told Agência FAPESP. “Its discovery in Brazil shows that the squamates were distributed throughout the world and were alive much earlier than we thought. This was only possible because, although the supercontinent Pangaea no longer existed, the continental lands were still relatively close to each other, allowing animals to disperse widely.”

The genus name Neokotus comes from Greek and means “novel and unfamiliar”. It was chosen because this animal’s morphology differs in several ways from that of all other species of Squamata. The specific epithet sanfranciscanus refers to the fact that the lizard’s fossilized remains were found in the Quiricó Formation, which is in the São Francisco River Basin.

“One of the morphological peculiarities of Neokotus is the shape of its ungual phalanges, which are terminal finger or toe bones. These bones end in nails in humans and in claws in other animals. In Neokotus, the base of the ungual phalanx was flat, a trait not found in any other known lizard. More detailed study of this feature is required, but it probably had something to do with locomotion,” Bittencourt said.

“Another peculiarity is the shape of its teeth, which had robust bases, tapering and curving inwards at the tip. We also have a theory about this: the shape of its teeth helped capture the insects it fed on.”

Bittencourt discovered Neokotus by chance. He was collecting scales from small sharks on a riverbank when he came across a block of sediment containing phalanges, vertebrae, teeth and other bones that did not appear to belong to fish. On assembling the bones and analyzing their mutual relationships, he realized they belonged to a lizard.

“I found approximately 30% of the fossil remains of a single individual,” he said. “The Quiricó Formation in the municipality of João Pinheiro in northern Minas Gerais must have included a large lake or several interconnected lakes in the remote past, as it’s very rich in fossils of lacustrine origin. I’ve been digging in the area since 2012. My field work consists of collecting chunks of rock, which I take back to the lab to be washed and broken up using hydrogen peroxide. I collect the tiny bones with brushes and tweezers.”

The rocks in which Neokotus was found were dated by means of microcrustaceans also embedded in the sediment.

“Many dinosaurs have been discovered in South America, but findings of small reptiles are also very important for the reconstruction of the scene at the time,” Langer said.

The article, “Discovery of the oldest South American fossil lizard illustrates the cosmopolitanism of early South American squamates”, can be read at: www.nature.com/articles/s42003-020-0926-0.

Journal

Communications Biology

DOI

10.1038/s42003-020-0926-0

Philadelphia, July 27, 2020--As the COVID-19 pandemic took hold, hospitals across the country cancelled elective procedures in an effort to flatten the transmission curve and prioritize personal protective equipment for frontline health care workers. Among those procedures were pediatric spine surgeries for patients with conditions like scoliosis and thoracic insufficiency syndrome.

Now, as hospitals resume elective procedures, including pediatric spine surgeries, surgeons from Children's Hospital of Philadelphia (CHOP) have outlined a framework for prioritizing pediatric spine surgeries amid the pandemic. The recommendations were published recently in the Journal of Bone and Joint Surgery.

"We've provided a framework for a reorientation of the thought process by which surgeons should plan pediatric spine surgery in the midst of this pandemic," said Jason B. Anari, MD, a pediatric orthopaedic surgeon with CHOP's Division of Orthopaedics and first author of the recommendations. "Although many families historically pick surgical dates that are based on school, sport seasons, or vacation schedules, we support the creation of a new urgency list to help guide rescheduling while also minimizing potential risk to patients."

The paper proposes classifying surgeries into four categories:

Class 1: Emergency surgeries that must happen right away;

Class 2: Urgent surgeries that must happen within a short timeframe;

Class 3: Semi-urgent surgeries in which a delay of several months would result in less-optimal clinical outcomes;

and Class 4: Elective surgeries that might require a prolonged stay in the intensive care unit, that will require more intensive use of health-care resources, or that involve children with competing risks of medical conditions, or cases for which the outcome will be no different if delayed up to 6 months.

The authors suggest that the classes of surgeries should occur in descending order on the epidemiological curve, with Class-1 emergency surgeries happening as soon as possible regardless of case counts, using preoperative COVID-19 screening and sufficient personal protective equipment, and the other classes happening as community case counts flatten and then decrease. Class-4 surgeries, the authors recommend, should occur once the pandemic has reached its low point.

The authors also advise health care systems and surgeons to develop strong partnerships to facilitate rescheduling patients whose surgeries had been postponed due to the pandemic. Scheduling patients beyond standard hours or on weekends, as CHOP has supported, and finding other ways to reschedule patients could potentially help decrease waiting times, which in turn could also minimize an uptick in surgeries that became more complex due to postponement. Additionally, finding alternate times for procedures helps families to social distance while in the hospital and improve overall access to care for patients.

"The pandemic has been understandably anxiety-provoking for patients in need of spine surgery and their families," Anari said. "Having a plan of action to ramp up in a safe and organized fashion benefits everyone: the health system, surgeons, care teams, and, most importantly, patients."

BROOKLYN, New York, Monday, July 27, 2020 - Fascinating opportunities are emerging from a new class of materials named two-dimensional (2D) semiconductors, which are only one atom thick. 2D materials are poised to have a bright future in the electronics and optoelectronics industry, as well as in Internet of Things devices. Any cell phone, computer, electronic device, and even solar cells, are all composed of the same basic electronic building block, the diode. Unfortunately, a major obstacle for the wide application of 2D materials in industry is the unsolved challenge of the scalable and robust nanofabrication of the core element of a diode, which is a "p-n junction".

Elisa Riedo, professor at the New York University (NYU) Tandon school of Engineering led an international team of investigators who demonstrated a novel approach based on thermal scanning probe lithography (t-SPL) to fabricate state-of-the-art "p-n junctions" on a single atomic layer of molybdeunum disulfide (MoS2) a transition metal dichalcogenide. The work, "Spatial defects nanoengineering for bipolar conductivity in MoS2," appears in Nature Communications.

To produce "p-n junctions", it is necessary to dope a semiconductor in such a way that part of it is n-doped (doped with an excess number of electrons) and another part is p-doped (doped with an excess number of positively-charged "holes"). Riedo and Davood Shahrjerdy, professor of electrical and computer engineering at NYU Tandon, showed that by combining t-SPL with defects nanoengineering was possible to obtain nanoscale-resolution bipolar doping of MoS2, yielding to both n-type and p-type conduction, which can be readily extended to other 2D semiconductors.

As part of the research, the team integrated t-SPL -- using a probe heated above 200 degrees Celsius -- with a flow-through reactive gas cell to achieve a unique nanoscale control of the local thermal activation of defects in monolayer MoS2. The defective patterns can give rise to either p- or n-type conductivity on demand, depending on the gasses used during the local heating process. Doping and defects formation mechanisms are elucidated at the molecular level by means of X-Ray photoelectron spectroscopy, transmission electron microscopy, and density functional theory.

The international team included researchers from the City University of New York (CUNY), Politecnico di Milano, the University of Illinois Urbana-Champaign, the University of Pennsylvania, and the National Research Council of Italy (CNR).

"In our previous research we showed that t-SPL outperforms electron beam lithography and other standard methods for fabricating metal electrodes on MoS2, an advance that could also decrease the cost of fabrication since t-SPL does not require markers or vacuum," said Riedo.

With this consecutive success in bipolar doping of 2D semiconductors, t-SPL is now able to offer both dopants patterning and chip manufacturing, which will rapidly advance the material science and chip design. "It is great to see how t-SPL is now taking up to enable the fabrication of functional transistor devices from 2D materials, including control of the doping levels" said Armin Knoll, from IBM Zurich, one of the pioneers together with Riedo of t-SPL.

TROY, N.Y. -- When the Shewanella oneidensis bacterium "breathes" in certain metal and sulfur compounds anaerobically, the way an aerobic organism would process oxygen, it produces materials that could be used to enhance electronics, electrochemical energy storage, and drug-delivery devices.

The ability of this bacterium to produce molybdenum disulfide -- a material that is able to transfer electrons easily, like graphene -- is the focus of research published in Biointerphases by a team of engineers from Rensselaer Polytechnic Institute.

"This has some serious potential if we can understand this process and control aspects of how the bacteria are making these and other materials," said Shayla Sawyer, an associate professor of electrical, computer, and systems engineering at Rensselaer.

The research was led by James Rees, who is currently a postdoctoral research associate under the Sawyer group in close partnership and with the support of the Jefferson Project at Lake George -- a collaboration between Rensselaer, IBM Research, and The FUND for Lake George that is pioneering a new model for environmental monitoring and prediction. This research is an important step toward developing a new generation of nutrient sensors that can be deployed on lakes and other water bodies.

"We find bacteria that are adapted to specific geochemical or biochemical environments can create, in some cases, very interesting and novel materials," Rees said. "We are trying to bring that into the electrical engineering world."

Rees conducted this pioneering work as a graduate student, co-advised by Sawyer and Yuri Gorby, the third author on this paper. Compared with other anaerobic bacteria, one thing that makes Shewanella oneidensis particularly unusual and interesting is that it produces nanowires capable of transferring electrons.

"That lends itself to connecting to electronic devices that have already been made," Sawyer said. "So, it's the interface between the living world and the manmade world that is fascinating."

Sawyer and Rees also found that, because their electronic signatures can be mapped and monitored, bacterial biofilms could also act as an effective nutrient sensor that could provide Jefferson Project researchers with key information about the health of an aquatic ecosystem like Lake George.

"This groundbreaking work using bacterial biofilms represents the potential for an exciting new generation of 'living sensors,' which would completely transform our ability to detect excess nutrients in water bodies in real-time. This is critical to understanding and mitigating harmful algal blooms and other important water quality issues around the world," said Rick Relyea, director of the Jefferson Project.

Sawyer and Rees plan to continue exploring how to optimally develop this bacterium to harness its wide-ranging potential applications.

"We sometimes get the question with the research: Why bacteria? Or, why bring microbiology into materials science?" Rees said. "Biology has had such a long run of inventing materials through trial and error. The composites and novel structures invented by human scientists are almost a drop in the bucket compared to what biology has been able to do."

The majority of U.S. gun owners support measures such as background checks, but report not vocally supporting these policies because they feel disrespected by health advocates.

A new Boston University School of Public Health (BUSPH) study sheds new light on the opinions and practices of U.S. gun owners, casting doubt on the way gun owners have been portrayed in policy discussions and media, and even how they perceive themselves.

The survey results, published in the American Journal of Preventive Medicine, show that the majority of gun owners support many gun violence prevention policies, including background checks, permit requirements, and prohibitions for individuals with domestic violence restraining orders. But most of these gun owners report that they do not make their support public because they are alienated by the rhetoric of gun violence prevention advocates.

"Most people think gun violence prevention is a contentious issue, but our survey reveals that gun owners overwhelmingly support policies such as universal background checks and red flag laws," says study co-author Claire Boine, a research scholar at BUSPH.

"Gun owners overwhelmingly support basic gun violence prevention policies, but they feel alienated because we in public health are not respecting their decision to own a gun for self-protection. This feeling of disrespect is what is keeping gun owners who support these policies from expressing their support publicly. Public health advocates must respect the decision that gun owners have made to protect themselves and their families. Educating gun owners about the risks associated with gun ownership is important, but needs to be done without criticizing gun owners or attacking gun culture," says study lead author Dr. Michael Siegel, professor of community health sciences at BUSPH.

The study is based on the responses of 2,086 gun owners in the 2019 National Lawful Use of Guns Survey.

The researchers found most gun owners in the U.S. view guns as a practical tool to protect themselves, and do not have strong identities as gun owners. Only 10% said they view guns as an important part of their identity, and 23% reported taking part in any gun-related activity more than rarely.

Ironically, only 8% of survey respondents identified themselves as being like the typical gun owner, according to the survey. "The NRA pulled one of the biggest illusions in history by making 8% of gun owners feel like they are the majority, and the other 92% feel like the minority. The NRA does not represent gun owners in this country, and it is time for the media and policymakers to give a voice to the silent majority," Boine says.

Despite the majority of the gun owners saying they support many gun violence prevention policies, 59% said they think that gun control advocates want to take their guns away. Among gun owners who said they supported universal background checks, 62% said that they nonetheless feel alienated from taking part in gun violence prevention because they perceive that gun control advocates are trying to eliminate aspects of gun culture.

"We need to view the decision to arm oneself for self-protection as a legitimate behavior," Siegel says. "We may not agree that it reduces actual risk, but if law-abiding gun owners feel disrespected, why should they believe that we are not aiming to take their guns away? That is respect that needs to be earned."

Boine notes that the survey found the policies with the least support among gun owners are the ones that ban certain types of firearms, while most gun owners support policies that instead focus on the risks associated with each potential firearm buyer. "Responsible gun owners don't want firearms to fall into the hands of people who are a danger to themselves or others," she says. "Policies that ban certain types of weapons and affect all gun owners alike make them feel like we are blaming them for the gun violence epidemic."

In previous research, Siegel and Boine have found that the policies that most effectively reduce gun violence are the ones that limit who can have a firearm, rather than what firearms are legal to own.

Analyses of lung fluid cells from COVID-19 patients conducted on the nation's fastest supercomputer point to gene expression patterns that may explain the runaway symptoms produced by the body's response to SARS-CoV-2.

A team led by Dan Jacobson of the Department of Energy's Oak Ridge National Laboratory used the Summit supercomputer at ORNL to analyze genes from cells in the lung fluid of nine COVID-19 patients compared with 40 control patients.

The computational analyses suggest that genes related to one of the body's systems responsible for lowering blood pressure -- the bradykinin system -- appear to be excessively "turned on" in the lung fluid cells of those with the virus. The results were published in eLife.

Based on their analyses, the team posits that bradykinin -- the compound that dilates blood vessels and makes them permeable -- is overproduced in the body of COVID-19 patients; related systems either contribute to overproduction or cannot slow the process. Excessive bradykinin leads to leaky blood vessels, allowing fluid to build up in the body's soft tissues.

Much attention has focused on what's known as the cytokine storm, a severe reaction in which the body releases an excess of cytokines, a variety of small proteins that help regulate the immune system. Jacobson's team thinks a bradykinin storm may instead be to blame for much of the viral pathogenesis. If the team's disease mechanism model is accurate and substantiated by experimental analysis, it may mean that existing medicines could be repurposed to slow the pathogenesis of COVID-19. This would require extensive clinical trials of drugs currently used to treat other bradykinin-related conditions.

"If we can block this pathogenesis in severe patients, we can keep the human response from going overboard and give their immune system time to fight off the virus so they can recover," Jacobson said.

The bradykinin storm could explain the wide variety of symptoms experienced by COVID-19 patients, such as muscle pain, fatigue, nausea, vomiting, diarrhea, headaches, and decreased cognitive function. Similar symptoms are also experienced by patients with other bradykinin-related conditions such as hereditary angioedema, a genetic condition that is characterized by episodes of severe swelling throughout the body.

"This is one of those rare times where you can really tie everything back to a eureka moment," said Jacobson, staff scientist in ORNL's Biosciences Division. "I was looking at data, and I suddenly saw some very distinct patterns happening in the pathways of the renin-angiotensin and bradykinin systems. That led us to do a deep dive of the gene families of the blood pressure regulatory system." The renin-angiotensin system, or RAS, and bradykinin pathway regulate blood pressure and fluid balance in the body.

Using the Summit and Rhea supercomputers at the Oak Ridge Leadership Computing Facility, the team compared the genes of COVID-19 patients against a control group and analyzed population-scale gene expression data -- 17,000 samples from uninfected individuals -- to see which genes were normally co-expressed, or turned on or off at the same time.

Summit is currently the nation's most powerful supercomputer, with a theoretical peak performance of 200 petaflops, or 200 quadrillion calculations per second. Jacobson and his colleagues required the power of Summit to run 2.5 billion correlation calculations that helped them understand the normal regulatory circuits and relationships for the genes of interest. With Summit, the team completed the calculations in one week rather than spending months doing them on a desktop computer.

Researchers found an increased expression of enzymes that can trigger the production of bradykinin and a decreased expression of enzymes that would break down bradykinin -- the perfect storm. The team also uncovered that an enzyme that forestalls the bradykinin cascade -- the angiotensin-converting enzyme, known as ACE -- was less expressed in COVID-19 patients. At least ten existing drugs are known to act on the specific pathways Jacobson's team studied, but large-scale clinical trials are needed to determine whether they might be effective at treating COVID-19.

"We believe that when you take the inhibition at the top of this pathway off, you end up with an out-of-control cascade that leads to an opening up of the blood vessels, causing them to leak," Jacobson said. "If that happens in the lung, that's not good. Immune cells that are normally contained in the blood vessels flood into the surrounding infected tissue, causing inflammation."

The lungs of COVID-19 patients are known to have an increased amount of hyaluronic acid, a gooey substance found in connective tissues that can trap around 1,000 times its own weight in water to form a hydrogel. The team also found that genes in the cells of COVID-19 patients increased the production of the substance and decreased its breakdown. The findings suggest that further experimental study of drug compounds known to slow the synthesis of hyaluronic acid and the mechanisms involved in the process is warranted.

"When the lungs end up with an excess of hyaluronic acid in them, it's like trying to breathe through Jell-O," Jacobson said. "It reaches a point where regardless of how much oxygen you pump in, it doesn't matter, because the alveoli in the lungs are filled with this hydrogel. With this excess of hyaluronic acid, any water leaking out of the blood vessels due to bradykinin will soak up this structure and the lungs become like a water balloon."

The team also used the Compute and Data Environment for Science, or CADES, at ORNL to determine which genes in the RAS-bradykinin pathways have vitamin D binding sites. The results of their analyses might help scientists determine through experimentation which parts of these pathways could potentially be influenced by vitamin D. Because vitamin D helps regulate the RAS and vitamin D deficiencies have already been associated with more severe illness in COVID-19 patients, Jacobson said it's another molecule worth further study.

WASHINGTON, D.C.--The signs of physical abuse among elderly people can be challenging for health care professionals to recognize, resulting in as few as one in 24 cases being reported to authorities. However, a new study in Annals of Emergency Medicine explores injury patterns and characteristics to help experts spot key differences between abuse and unintentional injury.

"The first place that many vulnerable older patients turn for care is the emergency department," said lead study author Tony Rosen, MD, MPH, FACEP, assistant professor of emergency medicine at Weill Cornell Medicine and director of the Vulnerable Elder Protection Team based at New York-Presbyterian/Weill Cornell Medical Center's emergency department. "Emergency physicians have a unique opportunity to identify the 'red flags' for elder abuse. Improving the ability to recognize, treat, and prevent these incidents can improve the lives of millions of older patients."

The study, "Identifying Injury Patterns Associated with Physical Elder Abuse: Analysis of Legally Adjudicated Cases," compares 78 physical abuse cases with visible injuries among patients aged 60 or older with 78 patients of similar age and sex who visited a New York City emergency department for an unintentional fall between 2001-2014.

Abuse-related injuries are frequently attributed to an unintentional fall, the authors note. By comparing a group of patients injured by an unintentional fall with medical and legal records of prosecuted abuse cases, the study reveals several distinct injury patterns:

Victims of abuse often have head or neck injuries without visible harm to other parts of the body. Abuse victims are more likely than patients who fall to have injuries on the face, head and neck area (67 percent versus 28 percent).

Abuse victims are less likely than patients who fall to have scrapes, fractures or injuries below the waist (8 percent versus 50 percent).

Facial injuries to the left cheek are frequent (22 percent) in abuse cases; a finding that confirms that abusers tend to be right-handed, the authors note.

Neck injuries raise suspicions of abuse because the neck is often protected by the head or the face during an unintentional fall. Among more than 800 examined injuries, researchers found neck injuries and ear injuries resulted from abuse rather than a fall (15 percent versus 0 percent for neck injuries and 6 percent versus 0 percent for ear injuries).

According to the study, 22 percent of cases identified and prosecuted had no visible injury recorded. In many of these cases, victims indicated pain in the arms, chest, abdomen, back, face and jaw, which can inform how to approach patients without visible injury when abuse is suspected.

"Identifying the victims of elder abuse is an important skill set for professionals working in emergency departments caring for older adults," said Dr. Rosen. "Recognizing injury patterns helps encourage an environment where more of these troubling cases of harm against some of the most vulnerable, at-risk older adult patients can be reported and addressed."

East Hanover, NJ. July 28, 2020. Researchers at Kessler Foundation conducted a pilot study comparing the effects of mental fatigue on brain activation patterns in people with and without multiple sclerosis (MS). Their findings indicate significant differences between the two groups in their recruitment of neural resources in response to increased task demands. The article, "Neural mechanisms underlying state mental fatigue in multiple sclerosis: A pilot study," was published in the Journal of Neurology on April 29, 2020. (Doi: 10.1007/s00415-09853-w) The authors are Michelle H. Chen, PhD, Glenn Wylie, DPhil, Rosalia Dacosta-Aguayo, PhD, John DeLuca, PhD, and Helen Genova, PhD, of Kessler Foundation, and Brian M. Sandroff, PhD, of the University of Alabama at Birmingham.

This pilot study extended the Foundation's investigation into the neural correlates of mental fatigue in MS. Mental fatigue comprises two types, state and trait, which are typically measured subjectively. The current study focused on state fatigue, which fluctuates over minutes to hours; trait fatigue is stable over longer periods, usually weeks.

The study comprised 36 participants, 19 with MS, and 17 controls. Participants underwent functional magnetic resonance imaging (fMRI) while performing the Symbol Digit Modalities Test (SDMT), a standard cognitive test modified for use with fMRI. Changes in brain activity were recorded while the SDMT was administered under two conditions: high and low cognitive loads. Neuroimaging studies were conducted at the research-dedicated Rocco Ortenzio Neuroimaging Center at Kessler Foundation.

"We found higher levels of fatigue and longer response times in the MS group," said Dr. Chen, postdoctoral fellow in the Center for Neuropsychology and Neuroscience Research at Kessler Foundation. "With increasing mental fatigue, the control group showed increased activation of the anterior brain regions and faster speed of response, to meet the demands of the high load condition, " added Dr. Chen. "The MS group did not show activation of these regions or an increase in processing speed, suggesting a less efficient response to the higher cognitive demands of the task."

Results of the pilot study were consistent with prior research into the functional reorganization of brain activity in response to mental fatigue, according to Dr. Genova, assistant director of the Center for Neuropsychology and Neuroscience Research. "In the absence of effective treatment for the disabling fatigue that affects many individuals with MS, it is essential to expand our understanding of these underlying brain mechanisms. Using fMRI allows us to determine how individuals with MS differ from their peers without MS in their cerebral responses to cognitive challenges, an important first step in the development of interventions to counter mental fatigue."

In a new study from the Wake Forest Institute for Regenerative Medicine (WFIRM) researchers have developed an optimized cellular platform for delivering Factor 8 to better treat patients with hemophilia A.

Hemophilia A is a genetic disorder caused by a deficiency in, or the absence of, coagulation Factor 8), an essential protein for blood to clot. Hemophilia A is an x-linked genetic disease, and thus almost always affects males, and it occurs in 1 in 5,000 live male births. Roughly 20,000 individuals in the United States suffer from hemophilia A, and it is estimated that more than 400,000 people worldwide have this devastating disease, according to http://www.hemophilia.org. Hemophilia A is currently treated with infusions of expensive Factor 8 products 2-3 times per week for the entire life of the patient.

While these treatments have dramatically improved the life expectancy of patients with hemophilia A, they are unavailable to nearly 75% of the world's patients, they cost well over $250,000 a year (per patient), and complications can send the price tag to more than $1 million. Moreover, as many as 30% of patients with the severe form of hemophilia A develop an immune response (inhibitors) to the infused Factor 8 protein, rendering subsequent treatments ineffective and placing the patient at risk of life-threatening bleeding events. In addition, and perhaps most important, these treatments are not curative.

The delivery of Factor 8 through gene and/or cellular platforms has, therefore, emerged as a promising approach to provide long-term correction of hemophilia A. For this study, the researchers investigated the suitability of human placental cells as delivery vehicles for Factor 8 and determined an optimal Factor 8 transgene to secrete therapeutic Factor 8 levels from these cells. Using cells that are modified to over express Factor 8 allows safeguards in production that are not possible when direct vector injection is used to treat patients.

"This is about the quality of life for these patients," said lead author Graca Almeida-Porada, MD, PhD of WFIRM. "We are trying to develop not just a treatment, but a cure."

The research group demonstrated, for the first time, that human placental cells constitutively secrete low levels of Factor 8, confirming these cells possess the machinery necessary to express and process this challenging protein, and suggesting they may be ideally suited as a cellular platform for delivering and producing Factor 8 to correct hemophilia A.

"We demonstrated human placenta-derived mesenchymal cells possess a set of several fairly unique properties that make them ideal both for cellular therapies/regenerative medicine, and as vehicles for Factor 8 delivery," said Almeida-Porada. "In addition, because the pharmaceutical properties of Factor 8 can be markedly enhanced by changing the coding sequence to facilitate Factor 8 processing and secretion by the cells, we identified a modified Factor 8 transgene, amongst the several developed by our colleagues at Emory, that yielded optimal Factor 8 expression and secretion from placental cells."

While our initial goal is to use this treatment to correct hemophilia A prior to birth, Almeida-Porada said the approach could also be used in those pediatric and adult patients who develop Factor 8 inhibitors during their lifetime. Further preclinical studies will be needed to establish in vivo safety and efficacy of this therapy, for both prenatal and postnatal recipients, she added.

"It is our hope this approach can be moved forward as a long-lasting and curative treatment option for patients with hemophilia A," added co-author and WFIRM Director Anthony Atala, MD.

AMHERST, Mass. - Evolutionary and developmental biologist Craig Albertson and colleagues at the University of Massachusetts Amherst report that they have identified a molecular mechanism that allows an organism to change the way it looks depending on the environment it is exposed to, a process known as phenotypic plasticity.

In addition to lead investigators Albertson and Rolf Karlstrom, the team includes recently graduated doctoral students Dina Navon and Ira Male, current Ph.D. candidate Emily Tetrault and undergraduate Benjamin Aaronson. Their paper appears now in Proceedings of the National Academy of Sciences.

Albertson explains that the project stems from a desire to better understand how genes and the environment interact to direct anatomical shape. "We know that our features are determined by genes, but we also know that many physical features are shaped by the environment as well. In identical twins, for example, if one becomes a long-distance runner and the other a body builder, they are going to end up with very different physiques. The skeleton is especially sensitive to such environmental inputs."

Albertson works with a system - cichlid fishes - known throughout the scientific world as champions of phenotypic plasticity that can alter, in a single season, jawbone hardness or shape to match feeding conditions. They are also well known for their rapid evolution and diversity in jaw shapes, which has enabled cichlids to adapt to many different food sources, including algae, plankton, fish, snails and even the scales of other fishes.

Albertson has spent much of the past two decades trying to reveal the genetic differences that underlie differences in jaw shape between species. Now he and colleagues identify the well-studied chemical/molecular system known as the Hedgehog (Hh) signaling pathway as an important player. More recently he explored whether the same pathway might also contribute to differences in jaw shape that arise within species through phenotypic plasticity.

An important clue came as Albertson learned more about how this molecular pathway works. He explains, "There is a well-known mechano-sensor on most cells, including those that make the skeleton, called the primary cilium. Cells that lack this organelle are unable to sense or respond to environmental input, including mechanical load. It turns out that several key protein components of the Hedgehog pathway are physically associated with this structure, making it an obvious candidate for an environmentally sensitive signal."

In the current study, the research team first showed that plasticity in the rate of bone deposition in cichlids forced to feed using different foraging modes was associated with different Hh levels. Greater levels of the signal were detected in fish from the environment where more bone was laid down and vice versa. To really nail the question, Albertson teamed up with Karlstrom, who had previously developed sophisticated tools to study Hh signaling in zebrafish.

He explains, "Rolf has a bunch of really slick transgenic systems for manipulating that molecular signal in real time. It is sort of like a volume knob on your stereo - you can turn it up or turn it down, and then see how it influences your trait of interest." In this case, they wanted to see whether Hh levels influenced plasticity in bone deposition rates.

They found that unmanipulated zebrafish deposited different amounts of bone in different foraging environments. When Hh levels were reduced, these differences went away, but when Hh levels were increased, differences in bone deposition rates were dramatically increased.

Albertson, explains, "Bone cells in these fish are innately sensitive to different mechanical environments. But we were able to play with this system using a single molecular switch - you turn up the Hh signal and the cells become more sensitive to the environment, or you turn the molecular sensor down and the cells become almost deaf to the environment."

"That the same molecular machinery underlies both the evolutionary divergence and plasticity of the jaw is notable," Albertson explains. "It is consistent with long-held theory that suggests short-term plasticity might bias the direction of long-term evolution, which explains why evolution can be predictable in lineages that have repeatedly evolved to similar habitats." Albertson adds, "The Hh signal has also been shown to regulate plasticity in beetle horns, so there may be something special that positions it to be an environmental sensor across tissues and animals."

Such intriguing questions will be the topic for future investigations, the authors add.

"A watched pot never boils," as the saying goes, but that was not the case for UC Santa Barbara researchers watching a "pot" of liquids formed from DNA. In fact, the opposite happened.

With research partners at the Ludwig-Maximilians University (LMU), in Munich, Germany, the team's findings appear in the Proceedings of the National Academy of Sciences.

Recent advances in cellular biology have enabled scientists to learn that the molecular components of living cells (such as DNA and proteins) can bind to each other and form liquid droplets that appear similar to oil droplets in shaken salad dressing. These cellular droplets interact with other components to carry out basic processes that are critical to life, yet little is known about how the interactions function. To gain insight into these fundamental processes, the researchers used modern methods of nanotechnology to engineer a model system -- a liquid droplet formed from particles of DNA -- and then watched those droplets as they interacted with a DNA-cleaving enzyme.

Surprisingly, they found that, in certain cases, adding the enzyme caused the DNA droplets to suddenly start bubbling, like boiling water.

"The bizarre thing about the bubbling DNA is that we didn't heat the system; it's as if a pot of water started boiling even though you forgot to turn on the stove," said project co-leader Omar Saleh, a UC Santa Barbara assistant professor of materials and bioengineering. However, the bubbling behavior didn't always occur; sometimes adding the enzyme would cause the droplets to shrink away smoothly, and it was unclear why one response or the other would occur.

To get to the bottom of this mystery, the team carried out a rigorous set of precision experiments to quantify the shrinking and bubbling behaviors. They identified two types of shrinking behavior: the first caused by enzymes cutting the DNA only on the droplet surface, and the second caused by enzymes penetrating inside the droplet. "This observation was critical to unraveling the behavior, as it put into our heads the idea that the enzyme could start nibbling away at the droplets from the inside," said co-leader Tim Liedl, a professor at the LMU, where the experiments were conducted.

By comparing the droplet response to the DNA particle design, the team cracked the case: they found that bubbling and penetration-based shrinking occurred together, and happened only when the DNA particles were lightly bound together, whereas strongly bound DNA particles would keep the enzyme on the outside. As Saleh noted, "It's like trying to walk through a crowd -- if the crowd is tightly holding hands, you wouldn't be able to get through."

The bubbles, then, happen only in the lightly bound systems, when the enzyme can get through the crowded DNA particles to the interior of the droplet, and begin to eat away at the droplet from the inside. The chemical fragments created by the enzyme lead to an osmotic effect in which water is drawn in from the outside, causing a swelling phenomenon that produces the bubbles. The bubbles grow, reach the droplet surface, and then release the fragments in a burp-like gaseous outburst. "It is quite striking to watch, as the bubbles swell and pop over and over," said Liedl.

The work demonstrates a complex relationship between the basic material properties of a biomolecular liquid and its interactions with external components. The team believes that the insight gained from studying the bubbling process will lead both to better models of living processes and to enhanced abilities to engineer liquid droplets for use as synthetic bioreactors.

The research was made possible by an award to Saleh from the Alexander von Humboldt Foundation, which enabled him to visit Munich and work directly with Liedl on this project. "These types of international collaborations are extremely productive," Saleh said.

URBANA, Ill. - As climate change becomes increasingly difficult to ignore, scientists are working to diversify and improve alternatives to fossil-fuel-based energy. Renewable bioenergy crops, such as the perennial grass Miscanthus, show promise for cellulosic ethanol production and other uses, but current hybrids are limited by environmental conditions and susceptibility to pests and diseases.

Breeders have been working to develop new Miscanthus hybrids for years, but the clonal crop's sterility, complex genome, and long time to maturity make conventional breeding difficult. In a new study, University of Illinois researchers mine the crop's vast genomic potential in an effort to speed up the breeding process and maximize its most desirable traits.

"The method we're using, genomic selection, can shorten the time it takes to breed a new hybrid by at least half," says Marcus Olatoye, lead author on the study and postdoctoral researcher in the Department of Crop Sciences at Illinois. "That's the overall goal."

In conventional breeding, one typical approach is for researchers to grow individuals from a diverse set of populations and select those with the best traits for mating. But, for Miscanthus, those traits don't show up until plants are 2-3 years old. Even after plants from this first generation are mated, it takes the offspring another 2-3 years to reveal whether the desired traits were faithfully passed on.

In genomic selection, scientists take genetic samples from seeds or seedlings in a target population. This is the group of plants that would ordinarily have to be grown to maturity before experimental crosses are made. Meanwhile, the researchers compile both genetic and phenotypic data from related populations, known as reference or training sets, into a statistical model. Cross-referencing genetic data from the target population with data in the model allows the researchers to predict the phenotypic outcome of hypothetical crosses within the target population.

This allows breeders to cut to the chase, pursuing only the most promising crosses with further field testing.

"Ideally, this process could allow breeders to make selections based on predicted phenotypic values before plants are even planted," says Alex Lipka, associate professor of biometry in the Department of Crop Sciences and co-author on the study. "Specifically, we want to make selections to optimize winter hardiness, biomass, disease tolerance, and flowering time in Miscanthus, all of which limit the crop's performance in various regions of North America."

Although it's not a simple process in the best of times, genomic selection in Miscanthus is orders of magnitude more challenging than in other crops. The hybrid of interest, Miscanthus × giganteus, is the product of two separate species, Miscanthus sinensis and Miscanthus sacchariflorus, each of which have different numbers of chromosomes and contain a great deal of variation within and across natural populations.

"As far as we know, no one has tried to train genomic selection models from two separate species before. We decided to go totally nuts here," Lipka says. "Unfortunately, we found the two parent species do not do a very good job of predicting biofuel traits in Miscanthus × giganteus."

The problem was twofold. First, the statistical model simply revealed too much genetic variation among parental subpopulations to capture the impact of genes controlling biofuel traits. This meant the parental populations chosen for the reference set were too diverse to reliably predict traits in the hybrid Miscanthus × giganteus. And second, the genes controlling a particular trait - like those related to biofuel potential - seemed to be different in the two parent species.

In other words, the genomes contributing to Miscanthus × giganteus are highly complex, explaining why the statistical approach had a hard time predicting traits in offspring from the two parents.

Still, the research team kept trying. In a simulation study, Olatoye created 50 Miscanthus × giganteus families, each derived from parents randomly selected from both species. He selectively dialed genetic contributions of each parent up and down, and these contributions formed the genetic basis of simulated phenotypes. The intention of the study was to provide a better view of which individuals and populations might be most valuable for crosses in real life.

"The results suggest the best strategy for utilizing diversity in the parents is to fit genomic selection models within each parental species separately, and then add the predicted Miscanthus × giganteus trait values from the two models separately," Olatoye says.

Although the researchers have more work to do, the simulation study proved genomic selection can work for Miscanthus × giganteus. The next step is further refining which populations are used to train the statistical model and evaluating crosses in the field.