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NEXT-GEN CHOLESTEROL DRUG WORKS FAST AFTER A HEART ATTACK TO LOWER 'BAD' CHOLESTEROL

Media Contact: Vanessa McMains, Ph.D., vmcmain1@jhmi.edu

Within a month following a heart attack, people are at increased risk for a second one. As a result, physicians treat these patients with medications to rapidly reduce cardiovascular risk factors for another event. Although statins are designed to reduce the risk from one underlying problem, low-density lipoprotein (LDL) or "bad" cholesterol, they often aren't able drop it to recommended levels within 30 days.

Now, testing a next-generation cholesterol-lowering drug known as a PCSK9 inhibitor, Johns Hopkins Medicine researchers showed they could lower blood cholesterol to safer levels faster when it is added to traditional therapies.

Although larger studies are needed to assess other outcomes, the researchers say the early finding, published July 27, 2020, in Circulation, suggests that a PCSK9 inhibitor is safe to use, significantly lowers LDL cholesterol during hospitalization and achieves the reduction within the month following a heart attack.

"As these are the most vulnerable patients, we need to most aggressively treat them to lower their risk factors," says Thorsten Leucker, M.D., Ph.D., assistant professor of medicine at the Johns Hopkins University School of Medicine. "With our study showing that we can lower these bad cholesterol levels with a PCSK9 inhibitor -- which in stable patients decreases cardiovascular events -- we hope that this approach also will reduce secondary events and perhaps even prevent early deaths in patients after an acute heart attack."

For the study, 57 people were randomly assigned to get either one dose of the cholesterol-lowering drug evolocumab -- which reduces activity of the PCSK9 protein and increases LDL cholesterol levels in the bloodstream -- or a placebo after they were admitted to the hospital for a heart attack. Over the course of the 30-day study period, the patients on evolocumab had their bad cholesterol reduced on average by 28.6 milligrams per deciliter more than patients given the placebo.

Upon hospital discharge, 80.1% of patients given the PCSK9 inhibitor were at or below the American Heart Association/American College of Cardiology recommended LDL cholesterol targets of 70 milligrams per deciliter compared with 38.1% of people given the placebo.

For future studies, the researchers plan to see whether the drug also reduces inflammation in the heart muscle and arteries to improve the healing and functioning of the heart following a severe heart attack.

Leucker and co-author Michael Blaha, M.D., M.P.H., professor of medicine at the Johns Hopkins University School of Medicine, are paid advisory board members to Amgen Inc. Amgen provided monetary and material support for this study. This arrangement has been reviewed and approved by The Johns Hopkins University in accordance with its conflict of interest policies.

CELLS UNDER STRESS GET INTO MOLECULAR 'TRAFFIC JAMS,' TRIGGERING A SUICIDE PATHWAY

Media Contact: Vanessa Wasta, M.B.A., wasta@jhmi.edu

When cells experience a high level of stress -- for example, when they are exposed to too much UV light -- ribosomes inside the cell collide and get into traffic jams. Now, Johns Hopkins scientists have found a protein that recognizes this traffic problem and pushes the cell down a path toward cell suicide.

Molecular understanding of this pathway could lead to ways to control its outcome. A report of the research was published June 30, 2020, in the journal Cell.

Molecular biologist Rachel Green, Ph.D., and her team have long been studying how cells recognize problems within their coding information and how this recognition relies on cellular structure called the ribosome. These problems can arise from errors encoded in the genome or from environmental damage to the cell.

The ribosome travels along a piece of genetic material called messenger RNA (mRNA). The ribosome's job is to decode the mRNA to provide a set of instructions for making a protein. When cell stress increases, and mRNAs are damaged, ribosomes can't travel down the mRNA highway, and they tend to collide with each other like molecular bumper cars. Since these ribosomes fail to reach the end of the mRNA, they produce incomplete proteins.

"Incomplete proteins aggregate and cause diseases," says Green, a Bloomberg Distinguished Professor of molecular biology and genetics at the Johns Hopkins University School of Medicine and Howard Hughes Medical Institute investigator. "The cell needs to stop incomplete proteins from being produced and aggregating."

When ribosome collisions aren't too abundant, cells can often recover. They initiate a pathway called the integrated stress response, which keeps them from dying. However, if the collisions are causing a major traffic headache, cells trigger the ribotoxic stress response, a pathway to cell suicide.

Green and her team aimed to find out how cells assess traffic conditions and spot these ribosomal collisions. So, they added an antibiotic that blocks ribosome movement to mammalian cells cultured in the laboratory.

The scientists found no problems with the traffic flow of ribosomes in untreated cells. With a high dose of the antibiotic, they found that ribosomes simply stopped moving all together. However, when the scientists treated the cells with an intermediate dose of the antibiotic, they saw widespread ribosome collisions in the cell, and to their surprise, activation of proteins involved in both the life-promoting integrated stress response and the death-promoting ribotoxic stress response.

In collaboration with her colleague, Johns Hopkins scientist Sergi Regot, Ph.D., Green identified a critical protein, called ZAK, which is part of a family of proteins called MAP3K. ZAK binds to colliding ribosomes and is itself activated.

Her team is planning studies to determine precisely where ZAK binds to ribosomes by using a cryoelectron microscope to create a 3D rendering of its structure. Green also aims to learn how different cell types may be more or less vulnerable to ribosome collisions.

Green says an exciting potential outcome of the research is that the ZAK-mediated molecular pathway could be targeted with drugs to alter cell fate when they are under stress in health and disease.

INTERNATIONAL JOHNS HOPKINS STUDY SAYS BROAD MEASURES NEEDED TO PREVENT TB SPREAD IN INDIA

Media Contact: Michael E. Newman, mnewma25@jhmi.edu

While tuberculosis, or TB, may not be a major health problem in the United States, the World Health Organization (WHO) reports it is still the leading cause of death worldwide from a single infectious agent (the microbe Mycobacterium tuberculosis) and is responsible for some 1.5 million fatalities annually. TB is especially serious in India, the country that accounts for 27% of all global cases of the disease.

Recently, the WHO changed its guidance for preventive treatment in countries with a high TB prevalence, recommending proactive drug therapy for all members of households exposed to TB by someone in the home with the pulmonary form of the disease. This is a departure from the current national guidelines in India that only require preventive TB therapy for children under age 6 and people living with the human immunodeficiency virus (HIV).

However, the new WHO recommendations for broader preventive measures is conditional and not based on strong evidence, so health officials in countries such as India wanted more proof that a switch in policy was warranted. Thanks to a new research study led by Johns Hopkins Medicine in collaboration with two Indian medical institutions, science and statistics are now backing the move.

The C-TRIUMPH (Cohort for TB Research with Indo-US Medical Partnership) study, which was reported in the July 29, 2020, issue of the journal PLOS One, was conducted under the Regional Prospective Observational Research in Tuberculosis Consortium for India (RePORT India), a consortium of coordinated TB research efforts across India funded by the governments of India and the United States. RePORT India is part of RePORT International, a larger collaborative undertaking similar work in five other high-burden TB nations: Brazil, China, Indonesia, the Philippines and South Africa.

The collaborating institutions on the study in India are the BJ Government Medical College (BJGMC) in Pune and the National Institute of Research in TB (NIRT) in Chennai.

The research team that conducted the study in India was directed by Amita Gupta, M.D., professor of medicine at the Johns Hopkins University School of Medicine. The data analysis was led by Mandar Paradkar, M.B.B.S., D.C.H., M.P.H., study coordinator at the BJGMC Clinical Research Site in Pune, in coordination with U.S. senior author Robert Bollinger, M.D., the Raj and Kamla Gupta Professor of Infectious Diseases and professor of medicine at the Johns Hopkins University School of Medicine.

For their study, the researchers in India enrolled 1,051 adults in the cities of Pune and Chennai who had been exposed to someone in their household with pulmonary TB. The 997 participants who completed the study were screened for both TB infection (presence of the bacteria) and TB disease using clinical, microbiologic and radiologic methods at enrollment, at sometime between four and six months, and at 12 and 24 months.

"We found that 707 of the 997 participants, or 71%, tested positive for TB infection at the start, and 20, or 2%, subsequently developed the disease during 24-month follow-up period," says Paradkar. "Based on these numbers, we estimate that that 12 people per 1,000 per year will get TB disease through a household contact. This is a large enough rate to support the new WHO guidelines for stopping the spread of the bacteria, calling for all residents in households with TB present to receive therapy without needing to first be tested for infection."

Paradkar adds that the development of TB disease through household exposure was not associated with smoking, alcohol consumption, diabetes mellitus or when TB infection was detected during the study period.

To increase the effectiveness of TB prevention on a large scale, the new WHO recommendations provide options for shorter-duration treatments in addition to the previous course of the antibiotic isoniazid daily for six months. The alternatives include: one month daily regimen of another antibiotic, rifapentine, plus isoniazid; three months weekly rifapentine plus isoniazid; three months daily rifampicin plus isoniazid; or four months of daily rifampicin alone.

"The findings from our study will help inform national protocols for the screening of household contacts of TB patients and the administration of appropriate preventive therapy in India and other high-burden TB regions of the world," says Bollinger.

CAMBRIDGE, MA -- Humans began to develop systems of reading and writing only within the past few thousand years. Our reading abilities set us apart from other animal species, but a few thousand years is much too short a timeframe for our brains to have evolved new areas specifically devoted to reading.

To account for the development of this skill, some scientists have hypothesized that parts of the brain that originally evolved for other purposes have been "recycled" for reading. As one example, they suggest that a part of the visual system that is specialized to perform object recognition has been repurposed for a key component of reading called orthographic processing -- the ability to recognize written letters and words.

A new study from MIT neuroscientists offers evidence for this hypothesis. The findings suggest that even in nonhuman primates, who do not know how to read, a part of the brain called the inferotemporal (IT) cortex is capable of performing tasks such as distinguishing words from nonsense words, or picking out specific letters from a word.

"This work has opened up a potential linkage between our rapidly developing understanding of the neural mechanisms of visual processing and an important primate behavior -- human reading," says James DiCarlo, the head of MIT's Department of Brain and Cognitive Sciences, an investigator in the McGovern Institute for Brain Research and the Center for Brains, Minds, and Machines, and the senior author of the study.

Rishi Rajalingham, an MIT postdoc,, is the lead author of the study, which appears today in Nature Communications. Other MIT authors are postdoc Kohitij Kar and technical associate Sachi Sanghavi. The research team also includes Stanislas Dehaene, a professor of experimental cognitive psychology at the Collège de France.

Word recognition

Reading is a complex process that requires recognizing words, assigning meaning to those words, and associating words with their corresponding sound. These functions are believed to be spread out over different parts of the human brain.

Functional magnetic resonance imaging (fMRI) studies have identified a region called the visual word form area (VWFA) that lights up when the brain processes a written word. This region is involved in the orthographic stage: It discriminates words from jumbled strings of letters or words from unknown alphabets. The VWFA is located in the IT cortex, a part of the visual cortex that is also responsible for identifying objects.

DiCarlo and Dehaene became interested in studying the neural mechanisms behind word recognition after cognitive psychologists in France reported that baboons could learn to discriminate words from nonwords, in a study that appeared in Science in 2012.

Using fMRI, Dehaene's lab has previously found that parts of the IT cortex that respond to objects and faces become highly specialized for recognizing written words once people learn to read.

"However, given the limitations of human imaging methods, it has been challenging to characterize these representations at the resolution of individual neurons, and to quantitatively test if and how these representations might be reused to support orthographic processing," Dehaene says. "These findings inspired us to ask if nonhuman primates could provide a unique opportunity to investigate the neuronal mechanisms underlying orthographic processing."

The researchers hypothesized that if parts of the primate brain are predisposed to process text, they might be able to find patterns reflecting that in the neural activity of nonhuman primates as they simply look at words.

To test that idea, the researchers recorded neural activity from about 500 neural sites across the IT cortex of macaques as they looked at about 2,000 strings of letters, some of which were English words and some of which were nonsensical strings of letters.

"The efficiency of this methodology is that you don't need to train animals to do anything," Rajalingham says. "What you do is just record these patterns of neural activity as you flash an image in front of the animal."

The researchers then fed that neural data into a simple computer model called a linear classifier. This model learns to combine the inputs from each of the 500 neural sites to predict whether the string of letters that provoked that activity pattern was a word or not. While the animal itself is not performing this task, the model acts as a "stand-in" that uses the neural data to generate a behavior, Rajalingham says.

Using that neural data, the model was able to generate accurate predictions for many orthographic tasks, including distinguishing words from nonwords and determining if a particular letter is present in a string of words. The model was about 70 percent accurate at distinguishing words from nonwords, which is very similar to the rate reported in the 2012 Science study with baboons. Furthermore, the patterns of errors made by model were similar to those made by the animals.

Neuronal recycling

The researchers also recorded neural activity from a different brain area that also feeds into IT cortex: V4, which is part of the visual cortex. When they fed V4 activity patterns into the linear classifier model, the model poorly predicted (compared to IT) the human or baboon performance on the orthographic processing tasks.

The findings suggest that the IT cortex is particularly well-suited to be repurposed for skills that are needed for reading, and they support the hypothesis that some of the mechanisms of reading are built upon highly evolved mechanisms for object recognition, the researchers say.

The researchers now plan to train animals to perform orthographic tasks and measure how their neural activity changes as they learn the tasks.

PULLMAN, Wash. - With social media use being as prevalent as ever, a new study from Washington State University's Edward R. Murrow College of Communication shows that adolescents may share marijuana-related content on social media in an effort to fit in with their peers.

Led by Murrow College Associate Professor Jessica Willoughby, this recently published study, "An Exploratory Study of Adolescents' Social Media Sharing of Marijuana-Related Content", examined the types of marijuana-related content that adolescents are posting on social media and what factors may influence adolescents' decisions to share marijuana-related content on social media.

The team of researchers surveyed 350 participants between the ages of 13-17 living in Washington state, where recreational marijuana use is legal for people 21 and older. The participants answered various questions related to their social media habits and whether they posted content relating to marijuana.

Previous research shows that young people may be exposed to a variety of marijuana-related content on social media, and this exposure may impact marijuana use. Other studies demonstrated youth and young adults' active engagement in displaying risky behaviors on social media, including marijuana use, which highlights a shared concern with the normalization of risky behaviors among young people.

"Nearly one-third of Washington adolescents we surveyed indicated that they shared marijuana-related content - primarily memes, pictures, and videos - on social media platforms such as Facebook, Snapchat, and Instagram," Willoughby said. "Even though many marijuana-related web sites require viewers to verify they are old enough to legally use the product, such verification processes are absent from social media."

"The adolescents we surveyed were also more likely to share marijuana-related social media content if they perceived their peers use marijuana and if they believed their parents would approve of them sharing such content," said Murrow College Associate Dean Stacey J.T. Hust, who is second author of the study. "In contrast, if they perceived that their parents were monitoring their behavior, in general, they were less likely to share marijuana-related content on social media.

"Essentially, adolescents who reported their parents were aware of where they were going and who they were spending time with, were less likely to share marijuana-related content," Willoughby said. "But, we didn't find an association between parents checking their adolescents' social media and the sharing of marijuana-related content."

The motives behind sharing marijuana-related content are still unclear, according to this study. As young people use social media for a variety of reasons, including to present themselves to others, it is important to gauge the risk-related messages youth display on social media and what may be associated with this sharing on social platforms.

"Overall, our findings suggest adolescents may post content that is inconsistent with their personal beliefs in a desire to conform to their peers," Hust said. This is of potential concern because young people tend to overestimate peer use and acceptance of substance use, and social media posting related to substance use may imply an intention to use substances or increase perceptions of their use.

Scientists have found a novel way to prevent pesky magnetic bubbles in plasma from interfering with fusion reactions - delivering a potential way to improve the performance of fusion energy devices. And it comes from managing radio frequency (RF) waves to stabilize the magnetic bubbles, which can expand and create disruptions that can limit the performance of ITER, the international facility under construction in France to demonstrate the feasibility of fusion power.

Magnetic islands

Researchers at the U.S. Department of Energy's (DOE) Princeton Plasma Physics Laboratory (PPPL) have developed the new model for controlling these magnetic bubbles, or islands. The novel method modifies the standard technique of steadily depositing radio (RF) rays into the plasma to stabilize the islands -- a technique that proves inefficient when the width of an island is small compared with the characteristic size of the region over which the RF ray deposits its power.

This region denotes the "damping length," the area over which the RF power would typically be deposited in the absence of any nonlinear feedback. The effectiveness of the RF power can be greatly reduced when the size of the region is greater than the width of the island -- a condition called "low-damping" -- as much of the power then leaks from the island.

Tokamaks, doughnut-shaped fusion facilities that can experience such problems, are the most widely used devices by scientists around the world who seek to produce and control fusion reactions to provide a virtually inexhaustible supply of safe and clean power to generate electricity. Such reactions combine light elements in the form of plasma -- the state of matter composed of free electrons and atomic nuclei that makes up 99 percent of the visible universe -- to generate the massive amounts of energy that drives the sun and stars.

Overcoming the problem

The new model predicts that depositing the rays in pulses rather than steady state streams can overcome the leakage problem, said Suying Jin, a graduate student in the Princeton Program in Plasma Physics based at PPPL and lead author of a paper (link is external) that describes the method in Physics of Plasmas. "Pulsing also can achieve increased stabilization in high-damping cases for the same average power," she said.

For this process to work, "the pulsing must be done at a rate that is neither too fast nor too slow," she said. "This sweet spot should be consistent with the rate that heat dissipates from the island through diffusion."

The new model draws upon past work by Jin's co-authors and advisors Allan Reiman, a Distinguished Research Fellow at PPPL, and Professor Nat Fisch, director of the Program in Plasma Physics at Princeton University and associate director for academic affairs at PPPL. Their research provides the nonlinear framework for the study of RF power deposition to stabilize magnetic islands.

"The significance of Suying's work," Reiman said, "is that it expands considerably the tools that can be brought to bear on what is now recognized as perhaps the key problem confronting economical fusion using the tokamak approach. Tokamaks are plagued by these naturally arising and unstable islands, which lead to disastrous and sudden loss of the plasma."

Added Fisch: "Suying's work not only suggests new control methodologies; her identification of these newly predicted effects may force us to re-evaluate past experimental findings in which these effects might have played an unappreciated role. Her work now motivates specific experiments that could clarify the mechanisms at play and point to exactly how best to control these disastrous instabilities."

Original model

The original model of RF deposition showed that it raises the temperature and drives current in the center of an island to keep it from growing. Nonlinear feedback then kicks in between the power deposition and changes in the temperature of the island that allows for greatly improved stabilization. Governing these temperature changes is the diffusion of heat from the plasma at the edge of the island.

However, in high-damping regimes, where the damping length is smaller than the size of the island, this same nonlinear effect can create a problem called "shadowing" during steady state deposition that causes the RF ray to run out of power before it reaches the center of the island.

"We first looked into pulsed RF schemes to solve the shadowing problem," Jin said. "However, it turned out that in high-damping regimes nonlinear feedback actually causes pulsing to exacerbate shadowing, and the ray runs out of power even sooner. So we flipped the problem around and found that the nonlinear effect can then cause pulsing to reduce the power leaking out of the island in low-damping scenarios."

These predicted trends lend themselves naturally to experimental verification, Jin said. "Such experiments," she noted, "would aim to show that pulsing increases the temperature of an island until optimum plasma stabilization is reached."

NASA's CloudSat passed over Tropical Storm Isaias as it was strengthening back into a hurricane on Aug. 3, and before it made landfall in North Carolina. CloudSat revealed areas of heavy rain and ice particles in high, powerful clouds.

Tropical Storm Isaias was going through a period of intensification from a tropical storm into a minimal hurricane as vertical wind shear weakened around the system. Wind shear is outside winds that can affect a tropical cyclone and weaken its structure or even blow it apart, if strong enough. The wind shear that had been affecting Isaias was weakening allowing the storm to intensify back into a hurricane as it did y 8 p.m. EDT on Aug. 3.

CloudSat passed east of the storm center revealing the large area of deep convection (rising air that condenses and forms the thunderstorms that make up a tropical cyclone). "The anvil of the system extended northwestward across North and South Carolina with maximum cloud heights estimated at 16-17 km (~10 to ~11 miles)," said Natalie Tourville of the Cooperative Institute for Research in the Atmosphere, Colorado State University, Fort Collins.

CloudSat also found areas of rain bands associated with Isaias in southeastern portion of the system. Those were smaller areas of convection over the Atlantic Ocean.

CloudSat is the first satellite to use an advanced cloud-profiling radar to "slice" through clouds to see their vertical structure, providing a completely new observational capability from space. The mission furnishes data that evaluate and improve the way clouds and precipitation are represented in global models, contributing to better predictions of clouds and their role in climate change.

New research from Boston Medical Center found that patients experiencing severe COVID-19 symptoms had improved outcomes when administered an Interleukin-6 (IL6ri) inhibitor, sarilumab or tocilizumab, given to mediate severe systemic inflammatory responses. The treatment was more effective when administered earlier in the disease course and reduced mortality rates and the need for intubation. Published in the International Journal of Infectious Diseases, the results show Interleukin-6 inhibitors appear to be a more effective treatment compared to other options, including remedesvir and dexamethasone, which are recommended and currently used in the pandemic.

Elevated IL-6 levels may mediate the severe systemic inflammatory responses that occur in patients with severe acute respiratory syndrome or a COVID-19 infection. The Boston Medical Center patients in this study were divided into two groups, stage IIB and stage III based on their fraction of inspired oxygen (FiO2). Patients requiring up to 45 percent FiO2 were considered to be stage IIB and those more severe who were requiring greater than 45 percent FiO2 were considered to be stage III. The discharge rate was higher for the stage IIB group compared to the stage III group, showing the impact that earlier administration can have throughout the progression of COVID-19. The average length of stay in the hospital was 12.9 days, but patients treated in stage IIB had a shorter average length of stay (11.3 days) than those in stage III (15 days). A total of 68 patients (26.7 percent) required mechanical ventilation, and of these patients, 44 were intubated 24 hours later, after receiving IL6ri.

"At a time where treatments are being tested with urgency throughout the COVID-19 pandemic, our study results offer some hope towards finding solutions to better treat patients throughout this disease," said Manish Sagar, MD, an infectious diseases physician and researcher at Boston Medical Center, and associate professor of medicine and microbiology at Boston University School of Medicine.

This observational study included 255 COVID-19-confirmed patients being treated with IL6ri during stage IIB (149 patients) and stage III of the disease (106 patients). An institutional treatment panel consisting of providers from departments of adult and pediatric infectious diseases, rheumatology and pulmonary/critical care, as well as clinical pharmacy specialists collaborated to provide recommendations for or against treatment using IL6ri. Once an appropriate patient was identified, they were given IL6ri (sarilumab or tocilizumab) based on iteratively reviewed guidelines. The IL6ri was initially reserved for critically ill patients, but after review, the treatment was liberalized to patients with lower oxygen requirements.

The IL6ri recipients in this study had considerably higher supplementary oxygen requirements, indicating more advanced disease than patients in previous remdesivir and dexamethasone trials, and would have been expected to have a higher mortality rate. The study's sampling-with-replacement analysis found that the patients who received IL6ri had a lower mortality rate than patients in the intervention and control groups of the remdesivir and dexamethasone trials. The 22.9 percent mortality rate for the 105 BMC patients that required ICU care (41.1 percent) was considerably lower than previously published 45-50 percent mortality in other ICU studies.

"The greatest benefit with IL6ri use was seen in patients who received the drug in an earlier stage, prior to critical respiratory decompensation, showing the importance of prompt testing and treatment," said Pranay Sinha, MD, also an infectious diseases physician and researcher at Boston Medical Center. "We speculate that immunomodulatory drugs like IL6ri or dexamethasone may be more effective before immune-mediated damage has occurred. We hope these findings can help guide physicians as we seek solutions to reduce mortality, increase extubation, reduce length of stay in the hospital, and have more patients discharged from the hospital alive."

More than 1,000 bottlenose dolphins (Tursiops truncatus) live in the Indian River Lagoon year-round. The estuary system along the central east coast of Florida stretches about 250 kilometers and provides valuable shallow water habitat for this species. The lagoon also is popular for recreational fishing spots, which often coincide with bottlenose dolphin feeding habitats because they target the same species of fish. In fact, it very common to observe interactions between dolphins and recreational fishermen. These interactions include dolphins going after bait or captured fish, illegal feeding of dolphins, and dolphin encounters during release of undersized or non-targeted fish.

Unfortunately, free-ranging common bottlenose dolphins can become entangled in fishing line and other marine debris. Reports of entanglement include a variety of items such as crab trap lines, human clothing, spearfishing gear, Frisbees, box strapping, and other objects. Infrequently, dolphins can be successfully disentangled and released back into the wild. It is rare, however, to encounter a case that can be followed from physically handling the dolphin at a disentanglement event to later recovering its carcass, enabling pathologic descriptions after an entanglement wound has healed.

Researchers from Florida Atlantic University's Harbor Branch Oceanographic Institute and collaborators from Earth Resources Technology, Inc., the National Marine Mammal Foundation, and Georgia Aquarium Conservation Field Station, conducted a case study to examine the outcome of an entangled bottlenose dolphin calf found in the Indian River Lagoon with monofilament fishing line wrapped tightly around its maxilla or upper jaw. A multi-agency team successfully disentangled the dolphin and immediately released it back into its natural habitat.

Because local bottlenose dolphin populations demonstrate site fidelity to the Indian River Lagoon, they are relatively easy to re-sight and monitor. The shallow, soft substrate in several inshore areas along the lagoon also allows for safe targeted capture and disentanglement efforts involving appropriately skilled biologists and veterinarians in cases where entanglements are deemed life threatening.

For the study, published in the journal BMC Veterinary Research, the researchers compared data collected on presentation during the disentanglement event to data later collected during re-sighting and necropsy. Results demonstrate long-term damage from the entanglement involving maxillary bones, dentition and soft tissues of the rostrum or snout. One year after disentanglement, photos and visual observations indicated that the now independent calf showed a decline in body condition, characterized by grossly visible ribs and a prominent post-nuchal depression, also known as "peanut-head," a prominent depression behind the skull, which is indicative of poor nutritional condition.

More than two years post-disentanglement, the freshly dead carcass of this juvenile dolphin was recovered with extensive predation wounds. Despite the forestomach being about?50 percent full of fish, the dolphin was emaciated. During postmortem examination, researchers collected and evaluated detailed photographs and measurements of the maxillary damage resulting from the entanglement.

"Entanglements in cetaceans such as dolphins can impede movement and impair foraging abilities, leading to starvation, systemic infections, and debilitation from severe tissue damage, pain and distress, and in some cases, death," said Annie Page-Karjian, D.V.M., Ph.D., assistant research professor and clinical veterinarian at FAU's Harbor Branch, who co-authored the paper with Wendy Marks, program coordinator, and Steve Burton, M.S., program director of stranding and population assessment, who are all members of the marine mammals stranding, health and rehabilitation project team.

The monofilament entanglement caused permanent, bilateral deformation of the maxillary dental arcade, including a 4 to 4.2?centimeter long, 0.5?centimeter deep linear groove where the entanglement eroded the lateral edges of the maxilla. Entanglement in this 2-year-old dolphin did not cause bone fracture but did lead to bone deformity and maxillary malocclusion. External evidence of propeller scars and a fishing hook was discovered embedded in the laryngeal mucosa at necropsy, indicating repeated human interactions. The dolphin only survived for about two years after disentanglement and release.

"Educating fishermen about the importance of reeling in their lines when dolphins are present and proper disposal of fishing line can help reduce the risk of these interactions with bottlenose dolphins," said Page-Karjian. "Less lost fishing gear and fewer injured or dead marine wildlife benefits everyone. While the quick response to disentangle this dolphin may have initially saved its life, prevention of learned fishery interaction behaviors could have prolonged his life beyond the two plus years that were gained."

CORVALLIS, Ore. - As a first-year graduate student studying truffle ecology at Oregon State University, Dan Luoma attended a scientific meeting in 1981 on Orcas Island in Washington. Having recently learned how to search for truffles, he went out one day of the meeting looking for the prized fungi and found a collection.

He brought them back to Oregon State and showed them to his mentor James Trappe, who confirmed the collection was of an undescribed species. Trappe added it to the university's collection. Then it sat there.

Almost four decades later, with the help of new scientific technologies, Trappe and several other scientists confirmed that the truffle is unique. They recently published their findings in the journal Fungal Systematics and Evolution recognizing it as a new species. Fittingly, it's named Tuber luomae after Luoma, who retired this year after 40 years at Oregon State.

"This truffle in 1981 was among the first truffles I ever found," Luoma said. "To have it named in my honor the year I retired completes the circle for me. It's a wonderful way to celebrate retirement."

Some truffle species are highly prized for culinary purposes because of their distinct flavor. These species, which are black, white or brown, are hard to find and exist in limited geographic areas, meaning they command high prices.

Oregon and the Pacific Northwest are home to several of those prized species, making the region one of the world's hot spots for truffle hunting. The species discovered by Luoma, though, is a red truffle, which doesn't have the distinct flavor sought by chefs and cooks.

While the culinary use of truffles and the thrill of searching for them gets a lot of attention, they and other fungi are important for the health of forests. They provide nutrients to plants and can also help plants withstand drought.

Luoma studied the ecology of truffles and fungi while earning his doctorate from Oregon State in 1988 and until earlier this year worked as a researcher at the university.

Several graduate students who worked with him during his early years planned to name the truffle species he found on Orcas Island in honor of Luoma, but they graduated before doing so.

Then about 10 years ago Trappe, now Luoma's colleague, searched the Oregon State truffle collections, the largest in the world with about 50,000 collections, looking for truffles similar to the one Luoma found on Orcas Island. Trappe found three.

Joyce Eberhart, a truffle researcher at Oregon State and Luoma's wife, and Greg Bonito, an assistant professor at Michigan State University, studied the DNA of those three and determined they were the same species as the Orcas Island truffle.

Those three were all found in Oregon - one each in Benton (found in 1962), Clackamas (1995) and Jackson (2012) counties. While the Benton County specimen was found before Luoma dug up the Orcas Island one, it was never fully described until Trappe noticed the similarities between the two. Now the known distribution of the new species extends from southwestern Oregon to northwestern Washington.

Carolina Piña Páez, a doctoral student at Oregon State who also does truffle research, provided the final piece by documenting the microscopic structures inside the truffle with photos, confirming that the spores and outer layers were that of a unique species.

Trappe, who has studied truffles for more than 60 years and has discovered 230 new truffle species, still gets excited about a new species, such as this one named after Luoma.

"Many dozens of professional and amateur mycologists have sought truffles in western Oregon for over 100 years, but only these four collections of Luoma's truffle have been found. Each of those seems to be quite local in distribution, indicating that it's a very rare fungus," Trappe said.

A notable characteristic of several neurodegenerative diseases, such as Alzheimer's and Parkinson's, is the formation of harmful plaques that contain aggregates--also known as fibrils--of amyloid proteins. Unfortunately, even after decades of research, getting rid of these plaques has remained a herculean challenge. Thus, the treatment options available to patients with these disorders are limited and not very effective.

In recent years, instead of going down the chemical route using drugs, some scientists have turned to alternative approaches, such as ultrasound, to destroy amyloid fibrils and halt the progression of Alzheimer's disease. Now, a research team led by Dr Takayasu Kawasaki (IR-FEL Research Center, Tokyo University of Science, Japan) and Dr Phuong H. Nguyen (Centre National de la Recherche Scientifique, France), including other researchers from the Aichi Synchrotron Radiation Center and the Synchrotron Radiation Research Center, Nagoya University, Japan, has used novel methods to show how infrared-laser irradiation can destroy amyloid fibrils.

In their study, published in Journal of Physical Chemistry B, the scientists present the results of laser experiments and molecular dynamics simulations. This two-pronged attack on the problem was necessary because of the inherent limitations of each approach, as Dr Kawasaki explains, "While laser experiments coupled with various microscopy methods can provide information about the morphology and structural evolution of amyloid fibrils after laser irradiation, these experiments have limited spatial and temporal resolutions, thus preventing a full understanding of the underlying molecular mechanisms. On the other hand, though this information can be obtained from molecular simulations, the laser intensity and irradiation time used in simulations are very different from those used in actual experiments. It is therefore important to determine whether the process of laser-induced fibril dissociation obtained through experiments and simulations is similar."

The scientists used a portion of a yeast protein that is known to form amyloid fibrils on its own. In their laser experiments, they tuned the frequency of an infrared laser beam to that of the "amide I band" of the fibril, creating resonance. Scanning electron microscopy images confirmed that the amyloid fibrils disassembled upon laser irradiation at the resonance frequency, and a combination of spectroscopy techniques revealed details about the final structure after fibril dissociation.

For the simulations, the researchers employed a technique that a few members of the current team had previously developed, called "nonequilibrium molecular dynamics (NEMD) simulations." Its results corroborated those of the experiment and additionally clarified the entire amyloid dissociation process down to very specific details. Through the simulations, the scientists observed that the process begins at the core of the fibril where the resonance breaks intermolecular hydrogen bonds and thus separates the proteins in the aggregate. The disruption to this structure then spreads outward to the extremities of the fibril.

Together, the experiment and simulation make a good case for a novel treatment possibility for neurodegenerative disorders. Dr Kawasaki remarks, "In view of the inability of existing drugs to slow or reverse the cognitive impairment in Alzheimer's disease, developing non-pharmaceutical approaches is very desirable. The ability to use infrared lasers to dissociate amyloid fibrils opens up a promising approach."

The team's long-term goal is to establish a framework combining laser experiments with NEMD simulations to study the process of fibril dissociation in even more detail, and new works are already underway. All these efforts will hopefully light a beacon of hope for those dealing with Alzheimer's or other neurodegenerative diseases.

Fake audio or video content has been ranked by experts as the most worrying use of artificial intelligence in terms of its potential applications for crime or terrorism, according to a new UCL report.

The study, published in Crime Science and funded by the Dawes Centre for Future Crime at UCL (and available as a policy briefing), identified 20 ways AI could be used to facilitate crime over the next 15 years. These were ranked in order of concern - based on the harm they could cause, the potential for criminal profit or gain, how easy they would be to carry out and how difficult they would be to stop.

Authors said fake content would be difficult to detect and stop, and that it could have a variety of aims - from discrediting a public figure to extracting funds by impersonating a couple's son or daughter in a video call. Such content, they said, may lead to a widespread distrust of audio and visual evidence, which itself would be a societal harm.

Aside from fake content, five other AI-enabled crimes were judged to be of high concern. These were using driverless vehicles as weapons, helping to craft more tailored phishing messages (spear phishing), disrupting AI-controlled systems, harvesting online information for the purposes of large-scale blackmail, and AI-authored fake news.

Senior author Professor Lewis Griffin (UCL Computer Science) said: "As the capabilities of AI-based technologies expand, so too has their potential for criminal exploitation. To adequately prepare for possible AI threats, we need to identify what these threats might be, and how they may impact our lives."

Researchers compiled the 20 AI-enabled crimes from academic papers, news and current affairs reports, and fiction and popular culture. They then gathered 31 people with an expertise in AI for two days of discussions to rank the severity of the potential crimes. The participants were drawn from academia, the private sector, the police, the government and state security agencies.

Crimes that were of medium concern included the sale of items and services fraudulently labelled as "AI", such as security screening and targeted advertising. These would be easy to achieve, with potentially large profits.

Crimes of low concern included burglar bots - small robots used to gain entry into properties through access points such as letterboxes or cat flaps - which were judged to be easy to defeat, for instance through letterbox cages, and AI-assisted stalking, which, although extremely damaging to individuals, could not operate at scale.

First author Dr Matthew Caldwell (UCL Computer Science) said: "People now conduct large parts of their lives online and their online activity can make and break reputations. Such an online environment, where data is property and information power, is ideally suited for exploitation by AI-based criminal activity.

"Unlike many traditional crimes, crimes in the digital realm can be easily shared, repeated, and even sold, allowing criminal techniques to be marketed and for crime to be provided as a service. This means criminals may be able to outsource the more challenging aspects of their AI-based crime."

Professor Shane Johnson, Director of the Dawes Centre for Future Crimes at UCL, which funded the study, said: "We live in an ever changing world which creates new opportunities - good and bad. As such, it is imperative that we anticipate future crime threats so that policy makers and other stakeholders with the competency to act can do so before new 'crime harvests' occur. This report is the first in a series that will identify the future crime threats associated with new and emerging technologies and what we might do about them."

Artificial intelligence can increase the effectiveness of drug repositioning or repurposing research, according to a study published in Translational Psychiatry. In the study, which was supported by São Paulo Research Foundation - FAPESP, Brazilian researchers correlated information on genes associated with psychiatric and neurological disorders and drugs approved for use in treating other diseases that might potentially inhibit or activate these genes.

The study identified 63 drugs targeting 31 genes and potential candidates for testing against Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, bipolar disorder, schizophrenia and autism. A total of 1,588 genes were correlated with 722 drugs.

In addition to identifying these candidate drugs, the researchers also developed a novel drug screening approach that can be used in studies of other diseases. They then applied the novel methodology in another study with the aim of repurposing drugs to treat COVID-19.

"We are producing much more knowledge than we can absorb. Scientific journals publish more than a million articles per year, so it is impossible to keep abreast of the literature in areas other than one's research interests," Helder Nakaya , principal investigator for the study, told.

Nakaya is a professor at the University of São Paulo's School of Pharmaceutical Sciences (FCF-USP) in Brazil and a senior researcher at the Center for Research on Inflammatory Diseases (CRID), one of the Research, Innovation and Dissemination Centers (RIDCs ) funded by FAPESP.

Novel approach: network medicine

Drug development requires large amounts of time and money. Repurposing can be a vital shortcut because existing drugs have already passed the relevant safety tests. The usual approach is to study how drugs and diseases share molecular mechanisms.

To make these correlations more effective, the researchers used a machine learning approach known as network medicine to investigate the molecular characteristics and mechanisms of psychiatric and neurological disorders.

Network medicine is an emerging field that combines systems biology and network science to understand how genes interact in disease and health. "We organized and structured a network of knowledge about psychiatric and neurological disorders correlating with information about relevant drugs and genes," Nakaya explained. "Network medicine uses graph theory to analyze these complex interactions and suggest drugs that have never been tested for the treatment of certain diseases."

The group used IBM Watson for Drug Discovery (WDD), as well as programs developed in their own laboratory, to mine information in millions of scientific articles published in the last 50 years and construct a network connecting knowledge about disorders, genes and drugs.

"IBM WDD can read more than 20 million articles infinitely faster than a human being can. The computer used machine learning algorithms to make correlations based on the information in the articles, such as gene activation and inhibition by certain substances, and links between these processes and mental health problems," Nakaya said. "It is not magic. You do not just press a button to get results. It is hard to identify the associations that are significant."

Tool to direct future studies

The researchers found entirely novel candidates for drug repurposing studies. "The analysis revealed drugs never before described as alternatives for the treatment of psychiatric and neurological disorders. We hope other researchers will use the list produced by our research to begin testing in vitro, in animals, and in future clinical trials if all goes well to determine whether these drugs do in fact work against the indicated diseases," said Thomaz Lüscher Dias, first author of the paper. The study was conducted as part of his PhD research, which was supported by the Ministry of Education's Coordination for the Improvement of Higher Education Personnel (CAPES) and supervised by Nakaya.

The drug repurposing process was made more effective by the combination of machine learning and network medicine. "Instead of screening 2,000 possible candidates and then testing to determine which of them could treat a disease, it is possible to use the results of our study to analyze a much smaller, more assertive list of probable candidates," Dias said.

In a study to be published soon, the group led by Nakaya carried out laboratory experiments to test the effects of one of the drugs on the list when used to treat schizophrenia. "We have set up a research collaboration to determine whether treatment with this drug is effective. Experimental validations are fundamental to prove the utility of these analyses," he said.

The researchers are also applying the methodology to search for correlations between drugs, genes and COVID-19. "In this case, we are using a large volume of information on infectious diseases caused by all types of virus, as well as the main problems relating to severe COVID-19, to look for associations and create networks linking genes and drugs that can be used to treat the disease. In the current crisis, it is essential to narrow the field of study. Network medicine can contribute help us focus in this way," he said.

What The Study Did: This study uses 2018 data from the National Health and Aging Trends Study to assess how common it is for older adults in the United States to be unprepared to access video or telephone telemedicine because of disability or inexperience with technology.

Authors: Kenneth Lam, M.D., of the University of California, San Francisco, is the corresponding author.

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

(doi:10.1001/jamainternmed.2020.2671)

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

The tension in the outer membrane of cells plays an important role in a number of biological processes. A localised drop in tension, for example, makes it easier for the surface to be bending inward and form invaginations that will become free vesicles inside the cell. These are delimited by a membrane that contains all proteins originally present in the invaginations. A fundamental function of these so-called endosomes is to sort proteins to their cellular destination, e.g. reutilization or degradation. Are the functions of endosomes modulated by variations in tension? Scientists from the University of Geneva (UNIGE) and the Chemical Biology National Centre of Competence in Research have answered in the affirmative thanks to their high-precision research published in the journal Nature Cell Biology. Using molecular probes that they devised themselves, the multidisciplinary team has succeeded in two areas: they have measured the membrane tension of these endosomes that form part of the cell's sorting center; and they have succeeded in showing that this relaxation helps form vesicles within endosomes, i.e. vesicles within vesicles or "intraluminal vesicles", which carry the proteins to be degraded. It is a discovery of fundamental importance that could have implications in the field of cancer and degenerative diseases.

How can chemical tools be used in real-time to measure the physical properties of a cell's internals structures while still alive? This is one of the challenges that the National Centre of Competence in Research (NCCR) Chemical Biology - directed at the UNIGE - has been trying to meet since it was launched in 2010. To help reach this goal, a team from the NCCR developed molecular probes that have the capacity to penetrate cells and bind selectively the membrane of some organelles (mitochondria, endoplasmic reticulum, lysosomes, etc.) that function in the depth of the cytoplasm. One of the special features of these microscopic tools is that they change their fluorescence when they are distorted by a variation in the tension of the membrane in which they are inserted.

Garbage bags

The first physiological process that the research team decided to study using this new tool was the formation of intraluminal vesicles (ILVs) inside an organelle, the endosomes. These ILVs can be compared to tiny garbage bags that contain the proteins and other compounds that need to be processed. Endosomes then transport ILVs to the lysosomes, which are the cellular power plants for destroying and recycling waste from the cells. The aim of the Geneva study was to determine whether a drop in the tension of the organelle's membrane may be responsible for the formation of the ILVs, and thus whether protein sorting in the cell is regulated by the membrane physical properties.

"We submitted our cells to a hypertonic shock, meaning we increased the concentration of the solutes (compounds in solution) in their en- vironment," begins Vincent Mercier, a researcher in the Department of Biochemistry in UNIGE's Faculty of Science and the article's first au- thor. "In response, cells expelled water to equilibrate solutes concen- trations in and out of the cell. Their volume decreased as a result, as did the tension of the membrane. Using our probes, we observed that the membrane of the endosomes relaxed in the same way as the membrane of the entire cell."

Better still, this drop in tension was accompanied by the mobilisation on the surface of the organelles of the compounds needed to form a complex (called ESCRT-III) that is exactly the main molecular machine required to produce ILVs. A different experiment was carried out to correlate these findings with actual ILV production.

Tension control

"We also exposed our cells to epidermal growth factors (EGFs), which we know trigger the production of ILV after a cascade of reactions," says Aurélien Roux, Professor at UNIGE's Department of Biochemistry. "Using the same probes, we were able to calculate that this process is also accompanied by a drop in the tension of the organelle mem- branes. These results, obtained thanks to a multidisciplinary collaboration combining skills in biology, chemistry and physics, leads us to conclude that the tension of the membrane controls the functions of the organelles."

It is an important conclusion since the formation of ILV from the membrane of the endosomes is a process that is essential for the proper functioning of the cells. In the specific case of this study, this biomechanical apparatus can be used to trap and quickly destroy the EGFs, thereby interrupt the signal delivered by this growth factor before it gets carried away. A disturbance in this control mechanism is often associated with the onset of cancer or degenerative diseases.

The COVID-19 pandemic has led to a significant increase in video visits between patients and their doctors, but for many older adults, the shift has cut them off from care, rather than connecting them.

A study by researchers at UC San Francisco has found that more than a third of adults over age 65 face potential difficulties seeing their doctor via telemedicine, with the greatest challenges experienced by older, low-income men in remote or rural areas, especially those with disabilities or poor health. The findings appear online Aug. 3, 2020, in JAMA Internal Medicine.

"Telemedicine is not inherently accessible, and mandating its use leaves many older adults without access to their medical care," said lead author Kenneth Lam, MD, a clinical fellow in geriatrics at UCSF. "We need further innovation in devices, services and policy to make sure older adults are not left behind during this migration."

Older adults account for a quarter of U.S. medical office visits and often suffer from multiple morbidities and disabilities. The U.S. Department of Health and Human Services and other organizations have promoted video visits to reach patients at home, but these visits require patients to have the knowledge and capacity to get online, operate and troubleshoot audiovisual equipment, and communicate without the cues available during a personal visit.

In the JAMA Internal Medicine study, Lam and his colleagues analyzed 2018 data on 4,525 patients from the National Health and Aging Trends Study of Medicare beneficiaries age 65 or older. They examined various scenarios that would pose difficulties with a video visit, including poor hearing or eyesight; problems speaking or making oneself understood; possible or probable dementia; owning no Internet-enabled devices or lack of awareness in how to use them; and no use of email, texting or Internet in the past month. The average patient was 79.6 years old, and 69 percent were white, 21 percent Black and 6 percent Hispanic.

Overall, for 2018, the researchers estimated that 38 percent of all older Americans - 13 million total - were not ready for video visits, and 72 percent of those 85 or older were not, primarily due to inexperience with technology, followed by physical disability. Even with third-party support, 32 percent (10.8 million) of older adults still were unready, and 20 percent (6.7 million) could not even handle a telephone visit due to dementia or difficulty hearing or communicating.

A lack of readiness was more prevalent in patients who were older, male, unmarried, Black or Hispanic, lived rurally, and had less education, lower income and poorer self-reported health, the researchers said.

"To build an accessible telemedicine system, we need actionable plans and contingencies to overcome the high prevalence of inexperience with technology and disability in the older population," Lam said. "This includes devices with better designed user interfaces to get connected, digital accommodations for hearing and visual impairments, services to train older adults in the use of devices and, for some clinicians, keeping their offices open during the pandemic."

Despite enormous efforts to advance traditional pharmacology approaches, more than three quarters of all human proteins remain beyond the reach of therapeutic development. Targeted protein degradation (TPD) is a novel approach that could overcome this and other limitations, and thus represents a promising therapeutic strategy. TPD is based on small molecules, generally called"degraders", which can eliminate disease-causing proteins by causing their destabilization. Mechanistically, these degrader drugs repurpose the cellular protein quality control system, tweaking it to recognize and eliminate harmful proteins. In detail, they re-direct members of the protein family of E3 ubiquitin ligases (E3s) towards the disease-causing target protein. This leads to a "molecular earmarking" of the harmful protein via a process called "ubiquitination". Subsequently, the ubiquitinated protein is recognized and degraded by the molecular machine called the proteasome, which serves as the cellular garbage disposal system.

In this study, CeMM researchers turned their focus to a subset of degraders called "molecular glue degraders". This class of seemingly rare small molecules that has been shown to induce the degradation of target proteins that could not be blocked via ways of traditional pharmacology. Consequently, these proteins had been termed "undruggable". The best characterized examples are the clinically approved thalidomide analogs, effective for the treatment of different blood cancers. Unfortunately, the discovery of the few described molecular glue degraders has historically been a process entirely driven by serendipity and no rational discovery strategies existed.

To overcome this limitation, Georg Winter's group at CeMM set out to innovate a scalable strategy towards the discovery of novel molecular glue degraders via phenotypic chemical screening. To this end, first author and CeMM postdoctoral fellow Cristina Mayor-Ruiz and colleagues engineered cellular systems widely impaired in E3 activity. Differential viability between these models and E3-proficient cells was used to identify compounds that depend on active E3s, and therefore, potential molecular glue degraders. Researchers integrated functional genomics with proteomics and drug-interaction strategies, to characterize the most promising compounds. They validated the approach by discovering a new RBM39 molecular glue degrader, structurally similar to others previously described. Importantly, they discovered a set of novel molecular glues that induce the degradation of the protein cyclin K, known to be essential in many different cancer types. Interestingly, these novel cyclin K degraders function via an unprecedented molecular mechanism of action that involves the E3 CUL4B:DDB1 and that has never been therapeutically explored before.

This study, performed in close collaboration with CeMM PI Stefan Kubicek, thus provides the first framework towards the discovery of molecular glue degraders that can be highly scaled, but also strongly diversified. "I truly believe that we are only scratching the surface of possibilities. This study is chapter one of many chapters to follow. We will see a revolution in the way researchers perceive and execute therapeutic strategies for previously incurable diseases by crafting glue degrader strategies that will enable them to eliminate therapeutic targets that could not be explored with traditional pharmacologic approaches", says CeMM PI and last author of the study Georg Winter.