Culture

A basic science discovery by researchers at the Johns Hopkins Bloomberg School of Public Health reveals a fundamental way cells interpret signals from their environment and may eventually pave the way for potential new therapies.

The finding involves a signaling pathway in cells, called the Hippo pathway, which normally constrains cell division and regulates the size of organs, and also plays a role in tissue growth and development as well as tumor suppression. The Hippo pathway is so fundamental that it is found in species ranging from humans to flies.

The Bloomberg School researchers clarified the working of this signaling pathway by solving a long-standing mystery of how one of its core components, an enzyme called MST2, can be activated by multiple signaling inputs.

The discovery is reported in a paper on November 20 in the Journal of Biological Chemistry.

"We knew that this pathway could be activated by different upstream signals, and here we've revealed the mechanism by which that happens," says study senior author Jennifer Kavran, PhD, assistant professor in the Bloomberg School's Department of Biochemistry and Molecular Biology.

The Hippo pathway normally works as a brake on cell division that stops organs from growing larger once they have reached the appropriate size. Mutations or other abnormalities in the pathway that take the brakes off cell division have been found in many cancers, making elements of the Hippo pathway potential targets for future cancer treatments.

Due to its fundamental role of tissue and organ growth, the pathway also is of great interest to researchers who are developing techniques to improve wound healing and stimulate the regeneration of damaged tissue.

The heart of the Hippo pathway begins with the activation of two highly related enzymes, MST1 and MST2, which are almost identical and perform overlapping functions. A variety of biological events, including cell-to-cell contacts, certain nutrients, stress, and signaling through cell receptors, can cause MST1/2 to become activated--a process in which the enzyme becomes tagged with sets of phosphorus and oxygen atoms called phosphoryl groups.

Once activated by this "autophosphorylation," MST1/2 can send signals downstream to complete the signaling chain and inhibit cell division. Normally, proteins that undergo autophosphorylation are activated by a single molecular "event"--such as binding a particular molecule or interacting with another copy of the same enzyme. How such a variety of inputs can each trigger MST1/2's activation has been a mystery.

"In cell biology, we're used to the idea that when an enzyme is transmitting a signal, a single molecular event turned that enzyme on," Kavran says.

In the study, she and her colleagues used test tube and cell culture experiments with human MST2 to show that the myriad upstream activators of this enzyme trigger MST2 autophosphorylation the same way--simply by increasing the local concentration of these enzymes--thus reducing the distance between the enzymatic sites on individual enzymes and making it easier for them to phosphorylate one another.

The researchers believe their discovery is likely to apply not only to MST2 but also its twin MST1 as well as the very similar versions of the enzyme produced in other species.

Although this was principally a basic science study, the results should enhance the ability of researchers to manipulate Hippo pathway signaling, both for basic research as well as for potential therapeutic applications for tissue regeneration and anti-cancer therapies.

"The techniques we used to activate MST2 in cell cultures should be useful to other labs that are studying the Hippo pathway and need a way to turn it on in a controlled manner," Kavran says.

She and her lab plan to investigate how other enzymes in the pathway are regulated.

For more than a decade, Hiranmoy Das, Ph.D., has been investigating how Kruppel-like Factor 2 (KLF2), a gene that codes protein into a specific human chromosome, influences the development of bone and musculoskeletal diseases such as rheumatoid arthritis and osteoporosis.

In 2006, Das, a professor in the Department of Pharmaceutical Sciences at the Texas Tech University Health Sciences Center (TTUHSC) Jerry H. Hodge School of Pharmacy, was the first to publish research in the peer-reviewed scientific journal, Proceedings of the National Academy of Sciences, U.S.A., showing KLF2 regulates monocyte activation and function. Monocytes, the largest type of white blood cells in our immune system, help defend the human body from bacteria, viruses and fungi. His past research also has demonstrated that low levels of KLF2 promote osteoclast, a specialized cell that helps in the bone degradation process, a key factor in developing bone and musculoskeletal diseases as the body ages.

Homeostasis, a process by which new bone is built and old bone is removed, is maintained by two important cells: osteoclasts, which decrease bone levels by removing damaged bone; and osteoblasts, which form new bone. Through a process known as osteoblast differentiation, mesenchymal stem cells, which are found in bone marrow and fat, acquire the bone building characteristics of osteoblasts.

Most recently, the Das lab attempted to determine if inducing KLF2 levels in dental pulp derived stem cells (DPSCs) will promote osteoblast and the building of new bone. Their study, "KLF2 regulates dental pulp-derived stem cell differentiation through the induction of mitophagy and altering mitochondrial metabolism," was published in the September issue of Redox Biology. His team included TTUHSC research associates Jyotirindra Maity and Moonmoon Deb and research assistant Carl Greene.

Das said his team used DPSCs in their latest study because DPSCs have the same characteristics as mesenchymal stem cells, which means they also can differentiate into bone building osteoblasts.

"We wanted to see what happens in the DPSCs at the KLF2 level," Das explained. "To our surprise, we found that during the differentiation, the KLF2 level was very highly increased."

Das said KLF2 is known to play a protective role in certain aspects of human health. For instance, various statins used to treat high cholesterol also increase the KLF2 level in endothelial cells. Because endothelial cells are primarily found in arteries, veins and capillaries, increasing their KLF2 level helps protect against cardiovascular disease.

If osteoblastic differentiation can be promoted more efficiently by inducing KLF2 in the DPSCs, Das believes those stem cells can be used to help reduce the occurrence and severity of rheumatoid arthritis, osteoporosis and other bone and musculoskeletal diseases not yet tested.

"Think about it: if we can induce KLF2, that will help in osteoblastic differentiation and it will inhibit osteoclastic differentiation," Das said. "It also will help the stem cells to make more osteoblasts so they can form more bone. So basically, it is two different angles we are treating that will reduce bone related diseases such as osteoporosis, arthritis, spondyloarthritis and all kinds of diseases."

A new assessment tool developed by Kaiser Permanente researchers and physicians helps guide clinical decisions in emergency departments and urgent care centers

PASADENA, Calif. -- A study published in the American Journal of Emergency Medicine this month reports on an assessment tool developed by Kaiser Permanente researchers and physicians that helps ensure patients get the right care, when they need it, by accurately predicting the probability that patients with COVID-19 symptoms will experience severe disease or even death.

"As the pandemic surges again across the country and hospitalizations are increasing, front-line physicians often must make quick decisions to hospitalize or discharge patients with COVID-19 symptoms," said Adam Sharp, MD, an emergency medicine physician who also is a researcher for the Kaiser Permanente Southern California Department of Research & Evaluation. "We created a risk assessment that looks at many different patient variables that might predict a critical poor outcome -- without any lab or diagnostic testing."

The risk score is particularly helpful to physicians in making these decisions at the time of the emergency department visit, Dr. Sharp said.

The assessment tool, called the COVAS score because it looks at comorbidities, obesity, vital signs, age, and sex, has already been incorporated into the electronic health record system throughout Kaiser Permanente in Southern California, where it guides clinical decisions in emergency departments and urgent care centers. In this study, the COVAS score accurately predicted the probability of death or the need for critical respiratory care within 7 days for patients seen at Kaiser Permanente emergency departments in Southern California.

"I have used this tool successfully with my own patients in the emergency department and it helps provide necessary information to make informed decisions with patients," Dr. Sharp said. "It can help to reassure low-risk patients, and alternatively can encourage those at high risk to receive hospital-based care that may speed their recovery."

Researchers conducted a retrospective study of 26,600 emergency department visits by adults for symptoms suspicious for COVID-19 at 15 Kaiser Permanente hospitals in Southern California between March 1, 2020, to April 30, 2020, a period of time when substantial community spread of COVID-19 was prevalent in the region but immediate COVID-19 test results were not.

The results inform front-line health professionals and health systems about which patients with COVID-19 symptoms, which include fever, cough, difficulty breathing, and fatigue, are at greatest risk of death or respiratory decompensation that would require ventilation or high-flow oxygen.

Previous studies have focused on hospitalized patients, with little information about those treated outside of the inpatient setting. This work examines emergency department patients with suspected COVID-19 and provides helpful information to front-line physicians to inform care decisions, particularly during surges when hospital capacity can be limited.

Ludwig-Maximilians-Universitaet (LMU) in Munich physicists have introduced a new method that allows biological pattern-forming systems to be systematically characterized with the aid of mathematical analysis. The trick lies in the use of geometry to characterize the dynamics.

Many vital processes that take place in biological cells depend on the formation of self-organizing molecular patterns. For example, defined spatial distributions of specific proteins regulate cell division, cell migration and cell growth. These patterns result from the concerted interactions of many individual macromolecules. Like the collective motions of bird flocks, these processes do not need a central coordinator. Hitherto, mathematical modelling of protein pattern formation in cells has been carried out largely by means of elaborate computer-based simulations. Now, LMU physicists led by Professor Erwin Frey report the development of a new method which provides for the systematic mathematical analysis of pattern formation processes, and uncovers the their underlying physical principles. The new approach is described and validated in a paper that appears in the journal Physical Review X.

The study focuses on what are called 'mass-conserving' systems, in which the interactions affect the states of the particles involved, but do not alter the total number of particles present in the system. This condition is fulfilled in systems in which proteins can switch between different conformational states that allow them to bind to a cell membrane or to form different multicomponent complexes, for example. Owing to the complexity of the nonlinear dynamics in these systems, pattern formation has so far been studied with the aid of time-consuming numerical simulations. "Now we can understand the salient features of pattern formation independently of simulations using simple calculations and geometrical constructions," explains Fridtjof Brauns, lead author of the new paper. "The theory that we present in this report essentially provides a bridge between the mathematical models and the collective behavior of the system's components."

The key insight that led to the theory was the recognition that alterations in the local number density of particles will also shift the positions of local chemical equilibria. These shifts in turn generate concentration gradients that drive the diffusive motions of the particles. The authors capture this dynamic interplay with the aid of geometrical structures that characterize the global dynamics in a multidimensional 'phase space'. The collective properties of systems can be directly derived from the topological relationships between these geometric constructs, because these objects have concrete physical meanings - as representations of the trajectories of shifting chemical equilibria, for instance. "This is the reason why our geometrical description allows us to understand why the patterns we observe in cells arise. In other words, they reveal the physical mechanisms that determine the interplay between the molecular species involved," says Frey. "Furthermore, the fundamental elements of our theory can be generalized to deal with a wide range of systems, which in turn paves the way to a comprehensive theoretical framework for self-organizing systems."

Simon Fraser University professors Paul Tupper and Caroline Colijn have found that physical distancing is universally effective at reducing the spread of COVID-19, while social bubbles and masks are more situation-dependent.

The researchers developed a model to test the effectiveness of measures such as physical distancing, masks or social bubbles when used in various settings.

Their paper was published Nov. 19 in the journal Proceedings of the National Academy of Sciences
of the United States of America (PNAS).

They introduce the concept of "event R," which is the expected number of people who become infected with COVID-19 from one individual at an event.

Tupper and Colijn look at factors such as transmission intensity, duration of exposure, the proximity of individuals and degree of mixing - then examine what methods are most effective at preventing transmission in each circumstance.

The researchers incorporated data from reports of outbreaks at a range of events, such as parties, meals, nightclubs, public transit and restaurants. The researchers say that an individual's chances of becoming infected with COVID-19 depend heavily on the transmission rate and the duration - the amount of time spent in a particular setting.

Events were categorized as saturating (high transmission probability) or linear (low transmission probability). Examples of high transmission settings include bars, nightclubs and overcrowded workplaces while low transmission settings include public transit with masks, distancing in restaurants and outdoor activities.

The model suggests that physical distancing was effective at reducing COVID-19 transmission in all settings but the effectiveness of social bubbles depends on whether chances of transmission are high or low.

In settings where there is mixing and the probability of transmission is high, such as crowded indoor workplaces, bars and nightclubs and high schools, having strict social bubbles can help reduce the spread of COVID-19.

The researchers found that social bubbles are less effective in low transmission settings or activities where there is mixing, such as engaging in outdoor activities, working in spaced offices or travelling on public transportation wearing masks.

They note that masks and other physical barriers may be less effective in saturating, high transmission settings (parties, choirs, restaurant kitchens, crowded offices, nightclubs and bars) because even if masks halve the transmission rates that may not have much impact on the transmission probability (and so on the number of infections).

The novel coronavirus is relatively new but the science continues to evolve and increase our knowledge of how to effectively treat and prevent this highly contagious virus. There is still much that we do not know and many areas requiring further study.

"It would be great to start collecting information from exposures and outbreaks: the number of attendees, the amount of mixing, the levels of crowding, the noise level and the duration of the event," says Colijn, who holds a Canada Research Chair in Mathematics for Evolution, Infection and Public Health.

For COVID-19 Surveillance, Test Frequency and Turnaround Time Are Paramount, Modeling Suggests
Speed of test results and frequency of testing are paramount for effective COVID-19 surveillance, suggests a new study that modeled trade-offs in test sensitivity, test frequency, and sample-to-answer reporting time, in select scenarios. Test sensitivity is secondary to these factors in the scenarios studied, the authors say. "If the availability of point-of-care or self-administered screening tests leads to faster turnaround time or more frequent testing, our results suggest that they would have high epidemiological value," Daniel Larremore and colleagues write. Because SARS-CoV-2 can spread from individuals with pre-symptomatic, symptomatic, and asymptomatic infections, diagnosis and isolation based on symptoms alone won't prevent spread. Rather, robust population screening, for which virus testing is often central, will be critical. However, related surveillance testing programs must make concrete choices, including: What are the tradeoffs between cost, frequency, test sensitivity, and the speed with which diagnoses can be returned? To evaluate this, Larremore and colleagues modeled how changing viral load (different levels of infectiousness) impacted the ability of an assay, or test, to diagnose infection. They calculated what percentage of these people's total infectiousness would be removed by screening and isolation, using different testing approaches. They also evaluated the impact of surveillance at the population level using two epidemiological models that incorporated viral load dynamics, one of which mimicked aspects of the contact structure of New York City. Across their analyses of individuals and populations, the inclusion of viral load in surveillance modeling revealed that the limits in detection abilities of tests mattered less than previously thought, the authors say. But delays in returning diagnoses were highly impactful, with even one-day delays between sample and answer undercutting otherwise impactful surveillance plans. As well, the frequency of surveillance testing plays a crucial role, the authors say. They note that communities vary in their transmission dynamics, so specific strategies for successful population screening will depend on the current community infection prevalence and transmission rate in a given location. They also identify other limitations in their study. Still, they say their findings could aid some groups planning societal reopening, refocusing their efforts on rapid turnaround times instead of highly sensitive tests. They may also inform regulatory agencies and test manufacturers about the importance of developing and approving such tests, optimized for surveillance (as opposed to clinical diagnosis).

There is growing evidence that adipose tissue plays a key role in the aggravation of COVID-19. One of the theories under investigation is that fat cells (adipocytes) act as a reservoir for SARS-CoV-2 and increase viral load in obese or overweight individuals. Scientists also suspect that during infection fat cells release into the bloodstream substances that boost the inflammatory reaction triggered by the virus in the organism.

These hypotheses are being investigated by researchers at the University of São Paulo’s Medical School (FM-USP) in Brazil under the coordination of Marilia Cerqueira Leite Seelaender, a professor in the Department of Clinical Surgery. Peter Ratcliffe, a professor at the University of Oxford in the UK and one of the winners of the 2019 Nobel Prize for Medicine, is collaborating.

“A cytokine storm resulting in systemic inflammation similar to sepsis occurs in some severe COVID-19 patients. We believe these inflammatory factors come from adipose tissue. It’s been shown that when adipocytes expand too much, they can cause inflammation throughout the body, even in the brain,” Seelaender told Agência FAPESP.

The FM-USP group analyzed samples of adipose tissue obtained from autopsies of people who died from COVID-19, and also from patients infected with SARS-CoV-2 who had to be submitted to emergency surgery at the university’s hospital for appendicitis or other reasons not related to the viral infection. Preliminary results confirmed that the virus can be found in fat cells, whose membranes are rich in ACE-2, the main receptor used by the virus to invade human cells. The researchers have yet to confirm that once it has invaded adipocytes, it can remain there long enough to replicate inside them.

“It’s worth noting that visceral adipocytes [located deep in the abdomen and around internal organs] have much more ACE2 than subcutaneous adipose tissue,” Seelaender said. “In addition, they’re much more inflammatory. As a result, visceral obesity tends to be even more harmful as far as COVID-19 is concerned.”

The preliminary findings also brought to light a change in the pattern of exosome secretion in the adipose tissue of infected people. Exosomes are extracellular vesicles, comparable to tiny bubbles, released by cells into the bloodstream with proteins and other types of signaling molecules. This is one of the mechanisms whereby information is exchanged between different tissues as the body adapts to changes in its environment.

The aims of the research conducted by the FM-USP group include investigating whether infection by SARS-CoV-2 makes adipocytes release more exosomes containing inflammatory factors. So far it has shown that the number of vesicles released into the bloodstream does indeed increase. The researchers will now analyze the contents of these circulating vesicles, as well as those remaining inside cells. They also plan to investigate the inflammatory pathways presumably activated by these molecules.

“We first assumed that as a person gets fat, their adipose tissue becomes hypoxic, meaning the person has less oxygen available. Hypoxia is itself a cause of inflammation, so one of the things we want to investigate is whether COVID-19 causes hypoxia in adipocytes,” Seelaender said.

Research on how human cells adapt to hypoxia won Ratcliffe the Nobel with William G. Kaelin (Harvard University) and Gregg Semenza (Johns Hopkins School of Medicine).

Sir Radcliffe's group is now interested in exploring the possibility that the SARS-CoV-2 virus interacts with hypoxia signalling pathways, and the Brazilian and British groups are collaborating as to address this hypothesis.

The FM-USP group, meanwhile, is concentrating on an effort to understand the effect of infection on adipose tissue. “We’re analyzing everything secreted by fat cells: proteins, saturated fatty acids, prostaglandins [lipids with diverse hormone-like effects], microRNAs [small non-coding RNA molecules that regulate gene expression] and exosomes,” Seelaender said.

Inflammatory factors released by adipose tissue in COVID-19 patients may be the cause of damage to the heart, lungs, and nervous system described in such patients, she added. “Our hypothesis is that obese COVID-19 patients undergo a similar process to that observed in the adipose tissue of patients with cachexia [significant rapid weight loss and muscle wasting associated with AIDS, heart failure and cancer, among other diseases],” she said. “Adipocytes in cachexic individuals release more exosomes, and their contents are altered so that they have a pro-inflammatory profile. We know there’s inflammation in both cachexia and obesity. The difference lies in the type of inflammatory mediator released and the signaling pathways activated.”

Seelaender and her group have been researching the links between cachexia and inflammation since 2013 with FAPESP’s support.

Opposite but similar

In an article published in the journal Advances in Nutrition, Seelaender and her group discuss how nutritional status can influence a patient’s response to COVID-19. According to the authors, both obesity and malnutrition – including cachexia and sarcopenia (loss of skeletal muscle mass associated with aging) – can impair the immune response and prevent the organism from combating viral infection.

“Immune cells require more energy during an infectious process, especially if the body takes a long time to overcome it. Their metabolism needs to change so that they can multiply rapidly, but in an undernourished organism, this isn’t possible. During an infection the number of T-lymphocytes in a malnourished individual is much smaller than in a eutrophic [well-nourished] individual,” Seelaender said.

Moreover, she continued, undernourished organisms suffer from atrophy of the lymphoid organs (especially bone marrow, thymus and lymph nodes), in which the lymphocytes are produced and reach maturity. As a result, the number of circulating defense cells declines. Experiments with animals have also shown that an organism suffering from malnutrition takes longer to eliminate viruses.

“Fat can be a problem when it’s excessive or insufficient. However paradoxical it may seem, both extremes are dangerous,” she explained. “Adipose tissue secretes leptin, a hormone that regulates T-lymphocyte metabolism. Leptin signaling falls in a body with very low fat. Excessively high fat makes cells less sensitive to leptin, so the amount of leptin released rises sharply.”

Aging affects several of the factors mentioned by Seelaender. The immune system becomes less responsive. Skeletal muscle mass dwindles, visceral fat increases, and the proportion between lean and fat mass worsens.

“Loss of lean mass can worsen the outcome of chronic and acute diseases in older people. Muscle is a reservoir of energy substrate [amino acids] that can be mobilized at times of need, such as during an infection,” she said. “That’s why it’s important to stress that not just adiposity but also the lean-to-fat mass ratio is a problem in COVID-19 patients. If a person has a lot of fat and little muscle, it’s worse than if they have a lot of fat but a good muscular condition.”

If songbirds could appear on "The Masked Singer" reality TV competition, zebra finches would likely steal the show. That's because they can rapidly memorize the signature sounds of at least 50 different members of their flock, according to new research from the University of California, Berkeley.

In findings recently published in the journal Science Advances, these boisterous, red-beaked songbirds, known as zebra finches, have been shown to pick one another out of a crowd (or flock) based on a particular peer's distinct song or contact call.

Like humans who can instantly tell which friend or relative is calling by the timbre of the person's voice, zebra finches have a near-human capacity for language mapping. Moreover, they can remember each other's unique vocalizations for months and perhaps longer, the findings suggest.

"The amazing auditory memory of zebra finches shows that birds' brains are highly adapted for sophisticated social communication," said study lead author Frederic Theunissen, a UC Berkeley professor of psychology, integrative biology and neuroscience.

Theunissen and fellow researchers sought to gauge the scope and magnitude of zebra finches' ability to identify their feathered peers based purely on their unique sounds. As a result, they found that the birds, which mate for life, performed even better than anticipated.

"For animals, the ability to recognize the source and meaning of a cohort member's call requires complex mapping skills, and this is something zebra finches have clearly mastered," Theunissen said.

A pioneer in the study of bird and human auditory communication for at least two decades, Theunissen acquired a fascination and admiration for the communication skills of zebra finches through his collaboration with UC Berkeley postdoctoral fellow Julie Elie, a neuroethologist who has studied zebra finches in the forests of their native Australia. Their teamwork yielded groundbreaking findings about the communication skills of zebra finches.

Zebra finches usually travel around in colonies of 50 to 100 birds, flying apart and then coming back together. Their songs are typically mating calls, while their distance or contact calls are used to identify where they are, or to locate one another.

"They have what we call a 'fusion fission' society, where they split up and then come back together," Theunissen said. "They don't want to separate from the flock, and so, if one of them gets lost, they might call out 'Hey, Ted, we're right here.' Or, if one of them is sitting in a nest while the other is foraging, one might call out to ask if it's safe to return to the nest."

These days, Theunissen keeps a few dozen zebra finches in aviaries on and around campus, 20 of which were used in this latest experiment.

In a two-part experiment, 20 captive zebra finches were trained to distinguish between different birds and their vocalizations. At first, half the birds were tested on memorizing songs, while the other half were assessed on distance or contact calls. They then switched those tasks.

Next, the zebra finches were placed, one at a time, inside a chamber and listened to sounds as part of a reward system. The goal was to train them to respond to particular zebra finches by hearing several different renditions of those birds' distinct vocalizations and memorizing them.

By pecking a key inside the chamber, the bird subjects triggered an audio recording of a zebra finch vocalization. If they waited until the six-second recording ended, and it was part of the reward group, they received birdseed. If they pecked before the recording was finished, they moved to the next recording. Over several trials, they learned which vocalizations would yield birdseed, and which ones to skip.

Next, the zebra finches were introduced to more audio recordings from new zebra finches, to teach them to distinguish which vocalizations belonged to which bird. They soon learned to differentiate between 16 different zebra finches.

In fact, the zebra finches, both male and female, performed so well in the tests that four of them were given the more challenging task of distinguishing between 56 different zebra finches. On average, they succeeded in recognizing 42 different zebra finches, based on their signature sounds. Plus, they were still able to identify the birds based on their unique sounds a month later.

"I am really impressed by the spectacular memory abilities that zebra finches possess in order to interpret communication calls," Theunissen said. "Previous research shows that songbirds are capable of using simple syntax to generate complex meanings and that, in many bird species, a song is learned by imitation. It is now clear that the songbird brain is wired for vocal communication."

New Haven, Conn. -- A drug once used to treat high blood pressure can help alcoholics with withdrawal symptoms reduce or eliminate their drinking, Yale University researchers report Nov. 19 in the American Journal of Psychiatry.

In a double-blind study, researchers gave the drug prazosin or a placebo to 100 people entering outpatient treatment after being diagnosed with alcohol use disorder. All of the patients had experienced varying degrees of withdrawal symptoms prior to entering treatment.

According to the researchers, subjects with more severe symptoms -- including shakes, heightened cravings and anxiety, and difficulty sleeping -- who received prazosin significantly reduced the number of heavy drinking episodes and days they drank compared to those who received a placebo. The drug had little effect on those with few or no withdrawal symptoms.

"There has been no treatment readily available for people who experience severe withdrawal symptoms and these are the people at highest risk of relapse and are most likely to end up in hospital emergency rooms," said corresponding author Rajita Sinha, the Foundations Fund Professor of Psychiatry, a professor of neuroscience, and director of the Yale Stress Center.

Prazosin was originally developed to treat high blood pressure and is still used to treat prostate problems in men, among other conditions. Previous studies conducted at Yale have shown that the drug works on stress centers in the brain and helps to improve working memory and curb anxiety and craving.

Sinha's lab has shown that stress centers of the brain are severely disrupted early in recovery, especially for those with withdrawal symptoms and high cravings, but that the disruption decreases the longer the person maintains sobriety. Prazosin could help bridge that gap by moderating cravings and withdrawal symptoms earlier in recovery and increasing the chances that patients refrain from drinking, she said.

One drawback is that in its current form prazosin needs to be administered three times daily to be effective, Sinha noted.

Montréal and Québec City, November 19, 2020 - Using the Advanced Laser Light Source (ALLS) facility, the research team of Professor François Légaré of the Institut national de la recherche scientifique (INRS) has pushed back the boundaries of high-energy pulse propagation in a nonlinear medium through the observation of high-energy multidimensional solitary states (MDSS). This breakthrough allows the direct generation of extremely short and intense, laser pulses that are highly-stable in time and space. The results of this work were published in Nature Photonics.

Common laser systems restrict operation to a single transverse mode, which puts an upper limit on laser technology. So far, higher dimensions have been considered detrimental since they are prone to high instability and collapse. This makes the scientific impact of this work remarkable. The observed self-sustained multidimensional wave-packets are driven by picosecond, near-infrared pump pulses in a gas-filled hollow-core fiber, which will be of significant interest to many scientists around the globe.

These MDSS also have a huge technological impact.

INRS researchers were able to generate high-energy and spatiotemporally engineered coherent light fields. This discovery could lead to breakthroughs in laser science for a wide range of applications. The research involves enormous theoretical advances, highly complex numerical simulations and systematic experimental studies. It was performed in the ALLS facility at INRS, a world-class research facility focusing on developing new types of lasers with revolutionary applications.

"Light at high energy levels behaves differently from what we thought," says Reza Safaei, PhD student at INRS, "We were able to design the system working in an overdriven, chaotic regime where dramatic nonlinear enhancement happens by itself. Interactions between multidimensional states actually cause the light in the laser pulses to self-organize toward highly-stable multidimensional states. This is a huge surprise, since these solitary states come out of highly unstable chaos, like hearing a note coming out of a drum!"

"The immediate technological impact of this work is the generation of few-cycle pulses from picosecond Yb driver lasers using a simple, robust, and efficient approach that provides a new laser technology for strong-field physics," said Guangyu Fan, PhD student at INRS.

"It is especially useful for scaling tabletop extreme-ultraviolet (XUV) and soft X-ray sources up to higher photon energies due to the longer central wavelength of the output beam," said Professor François Légaré. "As we look to the future, lasers and amplifiers that can elegantly work in multidimensional states may have significantly higher power than devices based on a single mode, with significant controllable nonlinear enhancement. This possibility extends beyond ultrafast laser technology to all of laser science, since dimensionality and spatial/spatiotemporal nonlinearities represent key limitations for high-power lasers of all kinds."

The team believes this idea could push forward laser technology, which has pretty much been locked in one mode for more than 20 years. This will enable the development of very compact, high-power laser systems with a wide variety of industrial applications, including micromachining and material processing. In addition, this innovative laser technology is now used to develop very compact tabletop, ultrashort X-ray sources with potential applications for tracking ultrafast phenomena such as chemical reactions and magnetization dynamics, as well as for high-spatial-resolution biomedical imaging in the water window spectral range. INRS has also protected the intellectual property related to this potentially revolutionary laser method.

In a new publication from Cardiovascular Innovations and Applications; DOI https://doi.org/10.15212/CVIA.2019.0590, Liu Yue, Qin Zhu-Yun, Yang Xin, Tang Rong and Gao Ling-Yun from the The First Affiliated Hospital of Chongqing Medical University, Chongqing, China consider the use of a social media platform (WeChat) to provide faster treatment and improve prognoses for a group of patients with acute ST-segment Elevation Myocardial Infarction.

The authors explored the effect of establishing a WeChat platform for a chest pain center as a medium to increase the treatment speed and improve the prognosis of patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI).

The application of a WeChat platform significantly shortened the door-to-balloon time of patients receiving PPCI and increased the standard door-to-balloon time achievement rate for patients with STEMI. In addition, the platform is also conducive to integrating medical resources and sharing medical information. The establishment of the platform increased the treatment speed and improved the prognosis of patients with STEMI.

EAU CLAIRE, Wis. -- Before the COVID-19 pandemic, information about the dangers of vaping was emerging. To investigate the potentially serious health and respiratory implications of vaping, Mayo Clinic researchers wanted to better understand the factors influencing vaping in the community. They were ready to launch a survey of young adults in rural and urban areas when COVID-19 shifted the focus of this survey.

In a recent article in SAGE Open Medicine, the team of investigators report on vaping among adults ages 18-25 during the pandemic and their use of other common substances, such as alcohol, marijuana and tobacco. Inserting a timely additional survey question allowed the team to better understand the effects of compounding daily stresses with a public health crisis.

"As COVID-19 came on the scene, it was primarily thought to have severe respiratory implications," says Pravesh Sharma, M.D., a psychiatrist at Mayo Clinic Health System in Eau Claire, and the study's lead author. "Since we were about to launch a study examining the factors associated with vaping use, which can lead to lung injury, it made sense to revise our questionnaire slightly to address the broader question of the use of vaping and other common substances during a respiratory disease pandemic."

"We found shifts in substance use across the board," says Dr. Sharma. "Most concerning was a significant increase in alcohol use."

About the research

Dr. Sharma and his team developed a survey for patients who were seen for any reason in any outpatient setting at any Mayo Clinic location across the Midwest. The survey was emailed in April to 6,119 adults, ages 18-25 as of Jan. 24, who had been seen in the 4.2 months prior to the survey being sent. The survey came on the heels of state and local governments announcing stay-at-home orders and social distancing guidelines in March due to COVID-19.

The team's planned survey collected information on vaping attitudes and behaviors, as well as the types of vaping products used, including nicotine, marijuana extracts and oils, and other substances. The survey also asked respondents if any of their use had increased or decreased since the COVID-19 pandemic began.

"Substance use is highest in the young adult age group, so we wanted to target this population," says Dr. Sharma. "We would like to understand why they vape and what their attitudes were regarding the potentially harmful nature of vaping."

Of 1,018 respondents, more than half, or 542, reported vaping, or using marijuana, tobacco or alcohol, during the COVID-19 pandemic. Of the respondents, 269 self-reported having an anxiety disorder and 253 reported having depression. Of note, the authors write that study limitations are a reliance on self-reporting of these behaviors and disorders, as well as a 16.6% response rate.

Given that COVID-19 emerged as a primarily respiratory illness and vaping had been increasingly connected to lung damage, the team expected to see a reduction in vaping and smoking. The paper reports that 34.3%, or 186 people, reported a change in their use patterns due to COVID-19:

Nearly 70% increased alcohol consumption.

Vaping decreased in 44% of people, while 27.9% of people increased use.

Tobacco product use decreased in 47.3% of people, while 24.1% of people increased use.

Of the 140 people who described a change in marijuana use, 39.2% increased use and 36% decreased use.

Using a previously validated scale, the researchers also measured loneliness among the participants, and collected self-reported depression and anxiety information.

"We did see some reduction in inhaled substances, which could mean that young adults were reacting to the news coverage of COVID-19's respiratory effects," says Dr. Sharma.

"However, we saw that the more lonely, depressed or anxious these young people felt, the more likely they were to change their usage," he says. "They may be trying to cope with social and emotional strain by adding or replacing one substance with another, especially if their access to other support is limited."

"In this time of COVID-19, when we are focused on symptoms of infectious diseases, we need to remain vigilant about changes individuals experience with substance use," says Jon Ebbert, M.D., an internal medicine physician at Mayo Clinic in Rochester, Minn., and a study co-author.

"During the time of this pandemic, screening for substance use, loneliness, anxiety and depression is crucial," states Dr. Sharma. "Just asking, 'How are you holding up during this difficult time' goes a long way."

Drs. Sharma and Ebbert agree it is important for people to be aware of the effect of the pandemic on their well-being.

"As loneliness, anxiety and depression can potentially fuel increases in alcohol consumption during these times of social distancing, introspection with ourselves and observation of our social supports are critical for identifying and addressing substance use issues early," says Dr. Ebbert.

Dr. Sharma suggests checking in regularly with friends and family, inquiring about their well-being, and maintaining a connection. "Social distancing should not mean social isolation," he says.

He and fellow authors also highlight nontraditional socialization opportunities as essential during the continuing COVID-19 pandemic, especially for people with poor emotional health and loneliness.

In a new publication from Cardiovascular Innovations and Applications; DOI https://doi.org/10.15212/CVIA.2019.1262, Wen-Yuan Ding, Jia-Min Li, Fei Zheng, Li-Li Wang, Xin-Yi Wei and Guo-Hua Li from Shandong Provincial Qianfoshan Hospital, Ji'nan, China, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Ji'nan, China and Shandong First Medical University, Tai'an, China consider the challenges of treating acute myocardial infarction due to variant angina.

Coronary spasm plays an important part not only in the pathogenesis of variant angina (VA) but also in ischemic disease generally, including resting and effort angina, acute myocardial infarction (AMI), and sudden death. In approximately one in ten patients with AMI, angiography does not reveal any obstructive coronary artery disease. VA is characterized by chest pain that is not related to exercise and is frequently accompanied by transient ST segment elevation on ECG. The patient is symptom-free with normal ECG findings during the symptom-free periods. Although the underlying mechanism is not well understood, it appears to involve a combination of endothelial damage and vasoactive mediators.

In this case study, a 58-year-old man with myocardial infarction secondary to coronary artery vasospasm experienced recurrent chest pain and had a noncritical lesion as revealed by a normal coronary angiogram. The patient was treated with diltiazem. Diltiazem is a non-dihydropyridine CCB. CCBs seem to be the first-line therapy for VA. Nitrates were also found to be efficient therapy. Clinical trials have revealed that patients who received diltiazem have better outcomes than patients treated with other medical therapy. Diltiazem inhibits mainly L-type calcium channels. Diltiazem can reduce arterial wall injury caused by calcium overload, inhibit smooth muscle proliferation and arterial matrix protein synthesis, increase vascular compliance, inhibit lipid peroxidation, and protect endothelial cells.

This case provides information about the treatment with diltiazem of patients with AMI secondary to VA. VA can be life-threatening. Since the patient positively responded to the therapy, he was followed up without further intervention and did not have an additional episode of VA during a 3-month period of follow-up.

What The Study Did: Researchers report two cases of ophthalmic clinical examination findings in patients who underwent prolonged prone positioning in the intensive care unit during the COVID-19 pandemic.

Authors: Howard D. Pomeranz, M.D., Ph.D., of Northwell Health in Great Neck, New York, 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/jamaophthalmol.2020.4988)

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

November 19, 2020, New York - Water is a ubiquitous liquid with many highly unique properties. The way it responds to changes in pressure and temperature can be completely different from other liquids that we know, and these properties are essential to many practical applications and particularly to life as we know it. What causes these anomalies has long been a source of scientific inspiration with various theoretical explanations, but now an international team of researchers, which includes Nicolas Giovambattista, a professor at The Graduate Center, CUNY and chair for the Department of Physics at Brooklyn College, has proved that water can exist in two different liquid states -- a finding that can explain many of water's anomalous properties. Their research appears in a paper published in the November 20 issue of the journal Science. The possibility that water could exist in two different liquid states was proposed approximately 30 years ago, based on results obtained from computer simulations," Giovambattista said. "This counterintuitive hypothesis has been one of the most important questions in the chemistry and physics of water, and a controversial scenario since its beginnings. This is because experiments that can access the two liquid states in water have been very challenging due to the apparently unavoidable ice formation at the conditions where the two liquids should exist."

The usual "liquid" state of water that we are all familiar with corresponds to liquid water at normal temperatures (approximately 25 centigrade). However, the paper shows that water at low temperatures (approximately -63 centigrade) exists in two different liquid states, a low-density liquid at low pressures and a high-density liquid at high pressures. These two liquids have noticeably different properties and differ by 20% in density. The results imply that at appropriate conditions, water should exist as two immiscible liquids separated by a thin interface similar to the coexistence of oil and water.

Because water is one of the most important substances on Earth -- the solvent of life as we know it -- its phase behavior plays a fundamental role in different fields, including biochemistry, climate, cryopreservation, cryobiology, material science, and in many industrial processes where water acts as a solvent, product, reactant, or impurity. It follows that unusual characteristics in the phase behavior of water, such as the presence of two liquid states, can affect numerous scientific and engineering applications.

"It remains an open question how the presence of two liquids may affect the behavior of aqueous solutions in general, and in particular, how the two liquids may affect biomolecules in aqueous environments," Giovambattista said. "This motivates further studies in the search for potential applications."

Giovambattista is a member of the Physics and Chemistry Ph.D. programs at The Graduate Center of The City University of New York (CUNY).

The international team, led by Anders Nilsson, professor of chemical physics at Stockholm University, used complex experiments and computer simulations to prove this theory. The experiments, described as "science-fiction-like" by Giovambattista, were performed by colleagues at Stockholm University in Sweden, POSTECH University in Korea, PAL-XFEL in Korea, and SLAC national accelerator laboratory in California. The computer simulations were performed by Giovambattista and Peter H. Poole, professor at St. Francis Xavier University in Canada. The computer simulations played an important role in the interpretation of the experiments since these experiments are extremely complex and some observables are not accessible during the experiments.