Culture

By the end of the first year of the pandemic in metropolitan Stockholm, investigators estimate that one-fifth of adults in the region previously had COVID-19. The findings, which are published in the Journal of Internal Medicine, come from analyses of anti-viral antibody responses in healthy blood donors and pregnant women.

For the study, researchers examined blood from 2,600 blood donors and 2,500 pregnant women taken between March 14th 2020 and February 28th 2021. Blood donors and pregnant women had a similar rate of past infection, approaching 19% of the study group by the end of February 2021, shortly before mass vaccinations entered the adult population in Sweden. Nearly all (96%) positive samples screened displayed virus neutralizing responses comparable to those provoked by COVID-19 mRNA vaccines, suggesting that milder infections generally provide a degree of protection upon re-exposure to the virus that causes COVID-19.

"That nearly one in five individuals in these study groups had COVID-19 in the first year of the pandemic is striking. The data show how pervasive the virus is in Stockholm and highlight the need to reduce transmission to curtail viral evolution and prevent additional burden on the public healthcare system," said corresponding author Xaquin Castro Dopico, BVM&S, PhD, of the Karolinska Institute.

Unbound nickel atoms and other heavy elements have been observed in very hot cosmic environments, including the atmospheres of ultra-hot exoplanets and evaporating comets that ventured too close to our Sun or other stars. A new study conducted by JU researchers reveals the presence of nickel atoms in the cold gasses surrounding the interstellar comet 2I/Borisov. The team's finding is being published in Nature on 19 May 2021.

Interstellar comets and asteroids are precious to science because, unlike millions of minor bodies that formed in our Solar System, they originate from distant planetary systems. Until very recently, the existence of such cosmic vagabonds has merely been an interesting possibility, based on the fact that our Solar System ejected most of the primordial comets and asteroids into the interstellar space in its early days. The objects came to light in 2017 with the unexpected detection of the asteroidal 1I/'Oumuamua, followed by the discovery of the only known cometary interloper, 2I/Borisov, in 2019. "The scientific value of these objects is absolutely overwhelming, as they carry a plethora of information about their home planetary systems," says Piotr Guzik of the Jagiellonian University in Poland, author of the new study on 2I/Borisov.

The gasses around 2I/Borisov enabled astronomers to obtain the first precious insights into the chemical composition of an alien icy world. "We were curious what atoms and molecules make up the gasses around 2I/Borisov," explains study co-author Michał Drahus of the Jagiellonian University. There was only one way to find out. Over three nights in late January 2020, the Very Large Telescope of the European Southern Observatory in Chile was pointed at comet 2I/Borisov to collect the object's faint light. The incoming photons were directed to the X-shooter spectrograph, which split the light into its constituent wavelengths, enabling the identification of atoms and molecules through their characteristic spectral signatures.

Guzik and Drahus immediately scrutinized the incoming data and realized the existence of unforeseen spectral features. "At first, these features seemed impossible to identify with standard cometary species," says Guzik. After months of fruitless research, the team was close to giving up. But unexpectedly, a solution appeared on the horizon. "It was literally a 'Beautiful Mind' kind of situation, when the wavelengths of these lines materialized in a tabulated spectrum of comet Ikeya-Seki and pointed at atomic nickel," says Guzik, who first realized the surprising answer. "It didn't seem to make any sense," Drahus adds, "but it really did!"

The problem was that comet Ikeya-Seki passed so close to the Sun that the surrounding dust started evaporating, releasing various metals. The same mechanism could not apply to the cold comet 2I/Borisov, which passed too far from the Sun. "The nickel in 2I/Borisov seems to originate from a short-lived nickel-bearing molecule that is incorporated in the cometary ice and sublimates at low temperatures," explains Guzik. "This is really cool because heavy elements have not been observed in cold cosmic environments before." According to the study, nickel is not very abundant, accounting for less than 1 in 100,000 atoms in the gasses around 2I/Borisov.

HOUSTON - (May 19, 2021) - A new study from researchers at Rice University has found that bodily inflammation after the death of a spouse can predict future depression.

"Inflammation and future depressive symptoms among recently bereaved spouses" will appear in the June 2021 edition of the journal Psychoneuroendocrinology. Lead author Lydia Wu, a Rice psychology graduate student, and Christopher Fagundes, associate professor of psychology and principal investigator for the Biobehavioral Mechanisms Explaining Disparities (BMED) lab at Rice, led the study. The research team evaluated 99 people who lost their spouses within 2-3 months of the study on a number of factors, including physical and mental health, across a three-month period.

"Prior research has already linked bodily inflammation to a host of health issues, including cancer, memory issues, heart problems and depression," Wu said. "We were interested in how systemic inflammation affects the mental health of spouses after losing a loved one. In particular, can inflammation help us identify who will experience clinical levels of depression at a future point in time?"

The researchers found that widowed spouses who had higher levels of bodily inflammation right after the loss of their partners showed more severe symptoms of depression three months later than those with lower inflammation, especially if they didn't experience significant depression initially.

Fagundes said depression following the death of a spouse is normal, and research shows that undergoing psychotherapy right away can actually interfere with people's natural ability to cope.

"We know that most people are remarkably resilient," he said.

However, when depression is persistent or occurs six or more months after a spouse's death, it may be a sign that clinical intervention is needed, Fagundes said.

"Until this study, it was difficult to know who was at risk for these persistently high levels of depression and grief until the six-month mark," he said. "This study identifies a potential biomarker that could help us predict who is at greatest risk for long-term repercussions of loss."

"This information makes early intervention possible," Wu said. "We can identify at-risk bereaved persons and introduce them to interventions early on to improve their mental health."

The researchers said more research is needed to determine who might be at greatest risk.

PITTSBURGH, May 19, 2021 - Specialized immune cells that accumulate in the brain in the days and weeks after a stroke promote neural functions in mice, pointing to a potential immunotherapy that may boost recovery after the acute injury is over, University of Pittsburgh School of Medicine neurologists found.

The study, published today in the journal Immunity, demonstrated that a population of specialized immune cells, called regulatory T (Treg) cells, serve as tissue repair engineers to promote functional recovery after stroke. Boosting Treg cells using an antibody complex treatment, originally designed as a therapy after transplantation and for diabetes, improved behavioral and cognitive functions for weeks after a stroke in mice compared to those that did not receive the antibody complex.

"The beauty of this treatment is in its wide therapeutic window," said senior author Xiaoming Hu, M.D., Ph.D., associate professor in the Department of Neurology at Pitt's School of Medicine. "With most strokes, you have four and a half hours or less when you can give medication called tPA to reopen a blocked blood vessel and expect to rescue neurons. We're excited to identify a mechanism that may promote brain recovery by targeting non-neuronal cells well after this window closes."

Previous research in stroke has been focused on developing new drugs to reduce neuronal death. And whereas these acute stroke treatments quickly lose effectiveness after neurons die, Treg cells remain active for weeks after the injury.

True to their name, Treg cells are immune cells that regulate the immune response, including curtailing excessive inflammation that could harm more than help. Hu and her colleagues observed that the levels of Treg cells infiltrating the brain began to increase about a week after a stroke and continued increasing up to five weeks later. So, they did multiple tests in mice after they'd had strokes, paying particular attention to the brain's white matter--which is the brain tissue through which neurons pass messages, turning thoughts into actions, like lifting food to your mouth or saying the name of an object you're looking at.

Mice that were genetically unable to produce Treg cells fared worse than mice with a robust Treg cell response. Interestingly, it was only in the latter phases of stroke recovery that the Treg cell-depleted mice suffered impairments in white matter integrity and behavioral performance compared to mice with a normal Treg cell response.

Additionally, when normal mice were given an antibody complex called "IL-2:IL-2Ab" to boost their Treg cell levels after a stroke, their white matter integrity improved even more and neurological functions were rescued over the long term. The mice with more Treg cells had an easier time moving and had better memories, allowing them to navigate mazes faster after a stroke than their non-treated counterparts.

"This strongly suggests that, rather than working to preserve white matter structure and function immediately after a stroke, Treg cells influence long-term white matter repair and regeneration," said Hu, also a member of the Pittsburgh Institute of Brain Disorders and Recovery and a U.S. Department of Veterans Affairs (VA) investigator. "Our findings pave the way for a therapeutic approach to stroke and other neurological disorders that involve excessive brain inflammation and damage to the white matter. Treg cells appear to hold neurorestorative potential for stroke recovery."

Hu stressed that there are still many hurdles to cross before Treg cells could be used in humans for stroke recovery. Namely, research is needed to determine the best way to boost the number of Treg cells in stroke victims. This could be done by improving IL-2:IL-2Ab so that it better stimulates production of Treg cells with fewer side effects, or a personalized therapy could be developed where some cells are taken from an established Treg cell bank and used to grow custom Treg cells in the lab, which could then be infused back into the patient.

The yeast Candida albicans can cause itchy, painful urinary tract and vaginal yeast infections. For women in low-resource settings who lack access to healthcare facilities, these infections create substantial social and economic burdens. Now, researchers reporting in ACS Omega have developed color-changing threads that turn bright pink in the presence of C. albicans. When embedded in tampons or sanitary napkins, they could allow women to quickly and discreetly self-diagnose vulvovaginal yeast infections, the researchers say.

According to the Mayo Clinic, about 75% of women will experience a yeast infection, or vulvovaginal candidiasis, at least once in their lifetime. Although women in high-resource areas can easily be diagnosed with a vaginal swab at their doctor's office and then treated with an antifungal medication, many women throughout the world lack access to basic healthcare facilities. Moreover, in some resource-limited areas, societal taboos cause women to feel shame or embarrassment about the symptoms, which prevents them from seeking a doctor's care. Therefore, Naresh Kumar Mani and colleagues wanted to develop an inexpensive method that could be integrated into menstrual hygiene products, allowing women to quickly, easily and discreetly self-diagnose yeast infections.

The researchers began with ordinary multifilament cotton threads purchased at a local craft store. To increase the wicking properties of the threads, the team treated them with a heptane solution that removed waxes and binders added during manufacturing. Then, the threads were coated with a molecule called L-proline β-naphthylamide (PRO) -- the substrate for an enzyme secreted by C. albicans -- and embedded in the inner layers of sanitary napkins and pads. When the researchers added simulated vaginal fluid spiked with C. albicans and an indicator solution, the spots of the napkins or pads containing yeast changed to a bright pink color. The detection time was only 10 minutes, compared with 24-72 hours for conventional tests. In addition, the new test costs only 22 to 28 cents per napkin or tampon, and it could easily be adapted to simultaneously detect other pathogens, such as bacteria that also can cause urinary tract infections, the researchers say.

Researchers have found the elusive genetic element controlling the elongated grains and glumes of a wheat variety identified by the renowned botanist Carl Linnaeus more than 250 years ago.

The findings relating to Polish wheat, Triticum polonicum, could translate into genetic improvements and productivity in the field.

Wheat, in bread, pasta, and other forms, is a vital energy and protein source for humans. Each individual grain is nestled within the glumes and other leaf-like organs called lemma and palea which affect the grain's final size, shape, and weight.

Characterised by Linnaeus in 1762, Polish wheat has long grains, glumes, and lemmas. Previous research showed that all these characteristics were controlled by one gene, but which one among wheat's complex genome has been unclear.

Researchers at the John Innes Centre used genomic, field-based, and biotechnological approaches to identify the responsible molecular component as VRT-A2, a member of the MADS-box family of transcription factors which act as genetic switches controlling protein synthesis.

Dr Nikolai Adamski, first author of the paper, said: "These results highlight how changes in expression of transcription factors can impact on important agronomic traits for major crops such as wheat. Our goal is to use this knowledge to help deliver genetic solutions to improve wheat productivity."

The team identified a small sequence rearrangement leading to misexpression of VRT-A2 in different tissues at several growth stages of wheat. This variation is responsible for the longer grains and floral organs found in Polish wheat.

Introducing the VRT-A2 version from Polish wheat into a UK bread wheat cultivar led to higher grain weight, size, and test weight (a measure of the density of the grain) but did not increase yield in UK environments.

Professor Cristobal Uauy, a group leader at the John Innes Centre, explained the broader significance of the research: "Every day, each person on the planet eats the grains of the equivalent of 50 wheat plants. With a growing demand for wheat, and against the backdrop of climate change, it is urgent that we increase wheat production sustainably. As part of this effort, understanding the genetic control of grain size and weight is extremely relevant to deliver genetic solutions."

The experiments also revealed a strong positive correlation between VRT-A2 expression levels and the magnitude of its effects on grain length and floral organ size.

In Polish wheat, the VRT-A2 gene carries a small rearrangement in its first intron - a genetic sequence that does not code for protein, but instead is important for regulating the gene's expression. The researchers suggest that this rearrangement was caused by errors in DNA repair following a double strand break.

Next the research team aim to understand how the VRT-A2 expression pattern is controlled by the sequence rearrangement in the first intron of the gene. They also plan to identify the downstream genes affected by VRT-A2 misexpression.

Scientists, governments and corporations worldwide are racing against the clock to fight climate change, and part of the solution might be in our soil. By adding carbon from the atmosphere to depleted soil, farmers can both increase their yields and reduce emissions. A cover story in Chemical & Engineering News, the weekly newsmagazine of the American Chemical Society, explores what it would take to get this new practice off the ground.

Historically, agricultural soil has provided crops with the nutrients needed to grow, write Senior Editors Melody Bomgardner and Britt Erickson. Today, most soil is considered degraded, leading farmers to rely on fertilizer, irrigation and pesticides, all of which are costly. Scientific advancements in agriculture have shown that adding organic matter, like decaying plants and microbes, to soil can sequester carbon emissions and replenish soil nutrients, which benefits the farmer and the environment. Companies are also offering incentives to farmers who adopt sustainable practices, such as offering marketable carbon credits to those who help offset greenhouse gas emissions by utilizing techniques like low-till farming and planting cover crops.

Although these agricultural practices show great promise, experts say science needs to verify carbon sequestration's impact on greenhouse gas emissions. Companies and environmental groups alike have developed standards and methods to measure the impact of agricultural practices that earn carbon credits, and new technologies utilizing machine learning and artificial intelligence will help with these efforts. Governments are also looking to play a role in encouraging sustainable agriculture as a means to fight climate change, with the U.S. Congress considering legislation that would allow the U.S. Department of Agriculture to participate in carbon markets and set standards at the federal level. The European Union is also promoting carbon farming to its member states and will launch a carbon market later this year. While experts caution that carbon farming will not replace pollution regulations, the financial incentives and other benefits make it a strong model to follow.

Protein intake is more important than protein source if the goal is to gain muscle strength and mass. This is the key finding of a study that compared the effects of strength training in volunteers with a vegan or omnivorous diet, both with protein content considered adequate.

In the study, which was conducted by researchers at the University of São Paulo (USP) in Brazil, 38 healthy young adults, half of whom were vegans and half omnivores, were monitored for 12 weeks. In addition to performing exercises to increase muscle strength and mass, the volunteers followed either a mixed diet with both animal and plant protein, or an entirely plant-based diet, both with the recommended protein content (1.6 gram of protein per kilogram of body weight per day). At the end of three months, there was no difference between vegans and omnivores in terms of muscle strength and mass increase.

“Like any other protein in our organism, such as the proteins in our skin and hair cells, which die and are renewed, our muscles undergo synthesis and breakdown every day. Diet [protein intake] and exercise are the main protein balance regulators, favoring synthesis over breakdown,” said Hamilton Roschel, last author of the published study. Roschel is a University of São Paulo professor affiliated with both USP’s Sports and Physical Education School (EEEE) and Medical School (FM). He also heads the Applied Physiology and Nutrition Research Group jointly run by EEEE-USP and FM-USP.

Protein sources are characterized primarily on the basis of essential amino acids, especially leukin, which plays a key role in anabolic stimulation of skeletal muscles. “Animal protein has more leukin than plant protein. Leukin is an essential amino acid in the anabolic stimulus signaling process. A plant-based diet is often thought to contain less leukin and hence trigger less anabolic stimulation, potentially affecting vegans’ capacity for muscle mass gain,” Roschel said.

The study is published in Sports Medicine and resulted from the master’s research of Victoria Hevia-Larraín, with support from FAPESP.

The study innovated by including a clinical analysis of the effects of protein source quality on muscle adaptation in vegans as compared with omnivores, since most research on the topic to date has focused on the acute anabolic response of muscles to protein intake under laboratory conditions and not on muscle mass as such. “Our findings show that there is no impairment of muscle mass gain for young adult vegans if they ingest the right amount of protein. In fact, the outcome of both diets was the same in this respect,” Roschel said.

However, the researchers stress that, for the purposes of experimental control, protein intake was made the same in both diets by means of protein supplements. Omnivores and vegans were given milk serum protein isolate or soy protein respectively in accordance with individual dietary needs in order to attain the targeted protein intake.

“In clinical practice, we know foods of animal origin generally have a higher protein content,” Roschel said. “Meat, milk and eggs contain more protein per gram than rice and beans, for example. In a clinical application with plant-based foods as the sole protein source, vegans would need to ingest a large amount of food to obtain the same amount of protein. In some specific cases, this could be a major challenge.”

The protein source (mixed or plant-based diet) made no difference, provided each subject received an adequate amount of protein. “This result corroborates other data in the literature showing that a vegan diet can absolutely be complete if it is properly planned and executed,” Roschel said. “Previous studies suggest it can even be healthier than an omnivorous diet. For this to be the case, however, it requires appropriate nutritional counseling and education regarding people’s choices in restricting their intake to plant-based sources.”

Another point noted by Roschel is that the subjects were healthy young adults, and the results might be different for older people or subjects with health problems. “Aging entails a phenomenon known as anabolic resistance, meaning a suboptimal anabolic response to the stimuli provided by diet and exercise compared with young people. Optimal response is possible in older people only if their protein intake is higher than that of the average healthy youngster. So we should be cautious about generalizing our findings for the entire population.”

The article “High-protein plant-based diet versus a protein-matched omnivorous diet to support resistance training adaptations: a comparison between habitual vegans and omnivores” (doi: 10.1007/s40279-021-01434-9) by Victoria Hevia-Larraín, Bruno Gualano, Igor Longobardi, Saulo Gil, Alan L. Fernandes, Luiz A. R. Costa, Rosa M. R. Pereira, Guilherme G. Artioli, Stuart M. Phillips and Hamilton Roschel can be retrieved from: link.springer.com/article/10.1007/s40279-021-01434-9.

Journal

Sports Medicine

DOI

10.1007/s40279-021-01434-9

Artificial intelligence is providing new opportunities in a range of fields, from business to industrial design to entertainment. But how about civil engineering and city planning? How might machine- and deep-learning help us create safer, more sustainable, and resilient built environments?

A team of researchers from the NSF NHERI SimCenter, a computational modeling and simulation center for the natural hazards engineering community headquartered at the University of California, Berkeley, have developed a suite of tools called BRAILS — Building Recognition using AI at Large-Scale — that can automatically identify characteristics of buildings in a city and even detect the risks that a city's structures would face in an earthquake, hurricane, or tsunami. The team is comprised of researchers from UC Berkeley, the International Computer Science Institute, Stanford, and UCLA.

Charles (Chaofeng) Wang, a postdoctoral researcher at the University of California, Berkeley, and the lead developer of BRAILS, says the project grew out of a need to quickly and reliably characterize the structures in a city.

"We want to simulate the impact of hazards on all of the buildings in a region, but we don't have a description of the building attributes," Wang said. "For example, in the San Francisco Bay area, there are millions of buildings. Using AI, we are able to get the needed information. We can train neural network models to infer building information from images and other sources of data."

BRAILS uses machine learning, deep learning, and computer vision to extract information about the built environment. It is envisioned as a tool for architects, engineers and planning professionals to more efficiently plan, design, and manage buildings and infrastructure systems.

The SimCenter recently released BRAILS version 2.0 which includes modules to predict a larger spectrum of building characteristics. These include occupancy class (commercial, single-family, or multi-family), roof type (flat, gabled, or hipped), foundation elevation, year built, number of floors, and whether a building has a "soft-story" -- a civil engineering term for structures that include ground floors with large openings (like storefronts) that may be more prone to collapse during an earthquake.

The basic BRAILS framework developed by Wang and his collaborators automatically extracts building information from satellite and ground level images drawn from Google Maps and merges these with data from several sources, such as Microsoft Footprint Data and OpenStreetMap -- a collaborative project to create a free editable map of the world. The framework also provides the option to fuse this data with tax records, city surveys, and other information, to complement the computer vision component.

"Given the importance of regional simulations and the need for large inventory data to execute these, machine learning is really the only option for making progress," noted SimCenter Principal Investigator and co-Director Sanjay Govindjee. "It is exciting to see civil engineers learning these new technologies and applying them to real world problems."

LEVERAGING CROWDSOURCING POWER

Recently, the SimCenter launched a project on the citizen science web portal, Zooniverse, to collect additional labelled data. The project, called "Building Detective for Disaster Preparedness," enables the public to identify specific architectural features of structures, like roofs, windows, and chimneys. These labels will be used to train additional feature extraction modules.

"We launched the Zooniverse project in March and within a couple of weeks we had a thousand volunteers, and 20,000 images annotated," Wang said.

Since no data source is complete or fully accurate, BRAILS performs data enhancements using logical and statistical methods to fill in gaps. It also computes the uncertainty for its estimates.

After developing and testing the accuracy of these modules individually, the team combined them to create the CityBuilder tool inside BRAILS. Inputting a given city or region into CityBuilder can automatically generate a characterization of every structure in that geographic area.

Wang and his collaborators performed a series of validation demonstrations, or as they call them, testbeds, to determine the accuracy of the AI-derived models. Each testbed generates an inventory of structures and simulates the impact of a hazard based on historical or plausible events.

The team has created testbeds for earthquakes in San Francisco; and hurricanes in Lake Charles, Louisiana, the Texas coast, and Atlantic City, New Jersey.

"Our objectives are two-fold," Wang said. "First, to mitigate the damage in the future by doing simulations and providing results to decision- and policy-makers. And second, to use this data to quickly simulate a real scenario - instantly following a new event, before the reconnaissance team is deployed. We hope near-real-time simulation results can help guide emergency response with greater accuracy."

The team outlined their framework in the February 2021 issue of Automation in Construction. They showed that their neural network could generate realistic spatial distributions of buildings in a region and described how it could be used for large-scale natural hazard risk management using five coastal cities in New Jersey.

The team presented a testbed for Hurricane Laura (2020), the strongest hurricane to make landfall in Louisiana, at the 2021 Workshop on SHared Operational REsearch Logistics In the Nearshore Environment (SHORELINE21).

COMPUTATIONAL RESOURCES

To train the BRAILS modules and run the simulations, the researchers used supercomputers at the Texas Advanced Computing Center (TACC) -- notably Frontera, the fastest academic supercomputer in the world, and Maverick 2, a GPU-based system designed for deep learning.

"For one model, the training could be finished in a few hours, but this depends on the number of images, the number of GPUs, the learning rate, etc.," Wang explained.

TACC, like the SimCenter, is a funded partner in the NSF NHERI program. TACC designed and maintains the DesignSafe-CI (Cyberinfrastructure) -- a platform for computation, data analysis, and tools used by natural hazard researchers.

"This project is a great example of how advanced computing through DesignSafe can enable new avenues of natural hazards research and new tools, with many components of NHERI working together," said Ellen Rathje, professor of civil engineering at The University of Texas at Austin and principal investigator of the DesignSafe project.

BRAILS/CityBuilder is designed to work seamlessly with the SimCenter Regional Resilience Determination (R2D) tool. R2D is a graphical user interface for the SimCenter application framework for quantifying the regional impact from natural hazards. Its outputs include the damage state and the loss ratio -- the percentage of a building's repair cost to its replacement value -- of each building across an entire city or region, and the degree of confidence in the prediction.

"The hazard event simulations -- applying wind fields or ground shaking to thousands or millions of buildings to assess the impact of a hurricane or earthquake -- requires a lot of computing resources and time," Wang said. "For one city-wide simulation, depending on the size, it typically takes hours to run on TACC."

TACC is an ideal environment for this research, Wang says. It provides most of the computation his team needs. "Working on NSF projects related to DesignSafe, I can compute almost without limitations. It's awesome."

IMPACTS

To make our communities more resilient to natural hazards, we need to know what level of damage we will have in the future, to inform residents and policymakers about whether to strengthen buildings or move people to other places.

"That's what the simulation and modeling can provide, " Wang said. "All to create a more resilient built environment."

EVANSTON, Ill. --- Self-affirmation, the practice of reflecting upon one's most important values, can aid Black medical students in reaching their residency goals. But conversely, it can lead to the perception that they are less qualified for a prestigious residency than their peers.

The pandemic has underscored the racial disparities in the quality of healthcare, a field in which Black Americans are vastly underrepresented as medical physicians.

New Northwestern University research aims to address the "leaky pipeline" preventing Black medical students from completing medical school to pursuing residencies in high-need and underrepresented areas.

Sylvia Perry, assistant professor of psychology in the Weinberg College of Arts and Sciences at Northwestern, is the lead author of the study, which found that Black medical students reported higher levels of fatigue, a lower sense of belonging, and a greater likelihood of changing their medical residency plans than their white counterparts.

It is the first study to attempt experimentally to mitigate such discrepancies with a self-affirmation intervention and the first study to show that self-affirming can promote goal pursuit in a medical education context.

An unexpected finding of the study was that self-affirmation decreased a sense of competitiveness for prestigious residencies.

"This would suggest that if Black medical students are not properly supported during their training, then self-affirming may lead them to accept that extremely competitive residency is unobtainable," Perry said.

About the self-affirmation experiment:

For the longitudinal field experiment, the researchers sampled 234 Black and 182 white medical students across 50 schools in the U.S.

Students completed computerized tasks at three points during their second year of medical school. The self-affirmation intervention group ranked a list of values from most important to least important and wrote about why the most important value mattered to them. Control environment students were asked to write about why their least important value would be important to someone else.

Students were asked to report their well-being, sense of belonging, perceived residency competitiveness, and residency goals. Responses were coded during each wave of testing to see if responses changed or stayed the same.

The researchers found that Black students tended to report more fatigue and less belonging than white students.

They also found that the self-affirmation intervention did not significantly influence students' fatigue, depression, anxiety for belonging. Unexpectedly, Black students in the self-affirmation (vs. control) condition reported lower competitiveness of residency.

Analyses revealed that Black students, compared with white students, were less likely to indicate stable residency goals over time, which may be an indication of stereotype threat. However, this racial gap was eliminated with the intervention.

White students' perceived competitiveness for residency was unaffected by the intervention.

Next steps:

Perry says the researchers will look further into other predictors of well-being, belonging and residency goal stability, including whether going to medical school at a Historically Black College and University (HBCU), compared to a predominately white institution, provides supportive and protective effects that help Black medical students thrive.

BOSTON - In a major breakthrough, researchers at Massachusetts General Hospital (MGH) have discovered how amyloid beta--the neurotoxin believed to be at the root of Alzheimer's disease (AD)--forms in axons and related structures that connect neurons in the brain, where it causes the most damage. Their findings, published in Cell Reports, could serve as a guidepost for developing new therapies to prevent the onset of this devastating neurological disease.

Among his many contributions to research on AD, Rudolph Tanzi, PhD, vice chair of Neurology and co-director of the McCance Center for Brain Health at MGH, led a team in 1986 that discovered the first Alzheimer's disease gene, known as APP, which provides instructions for making amyloid protein precursor (APP). When this protein is cut (or cleaved) by enzymes--first, beta secretase, followed by gamma secretase--the byproduct is amyloid beta (sometimes shortened to Abeta). Large deposits of amyloid beta are believed to cause neurological destruction that results in AD. Amyloid beta formed in the brain's axons and nerve endings causes the worst damage in AD by impairing communication between nerve cells (or neurons) in the brain. Researchers around the world have worked intensely to find ways to block the formation of amyloid beta by preventing cleavage by beta secretase and gamma secretase. However, these approaches have been hampered by safety issues.

Despite years of research, a major mystery has remained. "We knew that Abeta is made in the axons of the brain's nerve cells, but we didn't know how," says Tanzi. He and his colleagues probed the question by studying the brains of mice, as well as with a research tool known as Alzheimer's in a dish, a three-dimensional cell culture model of the disease created in 2014 by Tanzi and a colleague, Doo Yeon Kim, PhD. Earlier, in 2013, several other MGH researchers, including neurobiologist Dora Kovacs, PhD (who is married to Tanzi), and Raja Bhattacharyya, PhD, a member of Tanzi's lab, showed that a form of APP that has undergone a process called palmitoylation (palAPP) gives rise to amyloid beta. That study indicated that, within the neuron, palAPP is transported in a fatty vesicle (or sac) known as a lipid raft. But there are many forms of lipid rafts. "So the question was, Which lipid rafts? And which ones are most relevant to the neuronal processes making up the neural networks of the brain?" says Tanzi.

The new investigation revealed that palAPP is stabilized and prepared for cleavage by beta secretase in special lipid rafts within the neuron known as mitochondria-associated endoplasmic reticulum membranes (MAMs). "We showed for the first time not only that the MAM is where palAPP is processed by beta secretase to make Abeta, but that this happens exclusively in axons and neuronal processes where Abeta does most of its damage," says Bhattacharyya, lead author of the Cell Reports paper. This role for MAMs was previously unknown, though earlier research indicated that they are increased in number and activity in the brains of people with Alzheimer's disease.

Next, the MGH team wanted to learn what happens when MAM levels and activity were intentionally altered. They showed for the first time that preventing assembly of MAMs, either with gene therapy or a drug that blocked a key protein called the sigma-1 receptor (S1R), dramatically decreased beta secretase cleavage of palAPP in axons and lowered Abeta production. Conversely, a drug that activated S1R triggered an increase in beta secretase cleavage of palAPP and increased production of amyloid beta in axons.

"Our results suggest that the sigma-1 receptor might be a viable therapeutic target for reducing Abeta production, specifically in axons," says Tanzi. The study also lends support for a strategy already under investigation by Tanzi and his team, which is developing an experimental treatment that inhibits the palmitoylation of APP, the process that produces palAPP. It's also known that another class of drugs that Kovacs is studying for preventing formation of amyloid beta, called ACAT inhibitors, works directly in MAMs. In the future, these and other interventions that thwart production of this most dangerous pool of axonal amyloid beta could be used in concert with early detection (through blood or imaging tests) to stop or slow the progression of AD.

The development of antibodies to the COVID-19 virus has been the great long-term hope of ending the pandemic. However, immune system turncoats are also major culprits in severe cases of COVID-19, Yale scientists report in the journal Nature.

These autoantibodies target and react with a person's tissues or organs similar to ones that cause autoimmune diseases such as lupus or rheumatoid arthritis. In COVID-19 cases they can attack healthy tissue in brain, blood vessels, platelets, liver, and the gastrointestinal tract, researchers report. The more autoantibodies detected, the greater the disease severity experienced by patients.

And the autoantibodies paradoxically also target and interfere with many immune system proteins that are designed to fend off infections, the study found.

"It's a two-edge sword," said Aaron Ring, assistant professor of immunobiology at Yale and senior author of the paper. "Antibodies are crucial to fend off infection, but some COVID-19 patients also develop antibodies that damage their own cells and tissues."

It is clear that in many cases the presence of coronavirus drove the creation of the damaging autoantibodies, Ring said. But it is also likely that some COVID-19 patients had pre-existing autoantibodies that made them more susceptible to infection, he said. Mice with these same autoantibodies were more susceptible to infection by the COVID-19 virus and more likely to die, the authors report.

The existence of these long-lived rogue autoantibodies could also help explain why some people infected with COVID-19 can later develop lasting medical symptoms, so-called long COVID cases. "This could be the unfortunate legacy of the virus," Ring said.

"Our findings reinforce the importance of getting vaccinated," added co-corresponding author Akiko Iwasaki, the Waldemar Von Zedtwitz Professor of Immunobiology at Yale. "The fact that even mild infections are associated with autoantibody production underscores the potential for long-term health consequences of COVID-19."

For the study, Ring's lab worked with Iwasaki's lab and members of the Yale IMPACT team -- a group of scientists, scholars, and physicians developing research and clinical efforts to combat COVID-19 -- to screen blood samples from 194 patients who had contracted the virus, with varying degrees of severity, for the presence of autoantibodies. Specifically, they used a novel technology developed by Ring's lab called Rapid Extracellular Antigen Profiling (REAP) to identify autoantibody interactions with nearly 3,000 human proteins.

Ring said the findings may lead to strategies to treat or prevent the damaging effects of autoantibodies in COVID-19 patients. In addition, the new REAP technology could be used to pinpoint important antibody responses for many other disease conditions beyond COVID-19. Ring's lab has found a host of novel autoantibodies in patients with autoimmune disease and is now searching for autoantibodies in patients with cancer and neurological illnesses.

HOUSTON -- The glutaminase (GLS1) inhibitor IACS-6274, discovered and developed by The University of Texas MD Anderson Cancer Center's Therapeutics Discovery division, appears to be well-tolerated with successful target inhibition and early signs of anti-tumor activity in a biomarker-driven Phase I trial. Interim results of the study will be presented at the 2021 American Society for Clinical Oncology (ASCO) Annual Meeting on June 4.

On the trial, 17 of 20 evaluable patients achieved a best response of stable disease, with a disease control rate of 60% at 12 weeks. Six patients with biomarker-defined advanced cancers had meaningful durable disease stabilization for greater than six months, with evidence of tumor shrinkage.

Comprehensive pharmacokinetics (PK) and pharmacodynamics (PD) analyses on serial tumor and/or blood samples from trial participants established a robust PK/PD relationship across dose levels. Using a clinical assay developed in-house to measure metabolic activity in patients' blood mononuclear cells, the team also observed strong inhibition of glutamine metabolism at the recommended Phase II dose level, suggesting IACS-6274 robustly functions as intended to block GLS1 activity.

This represents the first major clinical data reported by MD Anderson's Therapeutics Discovery division, a unique group of clinicians, researchers and drug development experts working collaboratively to advance impactful new therapies. By working seamlessly with MD Anderson physicians, the team gains unique clinical insights that aid in the development of impactful medicines.

"Within Therapeutics Discovery, we have focused our efforts to develop new therapies that meet the needs of our patients," said principal investigator Timothy A. Yap, M.B.B.S., Ph.D., associate professor of Investigational Cancer Therapeutics and medical director of the Institute for Applied Cancer Science (IACS). "Our comprehensive efforts to understand and advance IACS-6274 identified select groups of underserved patients as those most likely to benefit from treatment, and we are encouraged by the early results thus far in the study."

Developing a therapy for underserved patient groups

The development of IACS-6274, previously known as IPN60090, was led by a team of scientists and drug development experts in the IACS and Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platforms, both engines within Therapeutics Discovery.

IACS-6274 was selected for development based on its potency, selectivity and PK profile to provide sustained GLS-1 inhibition in patients. The research team then conducted patient-driven translational studies to identify unique populations of patients likely to respond.

Based on these studies, priority indications for the trial include non-small cell lung cancers (NSCLC) with KEAP1/NFEL2L2 mutations, ovarian cancers with low expression of asparagine synthetase (ASNS) and tumors with immune checkpoint inhibitor resistance. Additional insights have revealed that cancers with STK11 and NF1 mutations may respond to GLS1 inhibitors, so the trial also has enrolled those patients.

Evaluating IACS-6274 in a Phase I clinical trial

The first-in-human dose-escalation study was conducted by MD Anderson's Phase I Clinical Trials Program in the Department of Investigational Cancer Therapeutics. The study was designed to evaluate the safety and tolerability of IACS-6274, to identify the maximum tolerated dose and to establish a recommended Phase II dose. Secondary objectives included PK, PD, anti-tumor activity and correlation of biomarkers with clinical outcomes.

The study has enrolled 22 patients with a median age of 63.5, all of whom had received at least two prior therapies. Sixteen patients (73%) are female and six (27%) are male. The trial included patients with different tumor and molecular subtypes, including many of the identified priority patient populations.

The six patients with durable stable disease included those with advanced ASNS-low ovarian cancer, melanoma resistant to anti-PD-1 therapies, NF1-mutant leiomyosarcoma and STK11-mutant NSCLC.

The most common side effects were mild transient visual disturbances. Less common grade 3 toxicities at higher dose levels included reversible nausea, vomiting and fatigue. One patient experienced dose-limiting acute renal failure and posterior reversible encephalopathy syndrome (PRES) at the highest dose level, which fully resolved.

"IACS-6274 appears to be safe and well-tolerated at our recommended Phase II dose, with early signs of anti-tumor activity in patients with certain molecular features," Yap said. "As the study progresses and we continue to learn from those participating, we will work to explore rational combination therapies that are predicted to maximize the benefits for distinct groups of patients based on key biomarkers of response."

HAMILTON, ON (May 19, 2021) - Researchers have found that the inclusion of a third drug to commonly used dual-drug inhalers can reduce asthma exacerbations and improve control over the disease in children, adolescents, and adults with moderate-to-severe asthma.

A team from McMaster University and The Research Institute of St. Joe's Hamilton announced their findings from a systematic review and meta-analysis. Data from 20 randomized controlled trials, which included a total of almost 12,000 patients, were analyzed in the study.

Dual-drug inhalers used to treat asthma typically contain an inhaled corticosteroid (ICS) to reduce inflammation, as well as a long-acting beta-adrenoceptor agonist (LABA) that acts as a bronchodilator. High-certainty evidence showed that the inclusion of a third drug to ICS-LABA combination therapy, known as a long-acting muscarinic antagonist (LAMA), reduced severe asthma exacerbations and slightly improved asthma control without an increase in adverse events. Previously, the benefits and harms of adding a LAMA to ICS-LABA therapy for asthma treatment were unclear and based off of only 1300 patients - mainly adults - leading to weak recommendations in treatment guidelines.

"Our findings provide clear, high-quality evidence on the benefits and harms of triple therapy that will inform asthma care and should prompt revision of current asthma guidelines," said Dr. Derek Chu, lead author of the study.

Dr. Chu is a clinical scholar in the Departments of Medicine and Health Research Methods, Evidence, and Impact (HEI) at McMaster University and an affiliate of The Research Institute of St. Joe's Hamilton.

“If we can reach optimal control of patients’ asthma and reduce asthma exacerbation rates through the LAMA add-on therapy, patients may be able to avoid other treatments that carry a higher risk of adverse events, such as oral corticosteroids, or therapies that are substantially more expensive, such as biologics,” said Lisa Kim, a clinical scholar in the Department of Medicine at McMaster and co-author of the study.

Inhaled LAMAs are currently available in separate inhalers or as three-in-one inhalers that also contain an ICS and LABA. According to the study, both approaches to administering the third drug work similarly.

More than 8 percent of Canadians over the age of 12 have been diagnosed with asthma, making it the most common chronic condition among children. The disease is characterized by constriction of the bronchial tubes, which impedes air flow to and from the lungs. Symptoms can include coughing or wheezing attacks, shortness of breath, chest tightness, and more. The exact causes of asthma may vary, adding to treatment complexity.

The study was published in the Journal of the American Medical Association (JAMA) in coordination with a presentation by the authors at the Advances in Asthma Therapies symposium. The symposium is part of the American Thoracic Society's annual conference - ATS 2021 - which is being held virtually this year.

CASE STUDY SUGGESTS YOUNG PEOPLE SUSCEPTIBLE TO CHRONIC FATIGUE SYNDROME AFTER COVID-19

https://www.hopkinsmedicine.org/news/newsroom/news-releases/covid-19-story-tip-case-study-suggests-young-people-may-be-susceptible-to-chronic-fatigue-following-covid-19

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

With more adolescents and young adults being treated for COVID-19, clinicians are concerned that these people also will start showing post-COVID -- or "long haul" -- symptoms from their bouts with the virus. A recent Johns Hopkins Medicine review of three case studies provides some of the first evidence that one serious post-COVID problem may be myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), the complex, multisystem disorder previously known as chronic fatigue syndrome.

The findings were published April 29 in the journal Frontiers in Medicine.

"In the three patients studied -- all of whom had confirmed or highly probable COVID-19 infections early in the pandemic -- we observed ME/CFS-like symptoms within the first two weeks of illness," says Peter Rowe, M.D., director of the Chronic Fatigue Clinic at Johns Hopkins Children's Center and professor of pediatrics at the Johns Hopkins University School of Medicine. "At six months following their illness, all three still met the criteria for being diagnosed with ME/CFS."

In a recent report, the U.S. Centers for Disease Control and Prevention (CDC) noted that U.S. hospitals are seeing more adolescents and young adults admitted with COVID-19 as more contagious variants of SARS-CoV-2 -- the virus that causes the disease -- spread. The agency believes that the youthful case surge may be the result of those ages 10 to 24 being among the last prioritized to get the coronavirus vaccines, and the fact that many who are eligible have yet to receive their shots. Also, the CDC says, this group is more likely to be involved in high-risk behaviors such as playing close-contact sports and going out to bars.

The three patients evaluated in the recent study were a 19-year-old man and two women, ages 22 and 30, whose COVID-19 symptoms began between April and June 2020, and who were referred to the Chronic Fatigue Clinic between August and October of the same year. Symptoms of orthostatic intolerance -- a group of clinical conditions that includes fatigue, lightheadedness and difficulty concentrating, and are linked with greater than 90% of the people with ME/CFS -- were prominent in all three from the outset of their COVID-19 illness.

A six-month post-COVID symptom onset examination, including evaluations of movement, neurological function and continued orthostatic intolerance, was conducted on each of the patients to determine if ME/CFS could be diagnosed. All three easily met the criteria.

Interestingly, Rowe says, all three patients had relatively mild COVID-19 respiratory symptoms and none required hospitalization, yet it appears to have translated into the more serious secondary problem of ME/CFS for them all.

"This finding is consistent with previous studies in older patients with COVID-19 who showed persistent fatigue months after infection, regardless of the severity of the initial infection," he explains. "This raises the question of how many ME/CFS cases before the COVID-19 pandemic might have been due to mild, subclinical or asymptomatic viral infections [such as Epstein-Barr virus or human herpesvirus 6], including cases in adolescents, young adults and older people."

Rowe and his colleagues feel that further research is needed to define the biological mechanism by which ME/CFS arises from COVID-19, and then use that insight to develop treatment strategies that can return patients with post-COVID ME/CFS back to their previous quality of life.

Rowe is available for interviews.