Culture

Researchers develop molecule to store solar energy

image: Bo Durbeej and his group at Linköping University use advanced computer simulations of chemical reactions, which are performed at the National Supercomputer Centre, NSC, in Linköping.

Image: 
Thor Balkhed/Linköping University

Researchers at Linköping University, Sweden, have developed a molecule that absorbs energy from sunlight and stores it in chemical bonds. A possible long-term use of the molecule is to capture solar energy efficiently and store it for later consumption. The current results have been published in the Journal of the American Chemical Society, JACS.

The Earth receives many times more energy from the sun than we humans can use. This energy is absorbed by solar energy facilities, but one of the challenges of solar energy is to store it efficiently, such that the energy is available when the sun is not shining. This led scientists at Linköping University to investigate the possibility of capturing and storing solar energy in a new molecule.

"Our molecule can take on two different forms: a parent form that can absorb energy from sunlight, and an alternative form in which the structure of the parent form has been changed and become much more energy-rich, while remaining stable. This makes it possible to store the energy in sunlight in the molecule efficiently", says Bo Durbeej, professor of computational physics in the Department of Physics, Chemistry and Biology at Linköping University, and leader of the study.

The molecule belongs to a group known as "molecular photoswitches". These are always available in two different forms, isomers, that differ in their chemical structures. The two forms have different properties, and in the case of the molecule developed by LiU researchers, this difference is in the energy content. The chemical structures of all photoswitches are influenced by light energy. This means that the structure, and thus the properties, of a photoswitch can be changed by illuminating it. One possible area of application for photoswitches is molecular electronics, in which the two forms of the molecule have different electrical conductivities. Another area is photopharmacology, in which one form of the molecule is pharmacologically active and can bind to a specific target protein in the body, while the other form is inactive.

It's common in research that experiments are done first and theoretical work subsequently confirms the experimental results, but in this case the procedure was reversed. Bo Durbeej and his group work in theoretical chemistry, and conduct calculations and simulations of chemical reactions. This involves advanced computer simulations, which are performed on supercomputers at the National Supercomputer Centre, NSC, in Linköping. The calculations showed that the molecule the researchers had developed would undergo the chemical reaction they required, and that it would take place extremely fast, within 200 femtoseconds. Their colleagues at the Research Centre for Natural Sciences in Hungary were then able to build the molecule, and perform experiments that confirmed the theoretical prediction.

In order to store large amounts of solar energy in the molecule, the researchers have attempted to make the energy difference between the two isomers as large as possible. The parent form of their molecule is extremely stable, a property that within organic chemistry is denoted by saying that the molecule is "aromatic". The basic molecule consists of three rings, each of which is aromatic. When it absorbs light, however, the aromaticity is lost, such that the molecule becomes much more energy-rich. The LiU researchers show in their study, published in the Journal of the American Chemical Society, that the concept of switching between aromatic and non-aromatic states of a molecule has a major potential in the field of molecular photoswitches.

"Most chemical reactions start in a condition where a molecule has high energy and subsequently passes to one with a low energy. Here, we do the opposite - a molecule that has low energy becomes one with high energy. We would expect this to be difficult, but we have shown that it is possible for such a reaction to take place both rapidly and efficiently", says Bo Durbeej.

The researchers will now examine how the stored energy can be released from the energy-rich form of the molecule in the best way.

Credit: 
Linköping University

Vaccine narrows racial disparities in pneumococcal disease

image: Rameela Raman, PhD, associate professor of Biostatistics, Vanderbilt University Medical Center

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Vanderbilt University Medical Center

In a major public health success, the introduction of pneumococcal conjugate vaccine PCV13, or Prevnar 13, in 2010 in the United States is associated with reduction in socioeconomic disparities and the near elimination of Black-white-based racial disparities for invasive pneumococcal disease.

That's according to an upcoming study in the Journal of Infectious Diseases by Rameela Raman, PhD, Helen Keipp Talbot, MD, MPH, and colleagues at Vanderbilt University Medical Center. According to the authors, this is the first study to examine the effect of PCV13 on socioeconomic health disparities.

"Our data show that PCV13 is associated with a large decrease in the overall incidence of invasive pneumococcal disease and that race-based pneumococcal disease disparities are markedly reduced," said Raman, associate professor of Biostatistics. "There's reason to think that the 20 Tennessee counties we were able to study are representative of the state and the region."

The bacterium Streptococcus pneumoniae, or pneumococcus, is the main cause of community acquired pneumonia and meningitis in children and the elderly; other invasive pneumococcal diseases include infections of the heart, brain, bloodstream, bones and inner lining of the abdomen.

The team linked neighborhood-level socioeconomic information to individual-level data collected from 20 Tennessee counties participating in a Centers for Disease Control and Prevention (CDC) bacterial surveillance system. These counties represent approximately 55% of Tennessee's total population.

Under a previous, less broad-spectrum pneumococcal vaccine, PCV7, from 2001 to 2009 the incidence of invasive pneumococcal disease was 17.9 cases per year per 100,000 population. Following the introduction of PCV13, for the years 2011-16 the incidence dropped to 12.8.

Under the previous vaccine, the incidence of pneumococcal disease among blacks was approximately 1.5 times the incidence among whites: 24.7 and 16.4, respectively. Post-PCV13, the incidence among blacks was around 1.15 times the incidence among whites: 15 and 13.1, respectively. Post-PCV13, the incidence among blacks of pneumococcal disease with serotypes addressed by PCV13 was around 0.8 times the incidence among whites: 2.2 and 2.7, respectively.

Prior to the introduction in 2000 of PCV7, the incidence of PCV13-serotype disease in high poverty neighborhoods was around 2.8 times the incidence in low poverty neighborhoods: 17.8 and 6.4, respectively. Post-PCV13, incidence of PCV13-serotype disease in high poverty neighborhoods was approximately 2.2 times that of low poverty neighborhoods: 3.1 and 1.4, respectively.

Other VUMC researchers contributing to the study include Danielle Ndi, MPH, Tiffanie Markus, PhD, and William Schaffner, MD. They were joined by researchers from the CDC in Atlanta and Brigham Young University in Provo, Utah. The study was supported in part by the CDC.

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Vanderbilt University Medical Center

College students access eating disorders therapy via phone app

image: Studying college women with eating disorders, a team led by researchers at Washington University School of Medicine in St. Louis found that a phone-based app that delivers a form of cognitive behavioral therapy was an effective means of intervention in addressing specific disorders. Shown are examples of how participants engage with the app.

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WASHINGTON UNIVERSITY CENTER FOR HEALTHY WEIGHT AND WELLNESS

More than 13% of women and 3.6% of men on college campuses have an eating disorder of some kind, but fewer than 20% of those affected ever receive treatment due to lack of available clinicians and the stigma associated with seeking help. New research led by eating disorders experts at Washington University School of Medicine in St. Louis indicates a phone app may help change that.

In a study involving nearly 700 women on 27 U.S. college campuses, including Washington University in St. Louis, the researchers determined that a phone-based app that delivers a form of cognitive behavioral therapy was an effective means of intervention in addressing eating disorders. Those who used the app reported a decline over time in symptoms, including binge eating, purging, using diuretics, and concerns about weight and shape, as well as improvements in depression and anxiety, which often accompany eating disorders.

The findings are published Aug. 31 in the journal JAMA Network Open.

"College students are busy and often don't have spare time to seek the help they need, and many college counseling centers aren't equipped with clinicians who are trained in treating eating disorders, so we believe digital interventions like this one can dramatically increase access to care," said first author Ellen E. Fitzsimmons-Craft, PhD, an assistant professor of psychiatry. "In our study, this digital phone app was associated with dramatic increases in access to treatment. And in cognitive behavioral therapy, we know the app is providing a therapy that's proven to help."

The study focused on women on college campuses via a questionnaire that evaluated whether each woman was at risk for an eating disorder, such as binge eating disorder or bulimia nervosa. It did not include women with anorexia nervosa because they are more likely to benefit from a different treatment approach.

Once a participant was determined to have or to be at risk for binge eating disorder or bulimia, she was randomly assigned to receive cognitive behavioral therapy through a mobile app, or to be referred to typically prescribed care provided through the university's counseling services. Of the 4,894 women who were screened, 914 were eligible for the study. Of those, 690 agreed to participate, with 385 randomly placed in the group using the phone app and 305 assigned to standard care.

Women who were randomly assigned to use the cognitive behavioral therapy app had access to content that was designed to help them challenge and change unhelpful ways of thinking and behaving. The app also provided participants with the support of a coach, who sent text messages to help the participants stay motivated to use the program and apply concepts they were learning through the app to their daily lives.

"One striking finding was that so many women assigned to the digital intervention actually used the phone app, and it helped to reduce their symptoms, such as marked concerns about their shape and weight, body esteem issues, and binge eating or purging," said principal investigator Denise Wilfley, PhD, the Scott Rudolph University Professor of Psychiatry, who led the study along with co-principal investigator C. Barr Taylor, MD, an emeritus professor of psychiatry at Stanford University and research professor at Palo Alto University.

Study participants who were randomized into the group that used the mobile app were able to engage with the therapy on their own time, according to their own schedules, with therapy broken into a series of 40 sessions, each one about 10 minutes long. Each woman also had access to phone calls with therapy coaches at the start and conclusion of the intervention, as well as text-based communication with them throughout the program.

Part of the phone app's success in engaging participants was due to the students being more likely to use the app than to pursue and follow up with in-person counseling. Some 83% of those who were randomly selected to use the app completed at least some of the program, whereas 28% of the students assigned to usual care reported receiving any treatment at all. On average, those who used the app completed about a third (31%) of the app-based therapy sessions but still showed signs of improvement when examined during follow-up visits.

When the study began in 2014, the researchers used a more traditional, web-based intervention that involved longer sessions every week. But the researchers soon realized that relatively few of the women were completing those online therapy sessions, so they enlisted the help of a private company, Lantern, to help create the phone-based app. Then they divided up the treatment into a larger number of shorter sessions.

"Students have greater and greater expectations of their technology," said Fitzsimmons-Craft. "After a slow start with the online therapy, we found that engagement increased significantly once we switched to shorter sessions using the mobile app."

The researchers also found that women using the phone app experienced improvements in depression and anxiety that often accompany eating disorders. Such interventions may be especially important on college campuses during the COVID-19 pandemic, explained Wilfley, also a professor of medicine, of pediatrics and of psychological & brain sciences and director of the Center for Healthy Weight and Wellness.

"Students with eating disorders tend to isolate themselves socially, but now all students are charged with keeping themselves socially distant," she said. "There are data showing increases in symptoms of binge eating disorder and bulimia nervosa now that people are more isolated, with easier access to food and, obviously, unprecedented stress. We think these problems could increase in the coming months, so it's important that there be ways to reach students who are having difficulty. We believe delivering therapy with a phone-based app may be truly effective."

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Washington University School of Medicine

Fungi in gut linked to higher Alzheimer's risk can be reduced through ketogenic diet

WINSTON-SALEM, N. C. - August 31, 2020 - Specific fungi in the gut associated with a higher risk of Alzheimer's disease and found in people with mild cognitive impairment (MCI) can be altered in a beneficial manner by eating a modified Mediterranean diet, researchers at Wake Forest School of Medicine have found.

The small study is published in the current online edition of the journal EBioMedicine.

"Our study reveals that unique fungi co-living with bacteria in the gut of patients with MCI can be modulated through a Mediterranean ketogenic diet," said principal investigator Hariom Yadav, assistant professor of molecular medicine at Wake Forest School of Medicine, part of Wake Forest Baptist Health.

In the single-center, randomized, double-blind crossover pilot study, Yadav's team identified the organisms in the gut microbiome by sequencing the fungal rRNA ITS1 gene in 17 older adults (11 with diagnosed MCI and six with normal cognition) before and after a six-week intervention of a modified Mediterranean ketogenic diet or the American Heart Association Diet to determine its correlation with Alzheimer's markers in cerebrospinal fluid and gut bacteria.

"Although we do not fully understand how these fungi contribute to Alzheimer's disease, this is the first study of its kind to reveal their role in our mental health, which we hope will ignite thinking in the scientific community to develop better understanding of them in relation to Alzheimer's disease," Yadav said. "It also indicates that dietary habits such as eating a ketogenic diet can reduce harmful fungi in the gut which might help in reducing Alzheimer's disease processes in the brain."

Credit: 
Atrium Health Wake Forest Baptist

How antibiotics interact

It is usually difficult to predict how well drugs will work when they are combined. Sometimes, two antibiotics increase their effect and inhibit the growth of bacteria more efficiently than expected. In other cases, the combined effect is weaker. Since there are many different ways of combining drugs - such as antibiotics - it is important to be able to predict the effect of these drug combinations. A new study has found out that it is often possible to predict the outcomes of combining certain antibiotics by quantitatively characterizing how individual antibiotics work. That is the result of a joint study by Professor Tobias Bollenbach at the University of Cologne with Professor Gasper Tkacik and the doctoral researcher Bor Kavcic at the Institute of Science and Technology Austria. The paper 'Mechanisms of drug interactions between translation-inhibiting antibiotics' has been published in Nature Communications.

'We wanted to find out how antibiotics that inhibit protein synthesis in bacteria work when combined with each other, and predict these effects as far as possible, using mathematical models,' Bollenbach explained. As head of the research group 'Biological Physics and Systems Biology' at the University of Cologne, he explores how cells respond to drug combinations and other signals.

Bacterial ribosomes can gradually translate the DNA sequence of genes into the amino acid sequence of proteins (translation). Many antibiotics target this process and inhibit translation. Different antibiotics specifically block different steps of the translation cycle. The scientists found out that the interactions between the antibiotics are often caused by bottlenecks in the translation cycle. For example, antibiotics that inhibit the beginning and middle of the translation cycle have much weaker effects when combined.

In order to clarify the underlying mechanisms of drug interactions, the scientists created artificial translation bottlenecks that genetically mimic the effect of specific antibiotics. If such a bottleneck is located in the middle of the translation cycle, a traffic jam of ribosomes forms, which dissolves upon introducing another bottleneck at the beginning of the translation cycle. Using a combination of theoretical models from statistical physics and experiments, the scientists showed that this effect explains the drug interaction between antibiotics that block these translation steps.

Tobias Bollenbach concluded: 'A quantitative understanding of the effect of individual antibiotics allows us to predict the effect of antibiotic combinations without having to test all possible combinations by trial and error. This finding is important because the same approach can be applied to other drugs, enabling the development of new, particularly effective drug combinations in the long term.'

Credit: 
University of Cologne

Study finds missing link in the evolutionary history of carbon-fixing protein Rubisco

image: Rubisco is the most abundant enzyme on the planet. Present in plants, cyanobacteria (also known as blue-green algae) and other photosynthetic organisms, it's central to the process of carbon fixation and is one of Earth's oldest carbon-fixing enzymes. Researchers at UC Davis and LBNL have now discovered an alternative form of rubisco in environmental samples. 3D images of the form I rubisco (left) compared to the newly discovered form I-prime (right). The discovery could help understand how the enzyme works and be used in plant breeding.

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D. M. Banda et al, 2020

A team led by researchers at the University of California, Davis, has discovered a missing link in the evolution of photosynthesis and carbon fixation. Dating back more than 2.4 billion years, a newly discovered form of the plant enzyme rubisco could give new insight into plant evolution and breeding.

Rubisco is the most abundant enzyme on the planet. Present in plants, cyanobacteria (also known as blue-green algae) and other photosynthetic organisms, it's central to the process of carbon fixation and is one of Earth's oldest carbon-fixing enzymes.

"It's the primary driver for producing food, so it can take CO2 from the atmosphere and fix that into sugar for plants and other photosynthetic organisms to use. It's the primary driving enzyme for feeding carbon into life that way," said Doug Banda, a postdoctoral scholar in the lab of Patrick Shih, assistant professor of plant biology in the UC Davis College of Biological Sciences.

Form I rubisco evolved over 2.4 billion years ago before the Great Oxygenation Event, when cyanobacteria transformed the Earth's atmosphere by producing oxygen through photosynthesis. Rubisco's ties to this ancient event make it important to scientists studying the evolution of life.

In a study appearing Aug. 31 in Nature Plants, Banda and researchers from UC Davis, UC Berkeley and the Lawrence Berkeley National Laboratory report the discovery of a previously unknown relative of form I rubisco, one that they suspect diverged from form I rubisco prior to the evolution of cyanobacteria.

The new version, called form I-prime rubisco, was found through genome sequencing of environmental samples and synthesized in the lab. Form I-prime rubisco gives researchers new insights into the structural evolution of form I rubisco, potentially providing clues as to how this enzyme changed the planet.

An invisible world

Form I rubisco is responsible for the vast majority of carbon fixation on Earth. But other forms of rubisco exist in bacteria and in the group of microorganisms called Archaea. These rubisco variants come in different shapes and sizes, and even lack small subunits. Yet they still function.

"Something intrinsic to understanding how form I rubisco evolved is knowing how the small subunit evolved," said Shih. "It's the only form of rubisco, that we know of, that makes this kind of octameric assembly of large subunits."

Study co-author Professor Jill Banfield, of UC Berkeley's earth and planetary sciences department, uncovered the new rubisco variant after performing metagenomic analyses on groundwater samples. Metagenomic analyses allow researchers to examine genes and genetic sequences from the environment without culturing microorganisms.

"We know almost nothing about what sort of microbial life exists in the world around us, and so the vast majority of diversity has been invisible," said Banfield. "The sequences that we handed to Patrick's lab actually come from organisms that were not represented in any databases."

Banda and Shih successfully expressed form I-prime rubisco in the lab using E. coli and studied its molecular structure.

Form I rubisco is built from eight core large molecular subunits with eight small subunits perched on top and bottom. Each piece of the structure is important to photosynthesis and carbon fixation. Like form I rubisco, form I-prime rubisco is built from eight large subunits. However, it does not possess the small subunits previously thought essential.

"The discovery of an octameric rubisco that forms without small subunits allows us to ask evolutionary questions about what life would've looked like without the functionality imparted by small subunits," said Banda. "Specifically, we found that form I-prime enzymes had to evolve fortified interactions in the absence of small subunits, which enabled structural stability in a time when Earth's atmosphere was rapidly changing."

According to the researchers, form I-prime rubisco represents a missing link in evolutionary history. Since form I rubisco converts inorganic carbon into plant biomass, further research on its structure and functionality could lead to innovations in agriculture production.

"Although there is significant interest in engineering a 'better' rubisco, there has been little success over decades of research," said Shih. "Thus, understanding how the enzyme has evolved over billions of years may provide key insight into future engineering efforts, which could ultimately improve photosynthetic productivity in crops."

Credit: 
University of California - Davis

NOAA/NASA's Suomi NPP satellite shows two views of California's smoky skies

image: This image taken by Suomi NPP on August 30, 2020 shows the smoke and fires in California.

Image: 
NOAA/NASA

NOAA/NASA's Suomi NPP satellite captured two images that tell the story about the smoke coming off the fires in California. One instrument on the provided a visible image of the smoke, while another analyzed the aerosol content within. The images were captured on August 30, 2020.

The first image captured by the Suomi NPP satellite using the VIIRS (Visible Infrared Imaging Radiometer Suite) Corrected Reflectance imagery shows a true-color image (called true-color or natural color because this combination of wavelengths is similar to what the human eye would see) of the wildfires still burning across large swaths of the state. Smoke is pouring off the fires and traveling in two different directions. Some of the smoke is traveling northeast into Nevada and as far east (in this image) as Salt Lake City, Utah, and some is traveling west into the Pacific Ocean.

The second image was captured by Suomi NPP with the OMPS Aerosol Indexer and shows not only the direction of the smoke's travel but the thickness of the aerosol layer that has moved outward from the fires. The OMPS (Ozone Mapping and Profiler Suite) Aerosol Indexer on Suomi NPP is an instrument that indicates the presence of ultraviolet-absorbing particles in the air coming from dust (desert) or, as in this case, soot from fires. The Aerosol Indexer found on the image as a scale is unitless, that is, the lowest and highest range do not relate directly to each other. It just indicates whether the scale is low or high. In this image of smoke coming off the California fires, the aerosols found were mostly in the moderate range (yellow) with some higher range areas (red). Higher concentrations can reduce visibility and impact human health. The Aerosol index is also useful for tracking long-range transport of these aerosols that move along jet streams.

NASA's satellite instruments are often the first to detect wildfires burning in remote regions, and the locations of new fires are sent directly to land managers worldwide within hours of the satellite overpass. Together, NASA instruments detect actively burning fires, track the transport of smoke from fires, provide information for fire management, and map the extent of changes to ecosystems, based on the extent and severity of burn scars. NASA has a fleet of Earth-observing instruments, many of which contribute to our understanding of fire in the Earth system. Satellites in orbit around the poles provide observations of the entire planet several times per day, whereas satellites in a geostationary orbit provide coarse-resolution imagery of fires, smoke and clouds every five to 15 minutes. For more information visit: https://www.nasa.gov/mission_pages/fires/main/missions/index.html

NASA's Earth Observing System Data and Information System (EOSDIS) Worldview application provides the capability to interactively browse over 700 global, full-resolution satellite imagery layers and then download the underlying data. Many of the available imagery layers are updated within three hours of observation, essentially showing the entire Earth as it looks "right now." Actively burning fires, detected by thermal bands, are shown as red points. Image Courtesy: NASA Worldview, Earth Observing System Data and Information System (EOSDIS).

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NASA/Goddard Space Flight Center

Scientists develop first drug-like compounds to inhibit elusive cancer-linked enzymes

A team of scientists from the University of Michigan Rogel Cancer Center has developed the first drug-like compounds to inhibit a key family of enzymes whose malfunction is associated with several types of cancer, including an aggressive form of childhood leukemia.

The enzymes -- known as the nuclear receptor-binding SET domain (NSD) family of histone methyltransferases -- have long been an attractive drug target, but efforts to attack them have previously proved elusive because the shape of the binding sites in these enzymes makes it difficult for drug-like molecules to bind to it.

The research team -- led by Tomasz Cierpicki, Ph.D., and Jolanta Grembecka, Ph.D. -- used a variety of techniques including X-ray crystallography and nuclear magnetic resonance to develop first-in-class inhibitors of a key protein known as NSD1, according to findings published in
Nature Chemical Biology.

The team's lead compound -- known as BT5 -- showed promising activity in leukemia cells with the NUP98-NSD1 chromosomal translocation that is seen in a subset of pediatric leukemia patients.

"Our study, which was years in the making, demonstrates that targeting this key enzyme with small-molecule inhibitors is a feasible approach," says Cierpicki, an associate professor of biophysics and pathology at U-M. "These findings will facilitate the development of the next generation of potent and selective inhibitors of these enzymes, which are overexpressed, mutated or undergo translocations in several types of cancer."

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Michigan Medicine - University of Michigan

FSU researchers develop new X-ray detection technology

image: A researcher holds a flexible X-ray scintillator developed by Professor Biwu Ma and his research team. The team has developed a new material that could be used to make flexible X-ray detectors that are less harmful to the environment and cost less than existing technologies.

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Photo courtesy of Biwu Ma / Florida State University

Florida State University researchers have developed a new material that could be used to make flexible X-ray detectors that are less harmful to the environment and cost less than existing technologies.

The team led by Biwu Ma, a professor in the Department of Chemistry and Biochemistry, created X-ray scintillators that use an environmentally friendly material. Their research was published in the journal Nature Communications .

"Developing low-cost scintillation materials that can be easily manufactured and that perform well remains a great challenge," Ma said. "This work paves the way for exploring new approaches to create these important devices."

Biwu Ma, professor in the Department of Chemistry and Biochemistry
X-ray scintillators convert the radiation of an X-ray into visible light, and they are a common type of X-ray detector. When you visit the dentist or the airport, scintillators are used to take images of your teeth or scan your luggage.

Various materials have been used to make X-ray scintillators, but they can be difficult or expensive to manufacture. Some recent developments use compounds that include lead, but the toxicity of lead could be a concern.

Ma's team found a different solution. They used the compound organic manganese halide to create scintillators that don't use lead or heavy metals. The compound can be used to make a powder that performs very well for imaging and can be combined with a polymer to create a flexible composite that can be used as a scintillator. That flexibility broadens the potential use of this technology.

"Researchers have made scintillators with a variety of compounds, but this technology offers something that combines low cost with high performance and environmentally friendly materials," Ma said. "When you also consider the ability to make flexible scintillators, it's a promising avenue to explore."

Ma recently received a GAP Commercialization Investment Program grant from the FSU Office of the Vice President for Research to develop this technology. The grants help faculty members turn their research into possible commercial products.

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Florida State University

Novel Dual CAR T cell immunotherapy holds promise for targeting the HIV reservoir

BOSTON- A recent study published in the journal Nature Medicine, led by researchers Todd Allen, PhD, a professor of Medicine at Harvard Medical School (HMS) and group leader at the Ragon Institute of MGH, MIT and Harvard, and Jim Riley, PhD, a professor of Microbiology in the Perelman School of Medicine at the University of Pennsylvania, describes a new Dual CAR T cell immunotherapy that can help fight HIV infection. The paper's first authors are Colby Maldini, a graduate student at the University of Pennsylvania and Daniel Claiborne, PhD, a research fellow at the Ragon Institute.

"This study highlights how relatively straightforward alterations to the way T cells are engineered can lead to dramatic changes in their potency and durability," Riley said. "This finding has significant implications for using engineered T cells to fight both HIV and cancer."

The global HIV epidemic impacts more than 35 million people around the world. Antiretroviral therapy (ART) is a daily treatment that can control, but not cure, HIV infection. However, access and lifelong adherence to a daily regimen is a significant barrier for many people living with HIV. A major hurdle to HIV cure is the viral reservoir, copies of HIV hidden away in the genome of infected cells. If ART treatment is stopped, the virus is able to rapidly make new copies of itself, ultimately leading to the development of AIDS.

CAR T cells are a powerful immunotherapy, currently used in cancer treatments, in which a patient's own immune T cells are engineered to express Chimeric Antigen Receptors (CARs). These CARs re-program the T cells to recognize and eliminate specific diseased or infected cells, such as cancer cells or, potentially, HIV-infected cells.

Allen's and Riley's research groups worked together to design a new HIV-specific CAR T cell. They needed to design a CAR T cell that would be able to target and quickly eliminate HIV-infected cells, survive and reproduce once in the body, and resist infection by HIV itself, since HIV's primary target is these very same T cells.

"By using a stepwise approach to solve each issue as it arose, we developed protected Dual CAR T cells, which provided a strong, long-lasting response against HIV-infection while being resistant to the virus itself," Allen said.

This Dual CAR T cell, a new type of CAR T cell, was made by engineering two CARs into a single T cell. Each CAR had a CD4 protein that allowed it to target HIV-infected cells and a costimulatory domain, which signaled the CAR T cell to increase its immune functions. The first CAR contained the 4-1BB co-stimulatory domain, which stimulates cell proliferation and persistence, while the second has the CD28 co-stimulatory domain, which increases its ability to kill infected cells.

Since HIV frequently infects T cells, they also added in a protein called C34-CXCR4, developed in the lab of James Hoxie, MD, a professor of Hematology-Oncology at Penn. C34-CXCR4 prevents HIV from attaching to and then infecting the cell. The final CAR T cell was long-lived, replicated in response to HIV infection, killed infected cells effectively, and was partially resistant to HIV infection.

When the protected Dual CAR T cells were given to HIV-infected mice, the team saw slower HIV replication and fewer HIV infected cells than in untreated animals. They also saw reduced amounts of virus and preservation of CD4+ T cells, HIV's preferred target, in the blood of these animals. In addition, when they combined Dual CAR T cells with ART in HIV-infected mice, the virus was suppressed faster, which led to a smaller viral reservoir than in mice who were only treated with ART.

"The ability of these protected Dual CAR T cells to reduce the HIV burden in a variety of tissues and cell types, including long-lived memory CD4+ T cells, we believe supports the approach of using CAR T cell therapy as a new tool to target the HIV reservoir towards a functional cure for HIV," said Allen.

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Massachusetts General Hospital

Consortium of Brazilian researchers completes sequencing of native stingless bee's genome

image: It is a docile species of economic interest as a pollinator. Its workers are sterile, and some of its genetic sequences are identical to those found in other eusocial bees, pointing to the conservation of ancestral traits

Image: 
Cristiano Menezes

 A consortium of researchers funded by Brazil’s National Council for Scientific and Technological Development (CNPq) and FAPESP has sequenced the genome of Frieseomelitta varia, a native stingless bee (common name: marmelada). The feat extends scientists’ understanding of the evolution of stingless bees (Meliponini) and paves the way for the breeding of commercially useful species.

The researchers are affiliated with six Brazilian universities. The findings are published in BMC Genomics in a paper coauthored by researchers at the University of São Paulo (USP), São Paulo State University (UNESP), the Federal University of São Carlos (UFSCar), the Federal University of Alfenas (UFAL), the Federal University of Jequitinhonha and Mucuri Valleys (UFVJM), and the Federal Technological University of Paraná (UTFPR).

“We chose a species to test our ability to sequence a whole genome in a pilot project. F. varia is an emblematic species because its workers are completely sterile. This is a trait that distinguishes it from the vast majority of species in the tribe Meliponini,” said Klaus Hartmann Hartfelder, a professor in the University of São Paulo’s Ribeirão Preto Medical School (FMRP-USP) and corresponding author of the paper.

The study was part of a project supported by FAPESP. The principal investigator for the project was Zilá Luz Paulino Simões, a professor in the University of São Paulo’s Ribeirão Preto School of Philosophy, Science and Letters (FFCLRP-USP) and a coauthor of the paper. The sequencing was performed at the Central Laboratory for High-Performance Technologies in Life Sciences (LaCTAD) at the University of Campinas (UNICAMP), also with FAPESP’s support.

The sequencing revealed a large number of repeated noncoding long RNAs, which have a regulatory function. In humans, for example, these RNAs are associated with processes that regulate development of the central nervous system, among others. In F. varia, the researchers believe that these sequences may be linked to the lack of ovaries that makes the workers sterile. The queen is highly fertile, of course.

“As in the vast majority of social insects, the eggs are all the same. Any egg can develop into a worker or queen. During the larval stage, however, some molecular signaling pathways diverge so that the bees differentiate into two types of individuals, one fertile queen and many infertile workers,” Hartfelder said. “In the Western honeybee Apis mellifera, this is engineered by giving the queen different food in the larval stage, but in stingless bees, it seems to be more a matter of the amount of food.”

Evolutionary advantage

The group also found a high degree of conservation (synteny) in a block of genes described in A. mellifera related to pollen hoarding by colonies. This is typical of highly social species, whereas others collect only enough pollen to feed their larvae.

“The finding surprised us, given that A. mellifera and stingless bees diverged into different lineages more than 70 million years ago. That’s a long time for a species to conserve a trait as it evolves,” Hartfelder said. “We want to see if the same is true of other bees and if it happened by chance or afforded an evolutionary advantage.”

Another interesting finding was the difference between the stingless bee species studied and other bees in terms of the arrangement of genes in the mitochondrial genome, which was also sequenced as part of the study. The alteration of the cellular energy factory’s gene order may have evolutionary implications worthy of being studied in greater depth in the future.

Pollination of food crops

The nests built by colonies of F. varia are coated on the outside with plant resin that acts as a repellent to keep away ants and other potential invaders. The species produces little honey but is docile and sufficiently widely distributed, especially in the southeast of Brazil, to be used as a pollinator of high-added-value food crops grown in hothouses. The Western honey bee has not adapted well to indoor environments.

The discoveries regarding the genome of F. varia will also help guide the search for desirable traits in other species of commercial interest, such as Tetragonisca angustula (common name: jataí).

In the study, the group used the experience acquired by international consortia in sequencing bee genomes. In 2006, the researchers took part in the sequencing of A. mellifera’s genome. The result was published in Nature.

In 2015, they participated in a study, reported in Science, that sequenced ten bee genomes, including that of Melipona quadrifasciata, the first Brazilian stingless bee genome ever sequenced. In the same year, they participated in the sequencing of the genomes of two bumblebees (Bombini), which belong to the same lineage as honeybees (Apini) and stingless bees.

The next step in the research will entail a more detailed study of some regions of F. varia’s genome that drew attention. In addition, thanks to the knowledge gleaned from previous studies, the group have already selected five other species whose genomes will be sequenced.

Credit: 
Fundação de Amparo à Pesquisa do Estado de São Paulo

Asthma may not be a significant risk factor for severe COVID-19

image: Asthma may not be significant risk factor for severe COVID-19.

Image: 
ATS

August 31, 2020-- A new research letter published online in the Annals of the American Thoracic Society examines whether asthma is a significant risk factor for developing COVID-19 that is severe enough to warrant hospitalization and intubation. According to the Centers for Disease Control and Prevention, individuals with asthma are at higher risk for hospitalization and other severe effects from COVID-19, similar to the elevated risk from such health conditions as obesity, hypertension and diabetes.

In "Asthma in COVID-19 Hospitalizations: An Overestimated Risk Factor?," Fernando Holguin, MD, MPH, and co-authors compared the prevalence of asthma among patients hospitalized for COVID-19, as reported in 15 peer-reviewed studies, with that of the corresponding population's asthma prevalence. They also correlated the study's asthma prevalence with the four-year average asthma prevalence in influenza hospitalizations in the United States. In addition, they analyzed the medical records of 436 COVID-19 patients admitted to the University of Colorado Hospital to evaluate the likelihood that patients with asthma would be intubated more often than patients without asthma.

"The CDC places people with asthma at higher risk for COVID-related hospitalization," said Dr. Holguin, professor, Asthma Clinical & Research Program, Pulmonary Division, University of Colorado Anschutz Medical Campus.

"However, many international studies show low numbers of asthmatics among hospitalized COVID-19 patients. These findings challenge the assumption about asthma as a risk factor."

The researchers performed a focused review of English-language scientific literature in order to identify studies reporting asthma prevalence among patients hospitalized for COVID-19 infection. Three independent reviewers agreed on 15 studies to include in the analysis. Using local data from hospitalized COVID-19 patients, they performed a statistical analysis to determine the relationship between asthma status and intubation, once they took into account patients' age, gender and body mass index (BMI).

The authors stated, "We found that the proportion of asthmatics among hospitalized patients with COVID-19 is relatively similar to that of each study site's population asthma prevalence. This finding is in stark contrast to influenza, in which asthmatics make up more than 20 percent of those hospitalized in the United States."

"Using data from our hospital, we also observed that among COVID-19 patients, those with asthma, which had a 12 percent prevalence rate, did not seem to be more likely to be intubated than non-asthmatics," they added.
Dr. Holguin and colleagues theorize that the corticosteroid inhalers many people with asthma use make it more difficult for coronaviruses to enter their airways.

Specifically, these individuals may have lower levels of expression of ACE2, a protein that binds to SARS-CoV-2, the virus caused by COVID-19. People with asthma that is related to allergies may also have lower expression of ACE2, whether or not they use corticosteroids.

"The contribution of ACE2 receptor expression levels to COVID-19 susceptibility is still unclear, however, it should certainly be further investigated," said Dr. Holguin.
Dr. Holguin adds that the asthma-COVID-intubation risk relationship should be studied further.

Credit: 
American Thoracic Society

Living in disadvantaged neighborhoods doubles post-op delirium risk for older adults

Where you live can increase your risk for experiencing delirium after surgery. So said a study that showed older adults who live in the most disadvantaged neighborhoods are two times more likely to experience delirium after surgery than their counterparts from more affluent communities. These findings by researchers from the Aging Brain Center in the Hinda and Arthur Marcus Institute for Aging Research (Marcus Institute) at Hebrew SeniorLife were published today in the Journal of the American Geriatrics Society. Franchesca Arias, Ph.D., Assistant Scientist, and Sharon K. Inouye, M.D., Director of the Aging Brain Center, were lead and senior authors respectively on the study.

Delirium is a clinical syndrome characterized by acute decline in cognition, which can present as inattention, disorientation, lethargy or agitation, and perceptual disturbance. Delirium among older hospitalized patients can lead to poor outcomes, including prolonged hospital stays, deep psychological stress for patients and their families, functional decline, and in worst cases, death. To date, however, the association between delirium and community-based factors that can influence health outcomes, such as resources, health care access, and local economic conditions, has not been well-examined.

The study enrolled a prospective observational cohort of 560 patients aged 70+ undergoing major non-cardiac surgery between June 2010 and August 2013 at two academic medical centers in Boston. The research team used the Area Deprivation Index (ADI) to characterize participant's neighborhood socioeconomic disadvantage.

ADI uses 17 United States Census indicators of poverty, education, employment, and physical environment to characterize the socioeconomic disadvantage of a census block group. This study found that neighborhood characteristics, such as poverty, lack of infrastructure, and density contributed to the two-fold increase in the number of patients who developed delirium after surgery. When compared with other social and economic risk factors for diminished health outcomes in older adults, including income and level of education, neighborhood characteristics emerged as the strongest predictor of delirium incidence.

The COVID-19 pandemic has shone a light on the consequences of economic health care disparities in the U.S., and this study is yet another example of how social, economic, and environmental marginalization impacts the health of those who live in disadvantage communities.

"Our hope is that by building awareness of barriers to care present in disadvantaged neighborhoods, clinical teams will tailor support and treatment recommendations based on the resources available within a patient's community," said Dr. Inouye.

"Patients with higher ADI percentiles may benefit from having additional support and periodic check-ins with treatment teams prior to surgery and/or participating in rehabilitation programs postoperatively," said Dr. Arias.

Credit: 
Hebrew SeniorLife Hinda and Arthur Marcus Institute for Aging Research

People love winning streaks by individuals -- teams, not so much

COLUMBUS, Ohio - People enjoy witnessing extraordinary individuals - from athletes to CEOs - extend long runs of dominance in their fields, a new study suggests. But they aren't as interested in seeing similar streaks of success by teams or groups.

"Everyone wants Usain Bolt to win another gold medal for sprinting. Not so many people want to see the New England Patriots win another Super Bowl," said Jesse Walker, lead author of the study.

The reason? "Extraordinary success by individuals inspires awe in people in a way that team success does not," said Walker, an assistant professor of marketing at Ohio State University's Fisher College of Business.

"When we see Usain Bolt win three gold medals in a row, it expands what we thought was the limit of human potential. Team winning streaks don't change as much what we think humans can achieve," he said.

"People appear to be more moved by individual success than group success and so they're more interested in seeing individual success continue."

Walker and Thomas Gilovich, professor of psychology at Cornell University, did nine studies involving 2,625 Americans. Their results appear in the Journal of Personality and Social Psychology.

In one study, they examined people's views on the success of Usain Bolt, the Jamaican sprinter who won the 100-meter dash in the last three Olympics. Bolt was also a member of a team that won the gold medal in the 4x100-meter relay at those same Olympic games.

Many more people reported they would prefer to see Bolt win the gold medal in the individual event in the next Olympics than in the relay event, results showed.

But the preference for seeing individual streaks continue doesn't just apply to famous athletes in familiar sports. In one study, participants were told about an obscure Italian sport called Calcio Fiorentino.

Participants who were told about an individual version of the sport - and read about a fictional superstar who had won the championship six times in a row - were more likely to say they wanted him to win a seventh time, compared to those who read about a team that had won the championship six times in a row.

And it is not just sports superstars that inspire people to want to cheer on winning streaks.

Studies showed people supported individual runs of dominance over team dominance in the British Quizzing Championship and in the best closure rates on homicide cases in U.S. police departments.

This preference has implications in the business world, as well.

In one study, participants read about the real electronic components manufacturer AVnet, one of the 350 largest companies in America.

Half the participants were told that a (fictional) CEO of the company had guided the company for the last couple of decades, making a series of shrewd and successful decisions that led to AVnet's success. The other half were told a group of executives had guided the company, making the same shrewd decisions.

Participants who read that Avnet's success could be attributed to its CEO thought the company should command a greater share of the market than did the participants who were told the company's success was tied to a group of executives.

"This could be one of the reasons why customers connect personally with companies like Apple that are identified with their founders and CEOs," Walker said.

"Successful companies like IBM or Samsung that are more faceless have a harder time connecting with people on such a personal level and inspiring people to root for their continued success."

Other studies looked at why people feel differently about individual versus team winning streaks.

Results showed that people attributed individual streaks of success to the people themselves, while team success was attributed to situational factors.

"When an individual is on a streak of success, it is a lot easier to pinpoint who is responsible - they own their success. With a group or team, there are so many people involved and so many moving parts that it is less clear. There could be any number of factors that account for a group's success," Walker said.

"We found that people view individual streaks as attributable directly to the talents or efforts of the individuals involved, which inspired feelings of awe that they presumably enjoy and would like to continue."

Credit: 
Ohio State University

Hots dogs, chicken wings and city living helped wetland wood storks thrive

video: A wood stork and chicks in nest in urban South Florida.

Image: 
Betsy Evans, Ph.D.

Natural wetlands continue to disappear due to city and human development and are being replaced with manmade swales, ponds and canals. This degradation and replacement of natural wetlands suggest that urban areas may be imperative to wetland species, especially when natural conditions are unpredictable. Wetland birds are often seen in and around cities; however, they have been largely ignored in urban wildlife studies. In their historic ranges, wetland birds inhabit dynamic marshes, traveling long distances to locate food. Yet, does their ability to forage for food in natural environments translate to their ability to do so in an urban environment?

Using the Wood Stork (Mycteria americana), a large American wading bird found throughout southeastern swamps and wetlands, scientists from Florida Atlantic University's Charles E. Schmidt College of Science compared city storks with natural wetland storks to gauge their success in urban environments based on their diet and food opportunities.

Results of the study, published in Scientific Reports, provide evidence and a systematic understanding of how a wetland species persists and even thrives in an urban environment, by switching to human foods like chicken wings and hot dogs when natural marshes are in bad shape.

For the study, researchers sampled 160 nests during the 2015-2017 nesting seasons. Of the 160 sampled nests, 106 nests were in three urban colonies and 54 nests were in two natural wetland colonies in South Florida where a vast freshwater wetland, the Everglades, is located adjacent to a large urban area. They compared urban and natural wetland storks' productivity, body condition, reproductive performance, breadth of diet, and tested whether stork diets changed during suboptimal natural wetland conditions.

They found that storks were able to exploit urban areas when natural food resources were scarce. This ability to switch between habitats and thus resources allowed for better reproductive performance during periods of low natural food availability. Furthermore, body condition did not differ significantly between urban and natural wetland nesting birds during either optimal or suboptimal conditions, suggesting that supplemental environmental resources do not negatively impact body condition. These findings indicate that urban areas can buffer a species from the unpredictability of natural food resources.

"During suboptimal conditions, urban birds expanded their diets to include more prey types, including anthropogenic food, suggesting that urban birds were able to exploit urban areas during low natural wetland prey availability," said Betsy A. Evans, Ph.D., a natural resources specialist with the United States Army Corps of Engineers and lead author, who conducted the study as a graduate student in FAU's Department of Biological Sciences with co-author Dale E. Gawlik, Ph.D., a professor in biology and FAU's Environmental Science Program. "The ability of urban birds to switch their diet to include different prey types such as human-provided food that included chicken wings and hot dogs likely allowed them to produce more chicks during poor natural wetland prey availability conditions than their non-urban counterparts."

Evans and Gawlik discovered that not only were urban storks able to access human-provided food such as trash, but they also increased the proportion of amphibians such as frogs in their diet when natural wetland conditions were suboptimal. Larval frogs (tadpoles) occur in a wide range of wetland types in the study region; however, they were 10 times more abundant in roadside created wetlands such as swales, ponds and canals than in natural wetlands during the time-period of this study. This suggests that storks may also have been accessing created wetlands along roadways during suboptimal natural wetland conditions.

"Behavioral flexibility and the ability to travel long distances and exploit resources in dynamic systems may give wetland birds an ecological advantage in urban environments," said Gawlik. "Our findings demonstrated that urban storks expanded their diets during times of low natural wetland prey availability to include resources commonly found in urban areas, partially dampening the natural wetland food limitation on wading bird populations. Natural wetland birds, however, paid a greater reproductive penalty during suboptimal conditions than their urban counterparts. Furthermore, this ability to switch diets between resource pulses may reduce population fluctuations and lower the risk of extinction."

The study demonstrates that urban environments may support biodiversity in a variety of ways. To mitigate potential threats from urbanization it will be important to understand how species exploit new resources as well as how they are affected by loss of resources from human activities.

For the study, the researchers visited two natural wetland colonies and three urban colonies one to two times per week during the 2015-2017 breeding seasons (approximately March through June). They selected these study colonies based on their range of hydrological conditions and history of repeated use by nesting storks. They describe colony landscape type broadly as either "urban" or "natural wetland" with natural wetland colonies occurring within Everglades National Park and urban colonies occurring within the urban east coast corridor of South Florida. At each colony location, they marked individual nests from which they collected productivity, body condition, and diet information.

Credit: 
Florida Atlantic University