Culture

Implicit racial attitudes within a community can effectively explain racial disparities seen in rates of COVID-19 in the United States, according to a new study published this week in the open-access journal PLOS ONE by George Cunningham and Lisa Wigfall of Texas A&M University, USA.

There is a growing body of evidence showing that racial and ethnic minorities are more affected by severe illness, and more likely to be hospitalized, from COVID-19 compared to white people. This disparity can be only partially explained by the disproportionate rates of underlying medical conditions, such as asthma, diabetes, and obesity, seen among Black/African American people.

In the new study, researchers collected data from a variety of publicly available sources for 817 counties (26% of all counties) in the United States. The data included information on cumulative COVID-19 deaths and cases from January 22 to August 31, 2020 as well as explicit and implicit racial attitudes--collected through Harvard University's Project Implicit. The researchers also obtained a wide spectrum of demographic and economic information for these communities so that they could control for these factors.

The percent of Black residents in a county was positively associated with COVID-19 cases (r=0.47) and deaths (r=0.32) in the county. Moreover, both explicit and implicit racial attitudes were positively associated with COVID-19 (r=0.72). The results demonstrated that the relationship between race and COVID-19 cases was strongest when either explicit or implicit racial attitudes were highest. There was also an effect of implicit racial attitudes on COVID-19 deaths among the Black population. The authors conclude that implicit racial attitudes in a community can help explain racial disparities in COVID-19 rates.

The authors add: "These findings show that, even beyond the impact of county demographics, implicit and explicit racial attitudes impact the rates of COVID-19. Racial attitudes captured at the county level represent the bias of crowds and reflect deeper biases that are embedded into systems within society. These biases can negatively affect county residents, including their health and wellbeing."

Inspired by muscle-powered acceleration in biological jumpers, scientists have designed an elastic-driven strong contractile hydrogel that works by storing and releasing elastic potential energy in a polymer network.

By reversibly forming and breaking chemical bonds in hydrogel networks, the hydrogel designed by Prof. ZHOU Feng's group from the Lanzhou Institute of Chemical Physics (LICP) of the Chinese Academy of Sciences and Prof. HE Ximin's group from the University of California, Los Angeles (UCLA) can store and release elastic energy, thus performing swift and powerful motions.

The newly designed hydrogel can generate high contractile force rapidly at ultrahigh work density, outperforming current hydrogels and even matching biological muscles.

Environment-sensitive hydrogels, also called "stimuli-responsive" or "smart" hydrogels, are attractive because they have a large degree of deformability. However, they suffer mechanical weakness or slow response when used as "artificial muscles" in actuators, robots and medical devices.

In contrast, the results of this study show that the mechanism of the current hydrogel solves the longstanding dilemma of "high speed + large force simultaneously." It is thus able to break the material energy density limit while maintaining high water content.

In addition, it enables controllable multistable deformation in a fully reversible and programmable manner, which for the first time realizes "reversible elasticity-plasticity switchability," as well as anisotropic or isotropic deformation. This universal modular material design can be broadly applied to create unlimited powerful active polymers.

"With the high-power density and programmability via this customizable modular design, these hydrogels demonstrate potential for broad applications in artificial muscles, contractile wound dressing, and high-power actuators," said Prof. ZHOU.

Results have been published online in Science Advances in an article entitled "Bioinspired high-power-density strong contractile hydrogel by programmable elastic recoil."

Researchers at Washington University School of Medicine in St. Louis have identified a molecule that protects mice from brain infections caused by Venezuelan equine encephalitis virus (VEEV), a mosquito-borne virus notorious for causing fast-spreading, deadly outbreaks in Mexico, Central America and northern South America. As the climate changes, the virus is likely to expand its range and threaten more countries in the Americas, including the U.S.

Public health officials have struggled to contain such outbreaks in the absence of effective drugs and vaccines. As a potential drug, the molecule -- described in a paper published Nov. 18 in the journal Nature -- could serve as a much needed tool to control the deadly virus.

"This virus can infect many species of wild mammals, and every few years it jumps from animals to humans via mosquitoes and causes thousands of infections and many deaths," said senior author Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine and a professor of molecular microbiology, and of pathology and immunology. "There's concern that with global warming and population growth, we'll get more outbreaks."

Once injected under the skin by mosquitoes, the virus homes in on neurons. People start experiencing symptoms such as headache, muscle pain, fatigue, vomiting, nausea, diarrhea, sore throat and fever within a week. In the most serious cases, the virus gets past the blood-brain barrier, causing encephalitis -- brain inflammation that can be fatal in up to a quarter of patients.

To find the potential drug, Diamond and colleagues -- including first authors Hongming Ma, PhD, an instructor in medicine, and Arthur S. Kim, PhD, a postdoctoral researcher -- began by searching for the protein "handle" on the surface of animal cells that the virus attaches to and uses to get inside cells. A drug that stops the virus from grabbing that handle, the scientists reasoned, could stymie infection and prevent disease.

But first they had to make a form of the virus they could work easily with. During the Cold War, the U.S. and the Soviet Union attempted to weaponize the virus, and it is still classified as a select agent, meaning only certain high-security labs are allowed to work with it. So instead, the researchers and their colleagues took Sindbis virus, a related virus that causes mild fever and rash, and swapped out some of its genes for some from VEEV. The resulting hybrid virus, called Sindbis-VEEV, infects cells like authentic VEEV but is unable to cause severe disease.

Using a genetic engineering technique known as genome-wide CRISPR screening, the researchers deleted genes in mouse neuronal cells until they found one -- called Ldlrad3 -- whose absence kept Sindbis-VEEV from infecting cells. The missing gene codes for a little-studied surface protein.

Further experiments verified the importance of Ldlrad3. Adding the gene back to neuronal cells restored the virus's ability to infect cells. The human LDLRAD3 gene is almost identical to its mouse equivalent, and knocking out the human gene also reduced infection in multiple cell lines. When the researchers added Ldlrad3 to a different cell type that is normally resistant to infection, the virus was able to infect the cell. Co-author William Klimstra, PhD, at the University of Pittsburgh, separately replicated the findings using authentic, highly virulent VEEV.

Ldlrad3 doesn't appear to be the only way the virus gets inside cells, since a small amount of virus is able to infect cells lacking the protein. But it is clearly the primary way in. Since Ldlrad3 is naturally on our cells and can't be removed, the scientists decided to create a decoy handle using a piece of the Ldlrad3 protein. Any virus particles that mistakenly latch onto the decoy handle would fail to infect cells and instead would get destroyed by the immune system.

To test their decoy in a living animal, the researchers injected mice with authentic virulent VEEV in two different ways: under the skin to mimic a mosquito bite, or directly into the brain. They gave the mice the decoy handle or a placebo molecule for comparison, either six hours before or 24 hours after infection. In all experiments, all of the mice that received the placebo died within a week. In most cases, all of the mice that received the decoy molecule survived, although in the most stringent experiment -- in which the virus was injected into the brain -- two of the 10 mice died despite receiving the decoy.

"In an outbreak situation, you may be able to use a drug like this as a countermeasure to prevent transmission and further spread," Diamond said.

A major advantage to an antiviral drug based on a human -- rather than a viral -- protein is that it is unlikely the virus could evolve resistance to it. Any mutation that enables the virus to avoid the decoy probably would make it unable to attach to cells, too, the researchers said.

Skoltech researchers and their colleagues from Russia, the US, and Sweden have described an unusual RNA polymerase that helps a poorly studied crAss-like bacteriophage transcribe its genes. They "caught" this enzyme by a tiny -- less than 3% of its size -- portion of the amino acid sequence that was similar to other RNA polymerases. The paper detailing the discovery has been published in the journal Nature.

CrAss-like phages get their name from one recently discovered virus, crAssphage. The name means "cross-assembly phage", in honor of the method used for genome assembly. This virus was found when researchers were analyzing publicly available human fecal metagenomes (that is, indiscriminate genetic sequences of everything that was found in a sample). Surprisingly, crAssphage found only in 2014, turned out to be the most abundant phage in the human gut. Later scientists, including the team of this paper's coauthor, Eugene Koonin, found more of these viruses, none of which had been studied in a lab before.

"Since crAss-like phages are the most abundant viruses in the human gut, understanding how they infect their host cells will allow controlling the composition of the human microbiome, which in turn is important for human health and disease. We also became interested in studying crAss-like phages because it was predicted that these viruses use highly unusual RNA polymerases (enzymes that make RNA from a DNA template) to transcribe their genes," Maria Sokolova, assistant professor at the Skoltech Center of Life Sciences, says.

Sokolova and her colleagues took phi14:2, a crAss-like phage that preys on Cellulophaga baltica, a bacterium commonly found on beaches. This virus turned out to be a convenient model for lab research, and the team studied its putative RNA polymerase gp66, a rather large protein with a previously unknown function. By looking at its amino acid sequence, the researchers spotted a snippet that looked like a part of cellular multisubunit RNA polymerases. Researches first purified gp66 and demonstrated its RNA polymerase activity in vitro.

"The crAss-like phage RNA polymerase turned out to be inactive in a standard test for RNA polymerase activity, which works well for all other RNA polymerases. We knew that viral enzymes may have unusual features, and thus we continued to seek the activity in other tests -- and found it. We were very happy to find it eventually because before that moment, we were concerned whether the bioinformatics prediction was valid, since the similarity of gp66 to known enzymes was too low," Sokolova notes.

In vitro experiments showed that rifampicin, an antibiotic, shut down C. baltica's own RNA polymerase but did not affect gp66. And when the researchers looked at what phi14:2 genes ended up transcribed in an infected cell dosed with rifampicin, they found a lot of so-called early genes, ones that encode the machinery a virus needs to overtake the host cell at the early stages of an infection, but the fewer middle and late genes, active at later stages. This implies that phi14:2 is a Bring Your Own RNA Polymerase virus, relying on gp66 to work at the start of an infection before it can utilize the polymerase of the host cell.

The scientists managed to solve the crystal structure of the gp66 protein and discovered that most of its structural elements have no known counterparts, and their functions are unknown. However, the core of gp66 turned out to be very similar to an RNA polymerase that in higher organisms is involved in a process of RNA interference, which allows to silence the function of some genes. According to Konstantin Severinov, a coauthor of the paper, "this is a startling result that suggests that enzymes of RNA interference, a process that was thought to be specific for cells of higher organisms (eukaryotes), have originated, at least partially, from a phage, in other words, were "borrowed" from a bacterial virus, an ancestor of current crAss-like phages, sometime early in evolution. This discovery shows that the evolution of higher cells was a complex process that involved multiple acquisitions of bacterial and even phage enzymes by ancestral cells. Another textbook example of this is the acquisition of whole bacteria by an ancestral eukaryotic cell, that now became mitochondria."

Researchers also found that, in the crystal structure of gp66, its catalytic site is in an inactive conformation that has never been seen in any RNA polymerase. They suggested that prior to the packaging into the phage particle, gp66 is in a self-inhibited form.

"To this end, this enzyme possesses properties common to proteins that form virus shells (e.g. hemagglutinin, flavi- and alphavirus glycoproteins). These proteins undergo assembly-dependent maturation that is required for activity. CrAss-like phage RNA polymerase undergoes such maturation upon incorporation into the virus particle or upon translocation through the tail channel," notes Petr Leiman of the Sealy Center for Structural Biology and Molecular Biophysics at the University of Texas Medical Branch, a co-author of the paper.

Maria Sokolova says that this is the first study that addresses the function of crAss-like viruses at the molecular and atomic level of detail. "Our work paves a way to the regulation of crAss-like phage infection which in its turn may inform new approaches for manipulating the composition of the human gut microbiome," she adds.

BOSTON (Nov. 18, 2020, 2:00 p.m. ET)--Researchers at Tufts University School of Medicine have discovered a molecular mechanism that causes a "traffic jam" of enzymes traveling up and down neuronal axons, leading to the accumulation of amyloid beta - a key feature and cause of Alzheimer's disease. The enzyme, BACE1, gets backed up, causing the axons to clog and swell because of the increased production of the toxic amyloid protein.

The study, published today in Science Translational Medicine, reports that a human mutation more prevalent in African American patients with late onset Alzheimer's triggers a traffic jam of BACE1 in axons. Identifying this mutation is a key step in understanding the underlying molecular mechanisms of the disease and provides a possible strategy for early diagnosis and targeted treatments.

"In individuals with Alzheimer's disease, the onset of symptoms happens about 20 years after the first changes start to develop in the brain, making therapeutic intervention extremely difficult," said Giuseppina Tesco, professor of neuroscience at Tufts University School of Medicine and senior and corresponding author on the study. "So, we wanted to identify the mechanisms leading to the swelling of axons during the pre-symptomatic phase of Alzheimer's disease, which could in turn provide a way to detect the disease early and possibly treat it more effectively."

Tufts researchers previously identified a gene, Gga3, which helps regulate the traffic of BACE1, or beta-site APP-cleaving enzyme 1, along the axon. In the new study, the researchers found that when the Gga3 gene is mutated or missing in mice, their brains present the same distinctive traffic jam of BACE1 in swelling axons that are found in the postmortem brains of early stage patients with Alzheimer's disease. The researchers found that by disrupting the Gga3 gene, the traffic of BACE1 and other proteins along the axon is slowed or shut down. They also noted that a mutated or missing Gga3 leads to a severe accumulation of BACE1 in the axon, which results in axonal swellings both in cultured neurons and in a mouse model of Alzheimer's disease prior to amyloid deposition.

In multiple clinical trials, BACE inhibitors administered to patients with advanced disease who already had significant accumulation of amyloid beta protein and neuronal damage have been unsuccessful. The researchers asked whether application of the inhibitors at the earliest stages of disease might be more effective. They found that the inhibitors prevented swelling of axons in mice and even improved the two-way flow of BACE1. Their results suggest that earlier application of BACE1 inhibitors could be more effective at slowing the accumulation of amyloid beta protein.

Using datasets from the National Institutes of Health's National Institute of Mental Health and the Alzheimer's Disease Neuroimaging Initiative, the researchers discovered that mutations in Gga3 were more common among African Americans diagnosed with Alzheimer's disease than other populations. Although the sample size was small, the researchers believe this finding may provide a case for identifying early stage interventions and treatments for this group of patients.

"Our study provides a possible molecular explanation for the prevalence of axonopathy during the early stages of Alzheimer's disease, before the formation of amyloid plaques," said Tesco. "The mutation allowed us to determine that axonal alterations can be caused by accumulation of BACE1. Now an area of focus could be inhibiting BACE1 to prevent early axonal damage and perhaps this could also slow the development of amyloid plaques leading to disease."

The researchers note that the presence of neurofilament light chain (NfL) in blood plasma is a marker for axonal damage, and could be used to identify the best timing for use of BACE inhibitors to prevent or slow the progression of Alzheimer's disease during its early pre-symptomatic stages.

A high concentration of salt or sugar in the environment will dehydrate microorganisms and stop them from growing. To counter this, bacteria can increase their internal solute concentration. Scientists from the University of Groningen elucidated the structure of a transport protein OpuA, that imports glycine betaine to counter osmotic stress. The protein belongs to the well-known family of ABC transporters, but it has a unique structure and working mechanism. The results were published in Science Advances on 18 November.

Food preservatives are designed to make life difficult for microorganisms. Salt and sugar are well-known preservatives; they increase the electrolyte concentration to above that inside bacteria. The result is that water flows out of these bacteria until concentrations are approximately equal, leaving behind shrivelled cells that can no longer grow.

ABC transporter

'However, some bacteria have evolved defences against such preservatives,' says Bert Poolman, Professor of Biochemistry at the University of Groningen. Around 20 years ago, a food producer asked him to find ways to defeat those defences. It led to the discovery of OpuA, a transport protein that is triggered by dehydration and responds by importing a substance called glycine betaine. 'This increases the osmolyte concentration inside the cells without compromising the structure of proteins. The result is that the cells absorb more water and start to grow again,' explains Poolman.

OpuA belongs to a well-known class of proteins called ABC (ATP-binding cassette) transporters. This protein family is one of the largest known in biology. Humans have around 50 of these transporters, some plants have hundreds of them and bacteria have a number somewhere in between. OpuA is special because it can import glycine betaine in huge amounts, leading to a very high internal osmolyte concentration. That is why Poolman was intrigued to find out how it worked. 'I have worked on this problem, on and off, ever since.'

Breakthrough

The problem was elucidating the structure of the protein. Until a few years ago, the standard method was to grow crystals from proteins and investigate those using X-ray diffraction. It is very difficult to grow crystals from proteins that are embedded in the cell membrane and for OpuA, it turned out to be impossible. Based on the amino acid sequence and the structure of other ABC transporters, the scientist compiled a model of the structure, but this could not explain the way that OpuA functioned.

The breakthrough came with the introduction of cryo-electron microscopy, together with the work of PhD student Hendrik Sikkema and the collaboration with the research group of University of Groningen assistant professor of Cryo-EM Cristina Paulino. A large number of single proteins were scanned in an electron microscope at a very low temperature, after which all the images were combined to provide a direct view of the structure. The results showed not one but five different structures. 'The protein is a dynamic structure, as it changes conformation to suit the function, but the different parts also vibrate on their own,' explains Poolman. 'This means that one protein exists in many variant structures. And you cannot grow crystals amidst such diversity.'

Beautiful

The first conclusion from the cryo-EM studies was that most of what they thought they knew about the structure of OpuA was incorrect. 'For example, parts that we believed to be on the inside of the cell membrane sat on the outside.' The real structure was beautiful, according to Poolman. The second conclusion was that OpuA is in part regulated by cyclic di-AMP, a second messenger molecule that was only recently discovered. 'The protein primarily responds to ionic strength, which varies as a function of osmotic stress, but it uses cyclic di-AMP as a second brake to completely stop importing glycine betaine and prevent the cell from exploding under non-stress conditions.'

The ionic strength sensor of the OpuA protein carries a positive charge while the membrane has a negative charge. When water is drawn from the cells, the concentration of salts, such as potassium chloride, increases. 'This disrupts the interaction of the ionic strength sensor with the membrane, which activates the pumping mechanism.' Once the glycine betaine concentration is high enough to make the cell swell to its normal proportions, the protein-membrane interaction is normalized. 'However, the pump does not shut down completely, so it continues to import some glycine betaine. This will increase the pressure inside the cell and eventually cause it to pop.' That is why cyclic di-AMP is used to fully shut down the pump.

The paper describes the different structures and provides functional data on the transport protein. This combination gives a good insight into the workings of OpuA: a satisfying result for Poolman. 'It is the accumulation of twenty years of research, which has produced seven or eight PhD theses.' The results show how the resistance of bacteria to preservatives, such as salt or sugar, could be overcome. 'Furthermore, we are part of a consortium that is trying to construct a synthetic cell. OpuA is an important part of the design; it is meant to regulate the cell's internal pressure.'

For many years, investigators have been trying to pin down the tantalizing connection between vitamin D and cancer. Epidemiological studies have found that people who live near the equator, where exposure to sunlight produces more vitamin D, have lower incidence and death rates from certain cancers. In cancer cells in the lab and in mouse models, vitamin D has also been found to slow cancer progression. But the results of randomized clinical trials in humans haven't yielded a clear answer. The Vitamin D and Omega-3 Trial (VITAL), which concluded in 2018, found that vitamin D did not reduce overall incidence of cancer, but hinted at a decreased risk of cancer deaths. Now, in a secondary analysis of VITAL, a team led by investigators at Brigham and Women's Hospital has narrowed in on the connection between taking vitamin D supplements and risk of metastatic or fatal cancer. In a paper published in JAMA Network Open, the team reports that vitamin D was associated with an overall 17 percent risk reduction for advanced cancer. When the team looked at only participants with a normal body mass index (BMI), they found a 38 percent risk reduction, suggesting that body mass may influence the relationship between vitamin D and decreased risk of advanced cancer.

"These findings suggest that vitamin D may reduce the risk of developing advanced cancers," said corresponding author Paulette Chandler, MD, MPH, a primary care physician and epidemiologist in the Brigham's Division of Preventive Medicine. "Vitamin D is a supplement that's readily available, cheap and has been used and studied for decades. Our findings, especially the strong risk reduction seen in individuals with normal weight, provide new information about the relationship between vitamin D and advanced cancer."

The VITAL study was a rigorous, placebo-controlled study that took place over a span of more than five years. The VITAL study population included men who were 50 or older and women 55 or older who did not have cancer when the trial began. The study population was racially and ethnically diverse. VITAL was designed to test the independent effects of vitamin D and omega-3 supplements as well as to test for synergy between the two. Participants were divided into four groups: vitamin D (2000 IU/day) plus omega-3s; vitamin D plus placebo; omega-3s plus placebo; and placebos for both. Primary endpoints were major adverse cardiovascular events and incidence of cancer. VITAL did not find a statistical difference in overall cancer rates, but researchers did observe a reduction in cancer-related deaths.

In their secondary analysis, Chandler and colleagues followed up on the possible reduction in cancer deaths with an evaluation of advanced (metastatic or fatal) cancer among participants who did or did not take vitamin D supplements during the trial. They also examined the possible modifying effect of BMI.

Among the more than 25,000 participants in the VITAL study, 1,617 were diagnosed with invasive cancer over the next five years. This included a broad mix of cancers (breast, prostate, colorectal, lung and more). Of the almost 13,000 participants who received vitamin D, 226 were diagnosed with advanced cancer compared to 274 who received the placebo. Of the 7,843 participants with a normal body mass index (BMI less than 25) taking vitamin D, only 58 were diagnosed with advanced cancer compared with 96 taking the placebo.

While the team's findings on BMI could be due to chance, there is previous evidence that body mass may affect vitamin D action. Obesity and associated inflammation may decrease the effectiveness of vitamin D, possibly by reducing vitamin D receptor sensitivity or altering vitamin D signaling. In addition, randomized trials of vitamin D and type 2 diabetes have found greater benefits of vitamin D in people with normal weights and no benefit among those with obesity.

Vitamin D deficiency is common among cancer patients, with one study reporting rates of vitamin D deficiency as high as 72 percent among cancer patients. There is also evidence that higher amounts of body fat are associated with increased risk for several cancers.

"Our findings, along with results from previous studies, support the ongoing evaluation of vitamin D supplementation for preventing metastatic cancer -- a connection that is biologically plausible," said Chandler. "Additional studies focusing on cancer patients and investigating the role of BMI are warranted."

Human females have two X chromosomes, and males only one. This chromosome imbalance also extends to other branches of the animal kingdom. Interestingly, the humble fruit fly has devised a different way to "equalize" these differences. Whereas human and mouse females shut down one of their X chromosomes, in fruit flies it instead the male doing the work. An epigenetic factor known as the MSL complex binds to the single male X chromosome and uses its histone acetylation function to hyperactivate the X to try to reach RNA production levels equivalent to those achieved by the two X chromosomes carried by females. If this process fails, male flies die.

"One aspect that had always baffled researchers is how the MSL complex knows which of the 8 chromosomes carried by every fly cell is the X," explains Asifa Akhtar, Director at the MPI of Immunobiology and Epigenetics in Freiburg. This question motivated researchers in her team to design a novel and elaborate strategy to dissect how the MSL complex could identify the X. Instead of studying the fly MSL complex in its "native habitat", the researchers decided to transplant the complex into a totally foreign environment - a mouse cell.

Researchers give mouse cells all the components necessary to recreate a mini male fly X chromosome

The researchers decided to go back to basics and reverse engineer the mechanism of recognizing the X chromosome one component at a time. They started by expressing a single protein from the fly MSL complex, MSL2, in mice. At this point, they could not see anything happening. Based on previous work in flies, they hypothesized that another MSL complex component, the roX1 and roX2 long noncoding RNAs, might also be required. They, therefore, decided to throw one of these RNAs into the pot. After providing mouse cells with fly MSL2 and roX2 RNA, the researchers now observed distinct nuclear foci marked by roX2.

Furthermore, the condensation of MSL2 and roX2 at these foci appeared to upregulate the expression of genes. The discrete nature and activation potential of these foci are strongly reminiscent of the X-chromosomal territories marked by the MSL complex in the "native" situation of the male fly. Fascinatingly, these experiments indicate that supplementing mouse cells with fly MSL2 and roX2 appears to be sufficient to recreate a mini fly X chromosome in mouse cells. This innovative approach thereby illuminated the minimal molecular components required for the first steps in recognition and activation of the fly X chromosome by the MSL complex.

Specific recognition of the X chromosome is driven by the formation of a gel-like state

Now that the team had figured out the exact recipe for forming a mini fly X chromosome, they combined the two ingredients, roX RNA and MSL2, together in a test tube. They noted that these components took on a unique state. "When we mixed MSL2 and the roX RNA, we noticed something interesting. Both components - although they were liquid in isolation - started to form spherical particles and transitioned into a different phase that looked like a gel," says Claudia Keller-Valsecchi, co-first author of the study. Interestingly, both roX1 and roX2 RNAs are encoded by genes located on the X chromosome.

The team speculated about a model where roX RNAs synthesized from the X chromosome induce the nearby "trapping" of MSL2 via their interaction and propensity to assemble into a gel-like state. "Levels of roX RNAs are predictive of how well the MSL complex is able to find the X chromosome. The more roX is synthesized from the X, the better the complex can distinguish the X from autosomes," added co-first author of the work Felicia Basilicata. On the other hand, other chromosomes do not produce the roX RNAs, and therefore have little chance of efficiently trapping the MSL complex in their vicinities.

With their results, the team uncovered a new mechanism utilized by male flies to distinguish and mark the single X chromosome based on the assembly of a two-component roX-MSL2 gel. Male flies that fail to assemble this gel will die. "It is possible that the gel state also helps attract and trap other important components for dosage compensation, such as the transcription machinery required for increased RNA production," Asifa Akhtar explains future research questions.

In 2004, scientists with NASA's Galaxy Evolution Explorer spotted an object unlike any they'd seen in our Milky Way Galaxy: a large, faint blob of gas that seemed to have a star at its center. In the ultraviolet wavelengths used by the satellite, the blob appeared blue -- though it doesn't actually emit light visible to the human eye -- and careful observations identified two thick rings within it, so the team nicknamed it the Blue Ring Nebula. Over the next 16 years, they studied it with multiple Earth- and space-based telescopes, but the more they learned about it, the more mysterious it seemed.

A team of scientists including Princeton University’s Guðmundur Stefánsson, the Henry Norris Russell Postdoctoral Fellow in astrophysical sciences, combined ground-based observations with detailed theoretical modeling to investigate the object’s properties. The paper describing their findings appears in the Nov. 19 issue of Nature.

"We were in the middle of observing one night, with a new spectrograph that we had recently built, when we received a message from our colleagues about a peculiar object composed of a nebulous gas expanding rapidly away from a central star," said Stefánsson. "How did it form? What are the properties of the central star? We were immediately excited to help solve the mystery!"

Most stars in the Milky Way are in binary systems -- pairs of stars orbiting each other. If they are close enough together, such systems can meet their demise in a stellar merging event: As stars evolve, they expand, and if they are close enough together, one of the stars can engulf its orbiting companion, causing the companion to spiral inward until the two stars collide. As the companion loses its orbital energy, it can eject material away at high speeds.

Could that explain the mysterious Blue Ring Nebula?

To test this hypothesis, the team observed the nebula with two different spectrographs on large telescopes on the ground: the HIRES optical spectrograph on the 10-meter Keck Telescope on top of Maunakea in Hawaii, and the near-infrared Habitable-zone Planet Finder on the 10-meter Hobby-Eberly Telescope at McDonald Observatory in Texas, a new near-infrared spectrograph that Stefánsson helped design, build and commission to detect planets around nearby stars.

"The spectroscopic observations were key in allowing us to understand the object further, from which we see that the central star is inflated, and we see signatures of accretion likely from a surrounding disk of debris," Stefánsson said. 

"Indeed, the spectroscopic data coupled with theoretical modeling shows that the Blue Ring Nebula is consistent with the picture of a merging binary star system, suggesting that the inwards spiraling companion was likely a low-mass star," said Keri Hoadley, a postdoctoral fellow at Caltech and lead author of the paper.

Although the relics of a few such binary merging events have been observed before, all such objects have been enshrouded by opaque dust and clouds, obstructing the view of the properties of the central stellar remnant. The Blue Ring Nebula is the only object allowing an unobstructed view of the central stellar remnant, offering a clear window into its properties and yielding clues about the merging process.

"The Blue Ring Nebula is rare," said Hoadley. "As such, it is really exciting that we were able to find it, and we are excited about the possibility of finding more such objects in the future. If so, that would allow us to gain further insights into the remnants of stellar mergers and the processes that govern them."

"A blue ring nebula from a stellar merger several thousand years old," by Keri Hoadley, Christopher Martin, Brian Metzger, Mark Seibert, Andrew McWilliam, Ken Shen, James Neill, Guðmundur Stefánsson, Andrew Monson and Bradley Schaefer, appears in the Nov. 19 issue of Nature (DOI: 10.1038/s41586-020-2893-5). This research was supported by Princeton University, Caltech, the Pennsylvania State University, the Eberly College of Science and the Pennsylvania Space Grant Consortium. The authors wish to recognize and acknowledge the very significant cultural role and reverence that the summit of Maunakea has always had within the indigenous Hawaiian community: "We are most fortunate to have the opportunity to conduct observations from this mountain."

Lesbian, gay and bisexual -- or LGB -- people are more vulnerable to one of the fastest-growing health concerns in the country: dementia, according to new research from Michigan State University.

"Our study speaks to the unaddressed questions about whether members the LGB community are more likely to develop cognitive impairment at older ages and, if so, what factors contribute to their poorer cognitive health, " said Ning Hsieh, an assistant professor of sociology at MSU and lead author of the study published in the journal, The Gerontologist.

"We knew that stress and depression are risk factors for many chronic health problems, including cognitive impairment, in later life. LGB people experience more stressful events and have higher rates of depression compared to their heterosexual counterparts," she said.

Analyzing the elevated cognitive health risks among older members of the LGB community, the study was the first to use a national sample and screening tool to gauge cognitive health disparities between LGB and heterosexual older adults.

Hsieh and MSU colleagues Hui Liu, professor of sociology, and Wen-Hua Lai, a Ph.D. student of sociology -- compared cognitive skills of 3,500 LGB and heterosexual adults using a screening tool and questionnaire that tests for six domains. Those areas included temporal orientation; language; visuospatial skills; executive function; attention, concentration and working memory; and short-term memory.

The researchers found that on average, older LGB adults were more likely to fall into categories for mild cognitive impairment or early dementia compared to heterosexual older adults. The team also tested for specific health and social factors -- such as physical conditions, mental health conditions, living a healthy lifestyle and social connections -- and the only factor related to cognitive differences for sexual minorities was depression.

"Our findings suggest that depression may be one of the important underlying factors leading to cognitive disadvantages for LGB people," Hsieh said. "They may experience higher rates of depression than their heterosexual peers for many reasons, including not being accepted by parts of society, feeling ashamed of their sexual orientation or trying to hide their romantic relationships and being treated unfairly in school or at work."

The researchers felt surprised that other factors -- such as fewer social connections, drinking or smoking -- didn't have as great of an effect on LGB people's cognitive function later in life. But, they also recognized the need for additional research to understand how the stressors sexual minorities experience earlier in life can lead to cognitive impairments as they age. Additionally, Hsieh said, they hope that the study's findings shed light on the need for greater inclusivity for sexual minorities, as it can have an influence on their mental and cognitive well-being.

"Social inequality makes less privileged groups, including sexual minorities, more prone to develop cognitive impairment," Hsieh said. "Making the society more just and more accepting of diverse sexuality may help prevent dementia and reduce related health care burden on society."

That biofuels can contribute to a cleaner global energy mix is widely accepted, but the net benefits of bioenergy in terms of mitigating greenhouse gases (GHG) are moot. Some argue, for example, that biofuels are not sustainable because the conversion of non-agricultural land to grow energy crops could lead to a significant initial decrease in carbon storage, creating what is known as a "biofuel carbon debt".

A study by a cross-border group of researchers published in Proceedings of the National Academy of Sciences (PNAS) could help refute this argument.

The study showed that the GHG mitigation potential of switchgrass cultivation for cellulosic ethanol production in the US was comparable on a per-hectare basis to that of reforestation and several times greater than that of grassland restoration. Switchgrass (Panicum virgatum) is a widely grown North American native grass proposed as biomass for the biobased economy.

More advanced technology and integration of carbon capture and storage (CCS) could further increase the per-hectare mitigation potential of bioenergy systems by a factor of six, according to the study, which was supported by São Paulo Research Foundation - FAPESP via a project led by John J. Sheehan.

Sheehan is affiliated with the University of Minnesota in the US and is currently a visiting fellow at the University of Campinas's School of Agricultural Engineering (FEAGRI-UNICAMP) in the state of São Paulo, Brazil, under the aegis of the (São Paulo Excellence Chair (SPEC).

Co-lead author of the study, Lee R. Lynd, a professor at Dartmouth College in Hanover, New Hampshire (USA), began a project in February at UNICAMP's Center for Molecular Biology and Genetic Engineering (CBMEG), with funding from FAPESP under the SPEC program.

"The study highlights in detail the factors and strategies that are important to the implementation of biofuel production in a way that helps stabilize the climate," Lynd told.

Questions answered

According to the authors, critics of bioenergy question whether feedstock crops can be sustainably sourced without causing self-defeating reductions in ecosystem carbon storage.

Besides the "carbon debt" resulting from the conversion of non-agricultural land into energy crop plantations, the use of existing productive agricultural land with low carbon stocks can also be counterproductive if food production is displaced and GHG emissions increase elsewhere.

This effect, known as indirect land-use change, can be minimized or avoided by growing biofuel feedstocks on low-yield or abandoned cropland, or land spared from continued agricultural use through future agricultural intensification or changes in diet.

Reforestation offers an alternative use of such land for GHG mitigation. However, it is often claimed that assessment of bioenergy production in these areas should consider their "opportunity cost", i.e. the carbon sequestration foregone when land is used for feedstock production instead of reforestation.

"The main studies published to date suggest zero net land-use change, but indirect land-use change continues to be invoked as a key criticism of biofuels," Lynd said.

These arguments were initially directed at first-generation biofuels - obtained from sugar, starch or vegetable oil in food crops grown on farmland - but questions focusing on carbon debt, indirect land-use change, and opportunity cost have since been raised regarding the production of cellulosic biomass for use in advanced biofuel production or electricity generation.

Based on these and other arguments, recent studies suggest that using land to produce bioenergy feedstocks has a less-than-ideal impact in terms of mitigating the climate crisis, and recommend research and policy be refocused toward land-based biological carbon management.

However, those studies are often based on secondary estimates of bioenergy system performance and mitigation opportunity costs. Furthermore, they generally exclude consideration of CCS or future technology improvements, the authors note.

"Each of the critiques we discuss in the study has some legitimacy in terms of pointing to factors that can cancel out the beneficial impact of biofuels on the climate, but they shouldn't be taken as proof that biofuels can't or don't have any beneficial impact at all," Lynd said.

To refute the arguments presented by critics of biofuel sustainability, the researchers used ecosystem simulation combined with models of cellulosic biofuel production and CCS, estimating the potential of biofuel from energy grass to replace fossil fuels and sequester carbon directly compared with other land-based mitigation schemes, such as reforestation and grassland restoration.

They calibrated the ecosystem model to perform temporally explicit simulations of atmosphere-biosphere carbon exchange under different land-use choices at three case study sites in the US.

The analysis showed that where farmers transitioned from switchgrass to cellulosic ethanol the per-hectare mitigation potential was comparable to that of reforestation and several times greater than that of grassland restoration.

It also showed that the mitigation potential of plausible future improvements in energy crop yields and biorefining technology, together with CCS, could be four times greater than that of reforestation and 15 times greater than that of grassland restoration.

"In addition, we found that natural land cover and the technological maturity of the supply chain make a significant difference when it comes to estimating the relative benefits of GHG mitigation by biofuels and restoration of natural vegetation," Lynd said.

Switchgrass cultivation can be particularly useful in parts of the US where the natural plant cover consists of grass rather than trees, according to the study.

In future, the researchers plan to use the same modeling approach to discuss these issues for the US on a nationwide scale. "An important direction in which the study points is an analysis of a broader range of sites, energy crops, and conversion processes, including those designed to include biofuel production in a manner consistent with the circular economy," Lynd said.

The methodology could also be used to analyze the production of biofuel from sugarcane in Brazil, he added.

PROVIDENCE, R.I. [Brown University] -- Cigarette smoking causes more than 480,000 deaths each year in the United States, according to federal government data -- and some smokers find it nearly impossible to quit. Many of these smokers use regular, or combustible, cigarettes.

Physicians and scientists have for many years explored the health benefits and drawbacks of nicotine-based alternatives to cigarettes, and new research offers significant evidence that "pod" e-cigarettes are less damaging to health than traditional cigarettes.

"Nicotine is one of the most addictive substances on earth, both in animal models as well as to humans," said Dr. Jasjit S. Ahluwalia, a professor of behavioral and social sciences and medicine at Brown University. "So how can we help these people who can't quit smoking combustible cigarettes? They need other options, and e-cigarettes may be one such option. Our research shows that in the short-term, e-cigarettes are considerably safer than combustible cigarettes."

Ahluwalia is senior author of a new JAMA Network Open study, published on Wednesday, Nov. 18, on the world's first randomized clinical trial of fourth-generation pod e-cigarettes.

The trial included 186 African American and Latinx smokers, as racial and ethnic minority groups tend to experience higher rates of tobacco-related morbidity and mortality even when they smoke at the same rates as other groups. Two-thirds of the participants were provided e-cigarettes for six weeks, while the remaining participants were instructed to continue smoking combustible cigarettes as usual.

By the end of the study, participants who switched to e-cigarettes exhibited significantly lower levels of the potent pulmonary carcinogen NNAL compared to those who continued to smoke combustible cigarettes exclusively. The e-cigarette users also had significantly reduced carbon monoxide (CO) levels and reported fewer respiratory symptoms. These benefits -- reduced NNAL, reduced CO and respiratory symptom improvements -- were especially pronounced among participants who switched completely to e-cigarettes.

The researchers also measured participants' levels of cotinine, a breakdown product of nicotine, and determined that there were no significant differences between groups, an indication that e-cigarettes provided adequate replacement of nicotine.

"Anyone under 21 should not take up cigarettes, e-cigarettes or any nicotine product -- hands down, the best thing to do is to never start -- but if people use tobacco products, they should quit," Ahluwalia cautioned. "But if they cannot quit smoking combustible cigarettes, they should consider using novel nicotine products to either quit smoking altogether or to reduce their harm by transitioning fully to these products."

Going forward, work needs to be done to better understand the non-cancer risks associated with e-cigarettes, such as respiratory and cardiovascular disease. The researchers also plan to carry out year-long studies to further explore the harm-reduction potential of e-cigarettes.

"Most smokers who switched exclusively from combustible cigarettes to e-cigarettes during the study maintained this behavior at six months, but we need longer-term follow-up," said Kim Pulvers, a professor of psychology at California State University San Marcos who was the principal investigator of the study. "We also need continued study of dual users to determine whether they maintain harm reduction over time."

Ahluwalia said that because many individuals who use both e-cigarettes and combustible cigarettes will switch back to exclusively combustible cigarettes over time, there is a critical need for interventions that support those who try to switch to e-cigarettes but fail. He also emphasized the importance of alternatives to quitting outright, given the challenge that quitting poses for so many cigarette smokers.

"It's possible that nicotine e-cigarettes and other harm-reduction products will be game-changers for our field," Ahluwalia added. "I hope this study stimulates more people to do this research and to have an open mind about this. I also hope it inspires them to let science inform policy rather than emotion."

Scams and fraud exact a heavy toll on older adults, with estimates of yearly losses ranging from $3 billion to $36 billion in the U.S. alone.

Lasting damage can occur. Because many seniors live off of resources accumulated across their working lifetimes, such as retirement savings, victims may be unable to recoup what's taken from them. Considering the additional impact on family members and caretakers, financial exploitation in this growing demographic is a significant public health concern.

Two recent studies led by USC provide new insight into the little-studied question of which factors put older adults at risk for financial exploitation.

One, published in Frontiers in Aging Neuroscience, is only the second brain imaging study to center on financial exploitation in older adults. The scientists found that those who report being financially exploited show differences in the activity of brain regions tied to decision-making and social judgments compared to those without a history of financial exploitation.

The other, which appears in Gerontology and Geriatric Medicine, is the first study to focus specifically on the relationship between financial exploitation and frailty in older adults. The findings showed that those who reported being financially exploited are frailer physically -- with particular deficits in vision and hearing -- compared to their peers.

The papers come out of the Finance, Cognition, and Health in Elder Study at USC, which enrolls participants who are 50 years and older with no history of dementia. It is led by Duke Han, senior author on both publications and professor of family medicine, neurology, psychology and gerontology in the Keck School of Medicine of USC.

"Ultimately, we want older adults to experience all the best in life, to hold onto their wealth and to live life well into old age," said Han, who is also director of neuropsychology in the USC Department of Family Medicine. "It crushes us to see them financially exploited. However, not all older adults are at risk for financial exploitation, and we want to try to predict which people might be more at risk."

Brain differences correlate with falling victim to fraud

The Frontiers in Aging Neuroscience study used magnetic resonance imaging to examine neurological co-activity. Han and his colleagues compared 16 older adults who reported experiencing financial exploitation with 16 who did not, studying their brains while in a resting state. The scientists delved into functional connectivity -- in other words, which brain regions activate at the same time.

Functional connectivity can serve as a sort of canary in the coal mine, signaling changes that come with age-related diseases, including Alzheimer's, before alterations to structures in the brain are detectable.

The research team focused in on three areas of the brain tied to making decisions and evaluating social situations. The study demonstrated subtle but significant differences between connectivity in these regions among those who reported financial exploitation compared to the control group:

The medial frontal cortex, which is a seat of executive functioning in the brain

The hippocampus, which is tied to remembering specific events and envisioning future scenarios

The insula, which is associated with evaluating the trustworthiness of people or situations

"It makes sense that the ability to project a future self through the hippocampus and the ability to assess trustworthiness through the insula might be implicated in financial exploitation risk," Han said.

However, he emphasizes that the current study indicates correlation rather than causation. To zero in on cause and effect, a larger study that follows participants over time is necessary. Han is currently seeking federal grant funding to pursue such a study.

Problems seeing and hearing may put seniors at risk

For the Gerontology and Geriatric Medicine research, Han and his team employed a widely used questionnaire for identifying frailty to compare 24 seniors who reported financial exploitation with 13 peers who hadn't experienced it. The assessment asked about physical issues including fatigue, difficulty walking and poor hearing or vision; psychological issues such as anxiety and problems remembering; and social issues such as isolation and loneliness.

The participants who had experienced financial exploitation reported being significantly frailer than the control group, with that difference showing up on the physical scale but not the measures of psychological or social frailty. Specifically, they reported significantly poorer hearing and marginally poorer sight.

Although this study dealt in correlations, Han notes that it's unlikely that financial exploitation leads to hearing or vision loss.

"The methods that scammers and fraudsters use put a stress on being able to see and hear things accurately," he said. "It stands to reason that this would actually be a mechanism for how certain older adults might be more vulnerable to financial exploitation."

The researchers hope to build on these findings to conduct a larger study that investigates whether measures such as the use of hearing aids and properly calibrated corrective lenses provide protection against financial exploitation.

"This research really does point to the importance of regular visits with a doctor and keeping up on your hearing and vision," Han said. "If we can confirm the clinical relevance and then get the word out that the more you address sensory functioning, the more it potentially protects you against financial exploitation, then all the better."

Professor of Biomedical Engineering Adam Feinberg and his team have created the first full-size 3D bioprinted human heart model using their Freeform Reversible Embedding of Suspended Hydrogels (FRESH) technique. Showcased in a recent video by American Chemical Society and created from MRI data using a specially built 3D printer, the model mimics the elasticity of cardiac tissue and sutures realistically. This milestone represents the culmination of two years of research, holding both immediate promise for surgeons and clinicians, as well as long term implications for the future of bioengineered organ research.

The FRESH technique of 3D bioprinting was invented in Feinberg's lab to fill an unfilled demand for 3D printed soft polymers, which lack the rigidity to stand unsupported as in a normal print. FRESH 3D printing uses a needle to inject bioink into a bath of soft hydrogel, which supports the object as it prints. Once finished, a simple application of heat causes the hydrogel to melt away, leaving only the 3D bioprinted object.

While Feinberg's lab has proven both the versatility and the fidelity of the FRESH technique, the major obstacle to achieving this milestone was printing a human heart at full scale. This necessitated the building of a new 3D printer custom made to hold a gel support bath large enough to print at the desired size, as well as minor software changes to maintain the speed and fidelity of the print.

Major hospitals often have facilities for 3D printing models of a patient's body to help surgeons educate patients and plan for the actual procedure, however these tissues and organs can only be modeled in hard plastic or rubber. Feinberg's team's heart is made from a soft natural polymer called alginate, giving it properties similar to real cardiac tissue. For surgeons, this enables the creation of models that can cut, suture, and be manipulated in ways similar to a real heart. Feinberg's immediate goal is to begin working with surgeons and clinicians to fine tune their technique and ensure it's ready for the hospital setting.

"We can now build a model that not only allows for visual planning, but allows for physical practice," says Feinberg. "The surgeon can manipulate it and have it actually respond like real tissue, so that when they get into the operating site they've got an additional layer of realistic practice in that setting."

This paper represents another important marker on the long path to bioengineering a functional human organ. Soft, biocompatible scaffolds like that created by Feinberg's group may one day provide the structure onto which cells adhere and form an organ system, placing biomedicine one step closer to the ability to repair or replace full human organs.

"While major hurdles still exist in bioprinting a full-sized functional human heart, we are proud to help establish its foundational groundwork using the FRESH platform while showing immediate applications for realistic surgical simulation," added Eman Mirdamadi, lead author on the publication.

Published in ACS Biomaterials Science and Engineering, the paper was co-authored by Feinberg's students Joshua W. Tashman, Daniel J. Shiwarski, Rachelle N. Palchesko, and former student Eman Mirdamadi.

BOSTON - One of the first spectroscopic imaging-based studies of neurological injury in COVID-19 patients has been reported by researchers at Massachusetts General Hospital (MGH) in the American Journal of Neuroradiology. Looking at six patients using a specialized magnetic resonance (MR) technique, they found that COVID-19 patients with neurological symptoms show some of the same metabolic disturbances in the brain as other patients who have suffered oxygen deprivation (hypoxia) from other causes, but there are also notable differences.

While it is primarily a respiratory disease, COVID-19 infection affects other organs, including the brain. It is thought that the disease's primary effect on the brain is through hypoxia, but few studies have documented the specific types of damage that distinguish COVID-19-related brain injury. Several thousand patients with COVID-19 have been seen at the MGH since the outbreak began early this year, and this study included findings from three of those patients.

The severity of neurological symptoms varies, ranging from one of the most well-known -- a temporary loss of smell -- to more severe symptoms such as dizziness, confusion, seizures and stroke. "We were interested in characterizing the biological underpinnings of some of these symptoms," says Eva-Maria Ratai, PhD, an investigator in the Department of Radiology and senior author of the study. "Moving forward, we are also interested in understanding long-term lingering effects of COVID-19, including headaches, fatigue and cognitive impairment. So-called 'brain fog' and other impairments that have been found to persist long after the acute phase," adds Ratai, also an associate professor of Radiology at Harvard Medical School.

The researchers used 3 Tesla Magnetic Resonance Spectroscopy (MRS), a specialized type of scanning that is sometimes called a virtual biopsy. MRS can identify neurochemical abnormalities even when structural imaging findings are normal. COVID-19 patients' brains showed N-acetyl-aspartate (NAA) reduction, choline elevation and myo-inositol elevation, similar to what is seen with these metabolites in other patients with white matter abnormalities (leukoencephalopathy) after hypoxia without COVID. One of the patients with COVID-19 who showed the most severe white matter damage (necrosis and cavitation) had particularly pronounced lactate elevation on MRS, which is another sign of brain damage from oxygen deprivation.

Two of the three COVID-19 patients were intubated in the intensive care unit at the time of imaging, which was conducted as part of their care. One had COVID-19-associated necrotizing leukoencephalopathy. Another had experienced a recent cardiac arrest and showed subtle white matter changes on structural MR. The third had no clear encephalopathy or recent cardiac arrest. The non-COVID control cases included one patient with white matter damage due to hypoxia from other causes (post-hypoxic leukoencephalopathy), one with sepsis-related white matter damage, and a normal, age-matched, healthy volunteer.

"A key question is whether it is just the decrease in oxygen to the brain that is causing these white matter changes or whether the virus is itself attacking the white matter," says MGH neuroradiologist Otto Rapalino, MD, who shares first authorship with Harvard-MGH postdoctoral research fellow Akila Weerasekera, PhD.

Compared to conventional structural MR imaging, "MRS can better characterize pathological processes, such as neuronal injury, inflammation, demyelination and hypoxia," adds Weerasekera. "Based on these findings, we believe it could be used as a disease and therapy monitoring tool."