Culture

LEXINGTON, Ky. (May 26, 2021) - Using novel imaging methods for studying brain metabolism, University of Kentucky researchers have identified the reservoir for a necessary sugar in the brain. Glycogen serves as a storage depot for the sugar glucose. The laboratories of Ramon Sun, Ph.D., assistant professor of neuroscience, Markey Cancer Center at the University of Kentucky College of Medicine, and Matthew Gentry, Ph.D., professor of molecular and cellular biochemistry and director of the Lafora Epilepsy Cure Initiative at the University of Kentucky College of Medicine discovered that glucose - the sugar used for cellular energy production - was not the only sugar contained in glycogen in the brain. Brain glycogen also contained another sugar called glucosamine. The full study was recently published in Cell Metabolism.

Some forms of glucosamine, such as glucosamine sulfate and glucosamine hydrochloride, are common supplements used to improve joint movement. However, within cells, glucosamine is an essential sugar needed for the complex carbohydrate chains that are attached to proteins in a process called glycosylation. These sugar chains decorate proteins and the sugar decorations are critical for the appropriate function of myriad proteins.

Discovering that glucosamine is a major component of brain glycogen provides key insight into neurological diseases caused by aberrant glycogen-like cellular aggregates called polyglucosan bodies (PGBs). Lafora disease is a rare, inherited childhood dementia caused by PGBs and this study demonstrates that the Lafora disease PGBs sequester glucosamine, leading to numerous cellular perturbations. PGBs also accumulate in the brain as people age and in people with other forms of dementia. Thus, the discovery that glycogen is also a storage cache for glucosamine has broad implications for understanding neurological changes associated with aging.

Using biochemical approaches, the researchers determined the sugar composition of glycogen in the muscle, liver, and brain of mice. Unlike muscle glycogen, which had only 1% glucosamine, and liver glycogen, which had less than 1% glucosamine, brain glycogen contained 25% glucosamine. "The discovery that brain glycogen is comprised of 25% glucosamine was stunning," stated Sun.

Upon making this surprising discovery, they then identified the enzymes responsible for incorporating glucosamine into glycogen and for releasing glucosamine from glycogen. Again, the discovery was unexpected as these enzymes are the same ones used to incorporate glucose into and release glucose from glycogen.

To understand the implications of their findings for Lafora disease and neurological problems arising from PGBs, the researchers used their newly developed technique called matrix-assisted laser desorption/ionization traveling-wave ion-mobility high-resolution mass spectrometry (MALDI TW IMS) to measure and visualize the amount of glycogen in different regions of the brain. They also used this technique to quantify changes in the specific patterns of the sugar decorations on proteins in multiple regions of the brain.

The team applied MALDI TW IMS to analyze the brains of healthy mice and of two different mouse models of glycogen storage diseases: a model of Lafora disease and a model of glucose storage disease (GSD) type III. Sun commented, "This new technique allows us to quantify the amount of these sugars with high accuracy while also maintaining the spatial distribution within the brain regarding where the sugars are located. It is crucial that the brain has the correct sugars in the right location within the brain."

These studies revealed that without the ability to properly regulate brain glycogen metabolism, not only do PGBs form, which perturbs cell metabolism, but the sugar decoration of proteins is also altered. Excitingly, they could restore protein sugar decoration by injecting an antibody-enzyme fusion (VAL-0417) into the brains of Lafora disease mice to degrade the PGBs. Their findings show a direct connection between abnormal glycogen storage and defective protein function in the brain. Their findings have implications for many other GSDs and congenital disorders of glycosylation, which cause severe neurological symptoms, including epilepsy and dementia.

"Multiple neurological diseases have blockades in these metabolic pathways. I'm sure these pathways are going to be important in other neuro-centric diseases as well. Brain glycogen is comprised of glucose and glucosamine and brain metabolism has to balance both in order to stay healthy," explained Gentry.

The Gentry and Sun laboratories collaborated with several others from UK College of Medicine including Drs. Craig Vander Kooi, professor of molecular and cellular biochemistry, Charles Waechter, professor of molecular and cellular biochemistry, Lance Johnson, assistant professor of physiology, Christine Brainson, assistant professor of toxicology and cancer biology. They also worked with researchers from Indiana University School of Medicine including Drs. Anna A. DePaoli-Roach, professor of biochemistry and molecular biology, Peter J. Roach, professor of biochemistry and molecular biology, Thomas D. Hurley, professor of biochemistry and molecular biology. Richard Taylor, professor of chemistry and biochemistry, from the University of Notre Dame, and Richard Drake, professor of cell and molecular pharmacology and experimental therapeutics from the Medical University of South Carolina, also contributed to this work.

"This type of transdisciplinary collaborative research takes place at UK because of strong leadership from College of Medicine Dean Robert DiPaola, Dr. Mark Evers, Vice President for Research Lisa Cassis, Ph.D. and others," stated Sun.

Berkeley -- The lifestyle of the horned passalus beetle, commonly known as the bessbug or betsy beetle, might seem downright disgusting to the average human: Not only does this shiny black beetle eat its own poop, known as frass, but it uses its feces to line the walls of its living space and to help build protective chambers around its developing young.

Gross as it may seem, a new study suggests that this beetle's frass habits are actually part of a clever strategy for protecting the insect's health -- and could help inform human medicine, too.

Researchers at the University of California, Berkeley, have discovered that the frass of the horned passalus beetle is teeming with antibiotic and antifungal chemicals similar to the ones that humans use to ward off bacterial and fungal infections. These compounds are produced by a host of beneficial bacteria called actinomycetes that live in the beetle's frass and that appear to be passed from beetle to beetle, and from colony to colony, via the process of coprophagy -- the technical term for eating poop.

Understanding the symbiotic relationship between bessbug beetles, actinomycetes and their antimicrobial compounds could help speed the search for new antibiotic drugs, and help doctors create better strategies for preventing the rise of antibiotic-resistant infections, the researchers said.

"Most of the antibiotics and antifungals that humans take are actually made by microbes, and we're really interested in how microbes are using these molecules in the environment," said study senior author Matthew Traxler, an assistant professor of plant and microbial biology at UC Berkeley. "When scientists discover a new antibiotic and bring it into the clinic, it often only takes a few years before the pathogen population starts to develop antibiotic resistance. But these microbes have been using the same molecules for millions of years, and that tells us that the way the microbes are using them is different from how we use them."

With the discovery, bessbug beetles join a handful of other insects, including leaf-cutter ants, southern pine beetles and beewolves, or bee-killer wasps, that benefit from symbiotic relationships with actinomycete bacteria. Leaf-cutter ants and beewolves have even evolved special structures in their bodies -- in their thoraxes and antennae, respectively -- to carry these microbes.

No special structures for harboring bacteria have been identified on the bessbug beetle, but that may be the beetle's advantage. While the ants and wasps are each known to associate with only one specific species of actinomycete bacteria, the researchers identified more than 30 actinomycete species associated with bessbug beetle "galleries," the hollowed-out tunnels inside dead logs where they live. The greater diversity of actinomycetes in bessbug beetle frass appears to contribute to a greater diversity of protective antibiotics and antifungals in their galleries.

"We collected samples from galleries all over the southern and eastern U.S., and for almost all of them, we were able to detect some form of antibiotic. This was really surprising, because these compounds are usually very difficult to detect in the environment," said study lead author Rita de Cassia Pessotti, who completed the research as a postdoctoral researcher at UC Berkeley. "We think that we are seeing larger diversity of molecules because there's a more diverse set of bacteria, as well."

Having a diversity of antibiotic and antifungal compounds all working in tandem may be one of the reasons why these chemicals are able to stay ahead in the evolutionary battle against pathogens, the researchers said.

"When humans take antibiotics to treat diseases, we usually just take a single molecule, and that means that whatever pathogen we are fighting only has to become resistant to one compound," Traxler said. "But in these galleries, there are a variety of these molecules for a pathogen to overcome. On top of that, sometimes the molecules can work synergistically, meaning they become more potent when added together against a specific pathogen. This can make it very difficult for a pathogen to outsmart them, even over ecological and evolutionary time spans."

A cross-country trek in search of beetles

Before Traxler and Pessotti began their study, the complex digestive system of the bessbug beetle had already caught the attention of Javier Ceja-Navarro and Eoin Brodie, research scientists at Lawrence Berkeley National Laboratory. Ceja-Navarro and Brodie were intrigued by the beetle's ability to convert tough, difficult-to-digest plant polymers, like lignin and cellulose, into nutrient-rich frass, a digestive process that could inspire new ways to convert woody by-products into useful biofuels. To study this process, Ceja-Navarro and Brodie maintained an active bessbug beetle gallery in their lab.

Traxler and Pessotti were searching for a way to study actinomycete bacteria in the wild, and learned that actinomycetes had been found living in the guts of tropical beetles closely related to the bessbug beetle. They decided to ask Ceja-Navarro and Brodie, friends and colleagues of theirs, if they could test their beetles for the bacteria.

"I collected samples from all over the beetles and their gallery -- I even washed a beetle's mouth with some buffers to see what was in there -- and no matter where the sample came from, I always found the same species of Streptomyces," a type of actinomycete bacteria, Pessotti said. "We were pretty surprised that it was so common."

This strain of Streptomyces bacteria wasn't unique to Ceja-Navarro's beetles. Pessotti discovered that she could mail order bessbug beetles online -- "If you want to have a pet beetle, you can," she said -- and found that these beetles, originally from Georgia and North Carolina, also carried the same species of Streptomyces.

However, it took a trip to Oklahoma to finally convince Traxler and Pessotti that bessbug beetles could provide the ideal system for studying actinomycetes. After Traxler spotted Facebook photos of a beetle gallery located in his cousin's backyard in Oklahoma, Pessotti flew to the state to collect her first set of samples from beetles in the wild.

Sure enough, the Oklahoma beetles harbored now-familiar species of Streptomyces.

"That finding is what gave us the courage to go out and do this giant sampling trip, which in itself was a tremendous feat," Traxler said. "Rita is from Brazil, but at this point, I think she's probably visited more states in the U.S. than I have."

Pessotti spent a month crisscrossing the Southeastern U.S., trekking through forests to locate beetle galleries and gather samples to take back to the lab in Berkeley. In the end, she collected samples from a total of 22 galleries spread across 11 states.

In addition to managing logistical challenges -- like rerouting part of her trip at the last minute to avoid Hurricane Florence -- Pessotti also had to teach herself how to spot beetle galleries amidst the detritus of the forest floor. In the beginning, she made ample use of the cell phone app iNaturalist, in which naturalists and lay people alike can upload photos and descriptions of plants and animals, geotagged to their location.

The key to finding bessbug beetle galleries, she soon learned, is to keep an eye out for their sawdust-like frass.

"You don't need to go super far into the forest to find a beetle gallery -- I've actually found some next to trails," Pessotti said. "Usually, you can see tiny holes on the surface of a log with frass coming out of them, and frass all over the log and on the ground. And if you see evidence of frass by a log, that is a good hint there probably is a beetle in there."

The protective power of poop

Back in the lab, Pessotti isolated more than 300 strains of actinomycete bacteria from her gallery samples and detected antifungal and antibiotic compounds in all but one.

With the help of former UC Berkeley undergraduate student Jewel Reaso, Pessotti also devised a special experiment to confirm that actinomycete bacteria actually do help protect the beetles from infection. In the assay, Pessotti mixed sterilized beetle frass with a strain of Streptomyces isolated from the beetle galleries inside a test tube. She then exposed the frass to a fungal beetle pathogen she had collected during her field trip and observed what happened over the course of a week.

"I was super-lucky that doing the trip: I spotted a dead beetle laying on the top of a log -- it was like the beetle was waiting for me. And this dead beetle had a white/green material coming out of its body that I thought could be some sort of fungus," Pessotti said. "So, I brought this dead beetle to the lab, isolated the microbe that was responsible for the green/white material, and it turned out to be a strain of Metarhizium anisopliae, a fungal pathogen that can kill insects."

Pessotti's experiments showed that sterilized frass that had been mixed with Streptomyces bacteria was better able to resist the growth of the Metarhizium anisopliae pathogen than sterilized frass on its own, even in warm, damp conditions similar to that of a decaying log. Her findings confirmed that the antibiotic and antifungal molecules produced by actinomycete bacteria can, in fact, help ward off beetle pathogens found in the wild.

The results shine a new light on bessbug beetles' close relationship with their own poop: When the beetles use frass to line their galleries and to construct protective chambers around their developing larvae, they are actually defending themselves against fungal and bacterial pathogens that might otherwise thrive in the decaying logs where they build their homes. And when the beetles eat their own frass, and feed it to their young, they are ensuring that the bacteria stick around to benefit a new generation.

Traxler plans to continue studying the microbial communities associated with beetle galleries, both to better understand how the relationship between beetles and actinomycetes has evolved, and to potentially discover new antibiotics that can be used in human medicine.

"If you're out there in the world, and you see one of these bessbug beetles or their galleries, I hope you recognize that it's full of antibiotics and antifungals," Traxler said. "And, the beetles are using theses in a way that's pretty similar to how we would use them ourselves -- which is pretty cool."

In a new study, scientists at The Hong Kong University of Science and Technology (HKUST) have revealed that most T cell epitopes known to be targeted upon natural infection are seemingly unaffected by current SARS-CoV-2 variants.

In their latest research, the team compiled and analysed data from 18 immunological studies of T cell responses involving over 850 recovered COVID-19 patients from across four continents who are well-distributed in age, gender, disease severity and blood collection time. They demonstrated that T cells in these patients targeted fragments (epitopes) of almost all of the virus' proteins, including the spike protein that is a main target of many existing vaccines. As an important finding, based on analysis of over 850,000 SARS-CoV-2 genetic sequences from around the world, most of these epitopes appeared to be unaffected by the current variants of concern.

"We focused specifically on recovered COVID-19 patients as their immune responses are representative of effective responses against the virus," said Prof. Ahmed Abdul QUADEER, Research Assistant Professor from the Department of Electronic and Computer Engineering, who is the first author of the research.

"We believe this is good news, particularly for vaccines. In contrast to antibody responses which have been shown to be affected by variants, our analysis would suggest T cell responses may be relatively robust, assuming that vaccine responses mimic those of natural infection," said Prof. Matthew MCKAY from the Departments of Electronic and Computer Engineering and Chemical and Biological Engineering, who co-led the research.

While revealing more than 700 T cell epitopes, the team's analysis identified 20 specific epitopes--which they refer to as immunoprevalent--that induced T cell responses in multiple independent cohorts and in a large fraction of tested patients. Of these, five appeared highly immunoprevalent, registering T cell responses in at least four separate immunological studies.

"The identified immunoprevalent epitopes appear to represent parts of the virus that are commonly targeted by T cells in recovered COVID-19 patients," added Prof. McKay. "It is possible, but subject to further experimental investigation, that targeting these epitopes may play a role in contributing to favourable disease outcomes."

The compiled data has been integrated into a web platform, which the team plans to keep updated as more immunological studies of SARS-CoV-2 T cell epitopes are reported.

"The platform is an online resource for the global research community and complements ongoing research on understanding T cell responses against SARS-CoV-2. It serves to guide studies related to COVID-19 vaccines and diagnostics," added Prof. Quadeer.

Rough night of sleep? Relying on caffeine to get you through the day isn't always the answer, says a new study from Michigan State University.

Researchers from MSU's Sleep and Learning Lab, led by psychology associate professor Kimberly Fenn, assessed how effective caffeine was in counteracting the negative effects of sleep deprivation on cognition. As it turns out, caffeine can only get you so far.

The study -- published in the most recent edition of Journal of Experimental Psychology: Learning, Memory, & Cognition -- assessed the impact of caffeine after a night of sleep deprivation. More than 275 participants were asked to complete a simple attention task as well as a more challenging "placekeeping" task that required completion of tasks in a specific order without skipping or repeating steps.

Fenn's study is the first to investigate the effect of caffeine on placekeeping after a period of sleep deprivation.

"We found that sleep deprivation impaired performance on both types of tasks and that having caffeine helped people successfully achieve the easier task. However, it had little effect on performance on the placekeeping task for most participants," Fenn said.

She added: "Caffeine may improve the ability to stay awake and attend to a task, but it doesn't do much to prevent the sort of procedural errors that can cause things like medical mistakes and car accidents."

Insufficient sleep is pervasive in the United States, a problem that has intensified during the pandemic, Fenn said. Consistently lacking adequate sleep not only affects cognition and alters mood, but can eventually take a toll on immunity.

"Caffeine increases energy, reduces sleepiness and can even improve mood, but it absolutely does not replace a full night of sleep, Fenn said. "Although people may feel as if they can combat sleep deprivation with caffeine, their performance on higher-level tasks will likely still be impaired. This is one of the reasons why sleep deprivation can be so dangerous."

Fenn said that the study has the potential to inform both theory and practice.

"If we had found that caffeine significantly reduced procedural errors under conditions of sleep deprivation, this would have broad implications for individuals who must perform high stakes procedures with insufficient sleep, like surgeons, pilots and police officers," Fenn said. "Instead, our findings underscore the importance of prioritizing sleep."

Reverse transcription-polymerase chain reaction (RT-PCR) has been the gold standard for diagnosis during the COVID-19 pandemic. However, the PCR portion of the test requires bulky, expensive machines and takes about an hour to complete, making it difficult to quickly diagnose someone at a testing site. Now, researchers reporting in ACS Nano have developed a plasmofluidic chip that can perform PCR in only about 8 minutes, which could speed diagnosis during current and future pandemics.

Rapid diagnosis of COVID-19 and other highly contagious viral diseases is important for timely medical care, quarantining and contact tracing. Currently, RT-PCR -- which uses enzymes to reverse transcribe tiny amounts of viral RNA to DNA, and then amplify the DNA so that it can be detected by a fluorescent probe -- is the most sensitive and reliable diagnostic method. But because the PCR portion of the test requires 30-40 cycles of heating and cooling in special machines, it takes about an hour to perform, and samples must typically be sent away to a lab, meaning that a patient usually has to wait a day or two to receive their diagnosis. Ki-Hun Jeong and colleagues wanted to develop a plasmofluidic PCR chip that could quickly heat and cool miniscule volumes of liquids, allowing accurate point-of-care diagnosis in a fraction of the time.

The researchers devised a postage stamp-sized polydimethylsiloxane chip with a microchamber array for the PCR reactions. When a drop of sample is added to the chip, a vacuum pulls the liquid into the microchambers, which are positioned above glass nanopillars with gold nanoislands. Any microbubbles, which could interfere with the PCR reaction, diffuse out through an air-permeable wall. When a white LED is turned on beneath the chip, the gold nanoislands on the nanopillars quickly convert light to heat, and then rapidly cool when the light is switched off. The researchers tested the device on a piece of DNA containing a SARS-CoV-2 gene, accomplishing 40 heating and cooling cycles and fluorescence detection in only 5 minutes, with an additional 3 minutes for sample loading. The amplification efficiency was 91%, whereas a comparable conventional PCR process has an efficiency of 98%. With the reverse transcriptase step added prior to sample loading, the entire testing time with the new method could take 10-13 minutes, as opposed to about an hour for typical RT-PCR testing. The new device could provide many opportunities for rapid point-of-care diagnostics during a pandemic, the researchers say.

Adults with schizophrenia have an elevated risk of dying from suicide. Yet there's only limited understanding of when and why people with schizophrenia die of suicide --in part because research studies have looked at relatively small groups of patients.

Now a new study from Columbia that looked at a large population of adults diagnosed with schizophrenia has found the youngest group (18-34) had the highest suicide risk and those aged 65 and older had the lowest. By comparison, in the general U.S. population, younger adults have less risk and older age groups have greater risk.

The Columbia study, published online May 26 in the journal JAMA Psychiatry, (LINK TK) also showed that people with schizophrenia, overall, have a 4.5-fold increased risk of dying from suicide, the 10th leading cause of death in the United States.

"When a person with schizophrenia is becoming suicidal, an attempt can happen with little warning," said Mark Olfson, Elizabeth K. Dollard professor of psychiatry at Columbia and co-author of the study. "Often, suicidal behavior in schizophrenia is driven by psychotic processes. This aspect can make it difficult to anticipate and prevent."

The study, which provides a significant amount of data on age and suicide risk, could help suicide prevention efforts for people with schizophrenia. "Knowing more about which age groups and what personal characteristics are linked to higher risk could increase attention and support for the most vulnerable patients," Olfson said.

To conduct their research, the study's authors examined the records of 668,836 people diagnosed with schizophrenia aged 18 years and over.. All were covered by Medicare.

Much is still unknown about why suicide risk in people with schizophrenia declines across the life span, although some risk factors appear to be linked to age.

Young people with schizophrenia are more likely to experience suicidal ideation, suicide attempts, substance use disorders, inpatient mental health admissions, and emergency department visits. These characteristics might help to explain why younger adults with schizophrenia are at greater risk of dying of suicide, Olfson said.

Such factors occur less frequently as individuals age, leading to older males with schizophrenia having a suicide rate similar to older people in the general U.S. population. There also may be a "healthy survivor" bias for the decline in suicide risk with advancing age. This may occur because older people with schizophrenia have survived earlier health risks and those individuals who are most susceptible to suicide may have died at an earlier age.

Other serious psychiatric disorders have high risks of suicide as well. According to Olfson, schizophrenia falls in the middle of diagnoses linked to increased suicide, ranking below mood disorders including major depression and bipolar disorder.

The study's findings underscore the high risk of suicide among young adults with schizophrenia and the need for vigilance by therapists and physicians, especially for that group.

Suicide prevention for all with schizophrenia may be improved, the authors note, by expanding access to the antipsychotic clozapine, treating co-occurring substance use disorders, making early psychosis detection programs more widely available, providing suicide risk screening, and using cognitive behavioral therapy to counter hallucinations and reduce suicidal symptoms.

When enjoying a chocolate bar, most people don't think about how the molecules within it are organized. But different arrangements of the fats in chocolate can influence its taste and texture. Now, researchers reporting in ACS' Crystal Growth & Design have found that the side of a chocolate bar facing the mold has a more orderly crystalline structure than the side facing air, knowledge that might help chocolatiers produce tastier confections, the researchers say.

Chocolate is a mixture of cocoa solids, cocoa butter, sugar and other ingredients that interact with each other in complex ways. In particular, the fat molecules, or triacylglycerols, can remain liquid or crystallize into several phases with different melting points. The temperature at which a particular chocolate melts affects its taste and texture, with a melting point near body temperature being ideal. When chocolatiers make bars, they pour tempered chocolate into a mold and let it cool at temperatures that favor the most desirable crystal form. Fumitoshi Kaneko and colleagues wondered how the mold, which conveys heat more efficiently than air and also provides a physical barrier, affects fat crystallization.

To find out, the researchers analyzed the structure of fat components at three different positions in a chocolate bar using polarized Fourier transform infrared spectroscopy and attenuated total reflection sampling. They found that the mold-side face of the bar contained highly ordered, regularly packed fatty acid chains, whereas the air-side face had disordered, irregularly packed chains, and the midpoint showed intermediate characteristics. The mold side also contained more of the most desirable fat crystal form than the other locations. These results could be explained by the large difference in thermal conductivity between the mold's material and air, which causes the chocolate to preferentially cool and crystallize on the mold-side face. The mold also provides a barrier that controls the direction of crystallization, yielding a more orderly arrangement. These results suggest that a chocolate bar's structure is much less uniform than previously thought, and that improving the crystallization process might lead to better-tasting, melt-in-your-mouth and better-looking chocolate bars, the researchers say.

WHAT:

The immune system's attempt to eliminate Salmonella bacteria from the gastrointestinal (GI) tract instead facilitates colonization of the intestinal tract and fecal shedding, according to National Institutes of Health scientists. The study, published in Cell Host & Microbe, was conducted by National Institute of Allergy and Infectious Diseases (NIAID) scientists at Rocky Mountain Laboratories in Hamilton, Montana.

Salmonella Typhimurium bacteria (hereafter Salmonella) live in the gut and often cause gastroenteritis in people. The Centers for Disease Control and Prevention estimates Salmonella bacteria cause about 1.35 million infections, 26,500 hospitalizations and 420 deaths in the United States every year. Contaminated food is the source for most of these illnesses. Most people who get ill from Salmonella have diarrhea, fever and stomach cramps but recover without specific treatment. Antibiotics typically are used only to treat people who have severe illness or who are at risk for it.

Salmonella bacteria also can infect a wide variety of animals, including cattle, pigs and chickens. Although clinical disease usually resolves within a few days, the bacteria can persist in the GI tract for much longer. Fecal shedding of the bacteria facilitates transmission to new hosts, especially by so-called "super shedders" that release high numbers of bacteria in their feces.

NIAID scientists are studying how Salmonella bacteria establish and maintain a foothold in the GI tract of mammals. One of the first lines of defense in the GI tract is the physical barrier provided by a single layer of intestinal epithelial cells. These specialized cells absorb nutrients and are a critical barrier that prevent pathogens from spreading to deeper tissues. When bacteria invade these cells, the cells are ejected into the gut lumen--the hollow portion of the intestines. However, in previous studies, NIAID scientists had observed that some Salmonella replicate rapidly in the cytosol--the fluid portion--of intestinal epithelial cells. That prompted them to ask: does ejecting the infected cell amplify rather than eliminate the bacteria?

To address this question, the scientists genetically engineered Salmonella bacteria that self-destruct when exposed to the cytosol of epithelial cells but grow normally in other environments, including the lumen of the intestine. Then they infected laboratory mice with the self-destructing Salmonella bacteria and found that replication in the cytosol of mouse intestinal epithelial cells is important for colonization of the GI tract and fuels fecal shedding. The scientists hypothesize that, by hijacking the epithelial cell response, Salmonella amplify their ability to invade neighboring cells and seed the intestine for fecal shedding.

The researchers say this is an example of how the pressure exerted by the host immune response can drive the evolution of a pathogen, and vice versa. The new insights offer new avenues for developing novel interventions to reduce the burden of this important pathogen.

MOSCOW, Idaho -- May 26, 2021 -- University of Idaho researchers partnered with other scientists from the United States and Australia to study the evolution of Tasmanian devils in response to a unique transmissible cancer.

The team found that historic and ongoing evolution are widespread across the devils' genome, but there is little overlap of genes between those two timescales. These findings, published in Proceedings of the Royal Society B, suggest that if transmissible cancers occurred historically in devils, they imposed natural selection on different sets of genes.

Tasmanian devils suffer from a transmissible cancer called devil facial tumor disease (DFTD). Unlike typical cancers, tumor cells from transmissible cancers are directly transferred from one individual to another like an infectious disease. DTFD is most commonly transmitted from host to host as devils bite each other during mating season. The tumors become malignant and can kill their hosts within six months.

DFTD was first discovered in 1996, and the recent discovery of a second transmissible cancer in Tasmanian devils in 2016 suggests that they may be prone to this unique type of disease. The threat of these two cancers has prompted conservation efforts.

"For the conservation of Tasmanian devils, our work adds to the growing list of genes that we have observed to be evolving in response to DFTD," said Paul Hohenlohe, U of I Department of Biological Sciences associate professor, Institute for Bioinformatics and Evolutionary Studies (IBEST) principal investigator and senior author on the paper. "We can monitor genetic diversity of these genes in wild populations to understand whether and how these populations can adapt and survive in the face of DFTD."

Using genomic sequencing and data analysis, the research team tested for natural selection in Tasmanian devils in response to DFTD to find out whether they are evolving as a result of the disease. They also looked for evidence of natural selection in the devils' evolutionary history to test whether the genes that are evolving under DFTD show evidence of historical natural selection.

Finding little overlap in what genes are involved at historical and modern timescales, the team determined that if transmissible cancers have occurred historically in devils, they caused natural selection on different sets of genes. Their results and analysis of historical selection suggest that DFTD is a newly emerging selective force that distinctly shapes today's wild devils.

This information can be used to inform conservation efforts by identifying targets for genetic monitoring and guiding maintenance of adaptive potential in Tasmanian devil populations.

"Our work suggests that maintaining genetic diversity across a wide set of functionally important genes is critical to make sure Tasmanian devils are able to adapt to transmissible cancers and other threats to their survival," Hohenlohe said.

SAN FRANCISCO, CA--May 26, 2021--In January 2021, reports of a new coronavirus variant that had emerged in California raised many concerns. Preliminary data suggested that it is more transmissible than the unmutated strains of SARS-CoV-2 (the virus that causes COVID-19) from which it evolved.

Now, a multifaceted collaboration between researchers at UC San Francisco, Gladstone Institutes, and other organizations across California provides a comprehensive portrait of the variant--including its interaction with the immune system and its potential to spread.

"Our findings suggest that California's homegrown variant can infect people who already had COVID-19, but that it is vulnerable to vaccines," says Charles Chiu, MD, PhD, director of the UCSF-Abbott Viral Diagnostics and Discovery Center, and one of the co-senior authors of the study published in the journal Cell. He helped discover and report the new variant as a "variant of concern" earlier this year to the Centers for Disease Control and other health agencies.

"The take-home message is that everyone should get vaccinated, even if you've been infected before," says Chiu. The new findings appear in the journal Cell.

Tracking the Rise of the New Variant

Like all viruses, SARS-CoV-2 mutates over time, and new variants with distinct combinations of mutations arise continuously. Not all variants are cause for concern, but some variants appear to spread faster than others. This is thought to be due to mutations that enhance the function of the virus's spike protein, which it uses to latch onto and infect human cells.

California's variant actually comes in two different forms, dubbed B.1.427 and B.1.429, and each have a unique combination of mutations. But they are paired as a single variant because they share a few distinct mutations that affect the spike protein.

"When this variant emerged in California, it was important to determine how much of a risk it might pose," says Melanie Ott, MD, PhD, director of the Gladstone Institute of Virology and a co-senior author on the study. "But we needed to sequence--or analyze--its genome and conduct follow-up experiments to really understand it."

The researchers sequenced samples from 2,172 COVID-19 swab tests conducted in dozens of California counties. Analysis of the sequences suggested that the variant emerged in May 2020 and subsequently gave rise to the two current forms.

Between September 1, 2020, and January 29, 2021, the prevalence of the variant in the sequenced samples rose from 0 percent to more than 50 percent of cases. Its transmissibility appeared to be as much as 24 percent higher than unmutated viral strains, and people infected with the new variant had two times more virus present in their swab samples than people infected with unmutated strains.

"In a matter of months, this variant went from being practically undetectable to being the predominant variant circulating in California," says Raul Andino, PhD, a professor of microbiology and immunology at UCSF, and a co-senior author on the study.

Lab Tests Reveal Variant's Characteristics

Next, the researchers sought to better understand how the distinct mutations to the spike protein affected the California variant's ability to infect human cells.

To perform these studies safely, Ott and her team at Gladstone generated "pseudoviruses," harmless viruses that contain SARS-CoV-2 spike proteins with different mutations. This allowed the scientists to compare how the mutations affect the virus's ability to infect both individual cells and lung organoids--lab-grown, multicellular, miniature versions of a lung.

Specifically, the researchers compared three different spike protein mutations: two that are found in the California variant, and one that is commonly found in predominant variants worldwide. They found that pseudoviruses with one of the California variant's mutations, known as L452R, was better able to infect human cells than pseudoviruses carrying other mutations.

"This suggests that the L452R mutation enhances the ability of the virus to enter a cell, which could explain why the California variant has increased transmissibility," Ott says.

The researchers also conducted lab experiments to study how well the immune system's antibodies can neutralize--or block infection by--the new variant. They tested the variant against blood samples from people who had received both doses of either the Pfizer or Moderna vaccine, as well as from people who had previously been infected with what was most likely an unmutated form of SARS-CoV-2.

These experiments showed that the new variant was only moderately neutralized by antibodies from previously infected patients. But antibodies from vaccinated patients showed a higher degree of neutralization.

"Our results send a very strong message that, even if you've already had COVID-19, you may not necessarily be protected against reinfection by this variant," Andino says. "However, the vaccines do appear to protect against it."

Remaining Vigilant

These findings highlight the importance of getting vaccinated--and making sure to receive both doses to maximize the effects of vaccination. This is in line with research on other concerning variants emerging around the world.

"It appears that vaccination largely remains effective against all of the circulating variants that are known so far," Chiu says.

However, Chiu notes, the new study underscores the need for a robust surveillance system to closely monitor the emergence and spread of new variants. Such a system was lacking in California at the time the new variant emerged, Chiu says, but recent improvements mean that future variants may be detected more quickly.

"We are entering a new phase of the pandemic, where the virus continues to spread despite the availability of vaccines," Andino says. "We may eventually see the emergence of a variant that's partially or completely resistant to vaccination, so we must stay vigilant."

Ott notes that this is a quickly evolving situation, because it is unclear for how long the new variant will remain prevalent in California or other locations. In fact, a different variant known as B.1.1.7 is currently increasing in prevalence in California.

"What's more, our antibody experiments were performed with blood plasma from newly vaccinated people, so it will be important to see how the vaccine holds up in the long term," Ott says.

For now, the researchers are getting to know the new variant in even greater detail. They are conducting studies in animal models to tease out any subtle differences between the two lineages, which have so far appeared to be quite similar. They are also examining patient data to see if the new variant causes more severe cases of COVID-19 than other variants.

Key to the new findings and ongoing investigations is the researchers' dedication to fruitful collaboration.

"Our work is a great example of how the scientific community has rapidly risen to the occasion in a time of need and concern for the public," Ott says. "With this collaborative sprit, we are reaching across institutions and scientific disciplines; just doing whatever is necessary to help."

Annapolis, MD; May 26, 2021--A new study has mounted perhaps the most intricate, detailed look ever at the diversity in structure and form of bees, offering new insights in a long-standing debate over how complex social behaviors arose in certain branches of bees' evolutionary tree.

Published today in Insect Systematics and Diversity, the report is built on an analysis of nearly 300 morphological traits in bees, how those traits vary across numerous species, and what the variations suggest about the evolutionary relations between bee species. The result offers strong evidence that complex social behavior developed just once in pollen-carrying bees, rather than twice or more, separately, in different evolutionary branches--but researchers say the case is far from closed.

Diego Sasso Porto, Ph.D., has been studying the structure and form, or morphology, of bees for more than a decade, and his latest effort ventures into a longstanding conundrum about bee evolution. Corbiculate bees--those that possess corbicula, or pollen baskets, on their hind legs--encompass honey bees, stingless bees, bumble bees, and orchid bees. Among them, honey bees and stingless bees are the only groups with highly complex social behaviors, such as forming large colonies with queens, workers, and drones. Bumble bees display less complex sociality, and orchid bees are mostly solitary. Traditional morphological analyses have long indicated that honey bees and stingless bees are most closely related and that complex social behavior developed in their common ancestor before the groups diverged. However, in the 1990s, emergent techniques in molecular genetic analysis began to show that stingless bees and bumble bees were the more closely related "sister" groups, which would mean that honey bees and stingless bees each developed their complex social behavior independently, after their ancestral paths diverged.

Ever since, these different lines of evidence have persisted as a notorious case of incongruence between molecular and morphological data sets in animals. Porto, now a postdoctoral researcher in the Department of Biological Sciences at Virginia Tech, made his foray into the debate amid his doctoral work at the University of São Paulo in Brazil, under the guidance of Eduardo Almeida, Ph.D., co-author on the new study.

"The main criticism from some molecular researchers against morphology, and even from morphologists themselves, was we don't have enough data," Porto says. "This work was a big effort to try to get the best morphological data set we could ever get for this group of bees, and we tried several analyses to see if the problem is with morphological data itself or the way we interpret morphological data."

Porto evaluated past morphological studies of bees and then conducted new analysis of specimens from 53 species, dissecting each, imaging anatomical structures under optical and scanning electron microscopes, and ultimately scoring all of the specimens across 289 different traits. Often minute or even microscopic in detail, these traits ranged from the number of teeth on a bee's mandibles to the arrangement of barbs on its stinger.

With this massive trove of morphological data in hand, Porto applied multiple types of computerized statistical analyses to evaluate the possible phylogenies, or "family trees," that delineate the relationships among bee species. The results strongly support previous morphological findings, that honey bees (tribe Apini) and stingless bees (Meliponini) are most closely related. "The evidence from our dataset, if we just take it at plain sight, is really strong. We have a lot of traits supporting this," says Porto.

But, he sought to further explore the discrepancy between what molecular genetic analysis shows and what his own morphological data supports. To do so, Porto ran his data through a separate analysis that evaluated how well the morphological data could fit with the evolutionary tree supported by molecular analysis--that Meliponini and Bombini (bumble bees) are most closely related. As expected, it was not a great fit--a bit like putting a square peg in a round hole--but they were not completely incompatible, he says.

In their report in Insect Systematics and Diversity, Porto and Almeida offer a few hypotheses for evolutionary processes that could explain the continuing discrepancy in lines of evidence about corbiculate bee evolution.

"Morphological data is telling us one story, and molecular data is telling us another story. We are not going anywhere if we just keep these conflicting discussions," says Porto. "So, our decision was ... let's try to interpret the alternative scenario with our data. If the hypothesis given by molecular data is true, how can we interpret our strong morphological evidence for the other hypothesis?"

One possible explanation, they say, is that, if bumble bees and stingless bees share a common ancestor that first branched away from honey bees, they then rapidly diverged in a short time frame and evolved separately for much longer, gradually obscuring the shared traits bumble bees and stingless bees once had. Moreover, the earliest ancestor of stingless bees is believed to have been relatively small, and "miniaturization" is known to drive structural simplifications in anatomical traits, which would have further contributed to erasing similarities between bumble bees and stingless bees.

However, these possibilities don't explain why stingless bees then evolved to become more morphologically similar to honey bees, but Porto and Almeida posit that similar functional roles or similar social behaviors among stingless bees and honey bees could have driven them to evolve in similar ways.

Testing these hypotheses is what Porto says he would like to explore next--and encourages other researchers to do, as well. "It would be really good to have maybe the same data set, but including more specimens from fossils, and run the analysis again," he says.

Abstract 803: Impact of social isolation and quarantine on the course of diabetes mellitus and its complications during Covid 19 pandemic in Adjara Region Country of Georgia

Abstract 1337: Psychological distress in patients with hypocortisolism during mass quarantine for Covid-19 epidemic in Italy

Studies reveal that social isolation and quarantine throughout the COVID-19 pandemic may have a detrimental impact on people living with pre-existing conditions.

Social isolation and quarantine can have a detrimental impact on physical and mental health of people living with pre-existing conditions, according to two studies being presented at the 23rd European Congress of Endocrinology (e-ECE 2021) on Wednesday 26 May at 14:14 CET (http://www.ece2021.org).

The studies bring together research on the impact of social isolation and quarantine for people living with diabetes in the Adjara Region of Georgia, and on patients with hypocortisolism in Italy. Both studies reported that social isolation during the pandemic caused significant psychological and/or physical distress on the observed individuals.

Data from the first study revealed that the impact of quarantine on people living with diabetes in the Adjara Region caused blood pressure (BP) levels to increase in 88.2% of patients with 50% of these cases resulting in high BP hospitalisation. In addition to these physical factors, increased feelings of anxiety and fear were observed on 82% of patients. In the second study, patients with hypocortisolism experienced increased anxiety and depression, associated with a dissatisfaction feeling of self and a reduced resiliency, when compared with Italian healthy controls. As these are all contributing factors to overall health deterioration, these findings suggest further research is required to allow patients with pre-existing conditions to remain fit and healthy during the current pandemic.

In the Adjara Region study, Dr Liana Jashi and the research team disseminated an online questionnaire and collected answers from 16 endocrinologists and 22 family and general practice doctors. The study confirmed the negative, indirect effects social isolation and quarantine had on people living with diabetes. It reported a list of negative effects such as the reduced access to medical care, weight gain and increased cigarette and alcohol consumption. Physical activity decreased by 29.8%, a vital preventative to further physical and psychological problems.

"This study highlights that people living with diabetes require greater support during pandemics to maintain exercise and protect their physical and mental health. National health services should use these data and future studies to implement better social care around supporting people with pre-existing conditions," commented Dr Jashi.

In the second study, Dr Chiara Simeoli reported data collected during the last three weeks of the mass quarantine lasted 2 months in Italy, in a web-survey-based, multicenter, case- control research involving 12 different Italian centres. The study confirmed that a large cohort of 478 patients with hypocortisolism, and particularly, 363 with adrenal insufficiency and 115 with congenital adrenal hyperplasia, adequately treated with glucocorticoids, showed higher anxiety and depression, associated with a dissatisfaction feeling of self and a reduced resiliency, when compared with Italian healthy controls, suggesting the detrimental impact of social isolation on mental health of these patients, particularly frail and vulnerable to infections and stress. Moreover, patients with adrenal insufficiency reported a worse quality of life than patients with congenital adrenal hyperplasia.

"These findings confirmed that beyond the huge impact on physical health, COVID-19 epidemic, social isolation and mass quarantine represent significant psychological stressors, causing severe effects on mental health, even more on people with pre-existing conditions. An empowerment of psychological counselling for these vulnerable patients during COVID-19 should be considered by national health-care services," adds Dr Simeoli.

Both studies indicate that additional larger studies over a longer period of time are needed for further investigation.

REYKJAVIK, Iceland 26 May 2021 - Current vaccination programmes alone will have a limited effect in stopping the second wave of COVID infections in the US, according to a study conducted by scientists from Reykjavik University, University of Lyon, University of Southern Denmark and University of Naples Federico II, and published in the Nature Group journal Scientific Reports today. The findings suggest that strict social distancing and other non-pharmaceutical methods are still necessary to end the ongoing second wave in the US and prevent a new one from rising.

The study fed real-world data on human mobility into a mathematical model previously used to predict the second wave of COVID in the US. As a proxy for general human mobility between regions in the US, the authors use data from the OpenSky Network, a non-profit association that provides open access to real-world air traffic control data for research purposes. The mathematical model, previously developed by the authors, was first tested and calibrated using data on the pandemic's progression in the first wave. Here, deploying the model on flight-control data, they show that given current rates of mobility in the US and the rate of vaccination, the vaccination campaign alone will not stop the ongoing wave of infections.

Dr Anna Sigridur Islind and Dr Maria Oskarsdottir, assistant professors in the Department of Computer Science at Reykjavik University, led the work with the OpenSky Data. "Our analysis clearly demonstrates that continued vigilance is needed regarding social distancing and other non-pharmaceutical methods in the US, since not everyone can be vaccinated at once and because there is a considerable time lag from vaccination to immunity," Dr Islind said.

"Our results underscore the importance of using real-world data on human mobility relating to the pandemic and to inform public health strategies. This is especially important in a pandemic as complex as COVID and that has had such an uneven public health response, with huge variability in vaccination rates, social distancing regulations, and other measures. The flight-control data is very useful, as it comprises real-world information about rates of interstate travel and so provides a valuable broader view of human mobility on a large scale," Dr Oskarsdottir added.

Travelling elephants pay close attention to scent trails of dung and urine left by other elephants, new research shows.

Scientists monitored well-used pathways and found that wild African savannah elephants - especially those travelling alone - were "highly attentive", sniffing and tracking the trail with their trunks.

This suggests these scents act as a "public information resource", according to researchers from the University of Exeter and Elephants for Africa.

More research is now needed to find out whether humans can create artificial elephant trails to divert elephants away from farms and villages, where conflict with humans can cause devastation to communities.

Alternatively, scent trails could be placed to improve the efficiency of routes connecting elephant populations between protected areas.

"Our findings suggest an important role of an elephant's sense of smell in long-distance navigation," said lead author Connie Allen, of Exeter's Centre for Research in Animal Behaviour.

"As elephants follow these trails, they deposit their own urine and dung, which reinforces the pathway's presence for future elephants.

"We see great potential for these findings to be applied to elephant management and conservation - primarily as a method for manipulating elephant movements.

"We carried out this study in Botswana, where the main threat to elephants is conflict with humans.

"By removing the existing scent paths that lead elephants to close contact with humans in problem areas, and redirecting them, perhaps we could reduce such conflicts happening."

The proposed technique could also aid efforts in Botswana to reconnect elephants with populations across southern Africa.

The study, which examined a predominantly male population, also found that urine deposits from adult elephants were more likely to attract attention than that of younger (subadult) males.

"African elephants may therefore be able to discern the age and maturity of individuals they can expect to encounter from remote urine cues on pathways," Allen explained.

What information is retained in a memory over time, and which parts get lost? These questions have led to many scientific theories over the years, and now a team of researchers at the Universities of Glasgow and Birmingham have been able to provide some answers.

Their new study, which is published today in Nature Communications, demonstrates that our memories become less vibrant and detailed over time, with only the central gist eventually preserved. Moreover, this 'gistification' of our memories is boosted when we frequently recall our recent experiences.

The work could have implications in a number of areas, including the nature of memories in post-traumatic stress disorder, the repeated questioning of eye-witness testimonies and even in best practice for exam studying.

While memories are not exact carbon copies of the past - remembering is understood to be a highly reconstructive process - experts have suggested that the contents of a memory could change each time we bring it back to mind.

However, exactly how our memories differ from the original experiences, and how they are transformed over time, has until now proven difficult to measure in laboratory settings.

For this study the researchers developed a simple computerised task that measures how fast people can recover certain characteristics of visual memories when prompted to do so. Participants learned word-image pairs and were later required to recollect different elements of the image when cued with the word. For example, participants were asked to indicate, as fast as possible, if the image was coloured or greyscale (a perceptual detail), or whether it showed an animate or inanimate object (a semantic element).

These tests, probing the quality of the visual memories, happened immediately after learning and also after a two-day delay. Reaction time patterns showed that participants were faster to recollect meaningful, semantic elements than surface, perceptual ones.

Julia Lifanov, lead author of the study from the University of Birmingham, said: "Many memory theories assume that over time, and as people re-tell their stories, they tend to forget the surface details but retain the meaningful, semantic content of an event.

"Imagine reminiscing about a pre-COVID dinner with a friend - you realize that you cannot recall the table décor but know exactly what you ordered; or you remember the conversation with the bartender, but not the colour of his shirt. Memory experts call this phenomenon 'semanticization'."

Prof Maria Wimber, senior author on the study from the University of Glasgow, said: "The pattern towards recollection of meaningful semantic elements we demonstrate in this study indicates that memories are biased towards meaningful content in the first place - and we have shown in previous studies that this bias is clearly reflected in brain signals too.

"Our memories change with time and use and that is a good and adaptive thing. We want our memories to retain the information that is most likely to be useful in the future, when we encounter similar situations."

The researchers found that the bias towards semantic memory content becomes significantly stronger with the passage of time, and with repeated remembering. When participants came back to the lab two days later, they were much slower at answering the perceptual-detailed questions, but they show relatively preserved memory for the semantic content of the images. However, the shift from detail-rich to more concept-based memories was far less pronounced in a group of subjects who repeatedly viewed the images, rather than being asked to actively bringing them back to mind.

The study has implications for probing the nature of memories in health and disease. It provides a tool to study maladaptive changes, for example in post-traumatic stress disorder where patients often suffer from intrusive, traumatic memories, and tend to over-generalize these experiences to novel situations. The findings are also highly relevant for understanding how eyewitness memories may be biased by frequent interviews and repeatedly recalling the same event.

The findings also demonstrate that testing yourself prior to an exam (for example, by using flashcards) will make the meaningful information stick for longer, especially when followed by periods of rest and sleep.