Scientists know that microbiota — the trillions of beneficial microbes living harmoniously inside our gut — can protect people from bacterial infections, but little is known about how they provide protection. Scientists are studying the microbiota with an eye to finding or enhancing natural treatments to replace antibiotics, which harm microbiota and become less effective as bacteria develop drug resistance.

The scientists observed that microbiota that had experienced prior infection and transferred to germ-free mice helped prevent infection with Kpn. They identified a class of bacteria — Deltaproteobacteria — involved in fighting these infections, and further analysis led them to identify taurine as the trigger for Deltaproteobacteria activity.

Taurine helps the body digest fats and oils and is found naturally in bile acids in the gut. The poisonous gas hydrogen sulfide is a byproduct of taurine. The scientists believe that low levels of taurine allow pathogens to colonize the gut, but high levels produce enough hydrogen sulfide to prevent colonization. During the study, the researchers realized that a single mild infection is sufficient to prepare the microbiota to resist subsequent infection, and that the liver and gallbladder — which synthesize and store bile acids containing taurine — can develop long-term infection protection.

The study found that taurine given to mice as a supplement in drinking water also prepared the microbiota to prevent infection. However, when mice drank water containing bismuth subsalicylate — a common over-the-counter drug used to treat diarrhea and upset stomach — infection protection waned because bismuth inhibits hydrogen sulfide production.

Scientists from NIH’s National Institute of Allergy and Infectious Diseases led the project in collaboration with researchers from the National Institute of General Medical Sciences; the National Cancer Institute; the National Institute of Diabetes and Digestive and Kidney Diseases; and the National Human Genome Research Institute.

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Materials provided by NIH/National Institute of Allergy and Infectious Diseases. Note: Content may be edited for style and length.

Stanford University material scientists led by Jennifer Dionne have done just that by using light and advanced fabrication and characterization techniques to endow catalysts with new abilities.

In a proof-of-concept experiment, rods of palladium that were approximately 1/200th the width of a human hair served as catalysts. The researchers placed these nanorods above gold nanobars that focused and “sculpted” the light around the catalyst. This sculpted light changed the regions on the nanorods where chemical reactions — which release hydrogen — took place. This work, published Jan. 14 in Science, could be an early step toward more efficient catalysts, new forms of catalytic transformations and potentially even catalysts capable of sustaining more than one reaction at once.

“This research is an important step in realizing catalysts that are optimized from the atomic-scale to the reactor-scale,” said Dionne, associate professor of materials science and engineering who is senior author of the paper. “The aim is to understand how, with the appropriate shape and composition, we can maximize the reactive area of the catalyst and control which reactions are occurring.”

A mini lab

Simply being able to observe this reaction required an exceptional microscope, capable of imaging an active chemical process on an extremely small scale. “It’s difficult to observe how catalysts change under reaction conditions because the nanoparticles are extremely small,” said Katherine Sytwu, a former graduate student in the Dionne lab and lead author of the paper. “The atomic-scale features of a catalyst generally dictate where a transformation happens, and so it’s crucial to distinguish what’s happening within the small nanoparticle.”

For this particular reaction — and the later experiments on controlling the catalyst — the microscope also had to be compatible with the introduction of gas and light into the sample.

To accomplish all of this, the researchers used an environmental transmission electron microscope at the Stanford Nano-Shared Facilities with a special attachment, previously developed by the Dionne lab, to introduce light. As their name suggests, transmission electron microscopes use electrons to image samples, which allows for a higher level of magnification than a classic optical microscope, and the environmental feature of this microscope means that gas can be added into what is otherwise an airless environment.

“You basically have a mini lab where you can do experiments and visualize what’s happening at a near-atomic level,” said Sytwu.

Under certain temperature and pressure conditions, hydrogen-rich palladium will release its hydrogen atoms. In order to see how light would affect this standard catalytic transformation, the researchers customized a gold nanobar — designed using equipment at the Stanford Nano-Shared Facilities and the Stanford Nanofabrication Facility — to sit below the palladium and act as an antenna, collecting the incoming light and funneling it to the nearby catalyst.

“First we needed to understand how these materials transform naturally. Then, we started to think about how we could modify and actually control how these nanoparticles change,” said Sytwu.

Without light, the most reactive points of the dehydrogenation are the two tips of the nanorod. The reaction then travels through the nanorod, popping out hydrogen along the way. With light, however, the researchers were able to manipulate this reaction so that it traveled from the middle outward or from one tip to the other. Based on the location of the gold nanobar and the illumination conditions, the researchers managed to produce a variety of alternative hotspots.

Bond breaking and breakthroughs

This work is one of the rare instances showing that it is possible to tweak how catalysts behave even after they are made. It opens up significant potential for increasing efficiency at the single-catalyst level. A single catalyst could play the role of many, using light to perform several of the same reactions across its surface or potentially increase the number of sites for reactions. Light control may also help scientists avoid unwanted, extraneous reactions that sometimes occur alongside desired ones. Dionne’s most aspirational goal is to someday develop efficient catalysts capable of breaking down plastic at a molecular level and transforming it back to its source material for recycling.

Dionne emphasized that this work, and whatever comes next, would not be possible without the shared facilities and resources available at Stanford. (These researchers also used the Stanford Research Computing Center to do their data analysis.) Most labs cannot afford to have this advanced equipment on their own, so sharing it increases access and expert support.

“What we can learn about the world and how we can enable the next big breakthrough is so critically enabled by shared research platforms,” said Dionne, who is also senior associate vice provost for research platforms/shared facilities. “These spaces not only offer critical tools, but a really amazing community of researchers.”

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Materials provided by Stanford University. Original written by Taylor Kubota. Note: Content may be edited for style and length.

“RNA folding is a dynamic process that is fundamental for life,” said Northwestern’s Julius B. Lucks, who led the study. “RNA is a really important piece of diagnostic and therapeutic design. The more we know about RNA folding and complexities, the better we can design treatments.”

Using data from RNA-folding experiments, the researchers generated the first-ever data-driven movies of how RNA folds as it is made by cellular machinery. By watching their videos of this folding occur, the researchers discovered that RNA often folds in surprising, perhaps unintuitive ways, such as tying itself into knots — and then immediately untying itself to reach its final structure.

“Folding takes place in your body more than 10 quadrillion times a second,” Lucks said. “It happens every single time a gene is expressed in a cell, yet we know so little about it. Our movies allow us to finally watch folding happen for the first time.”

The research will be published Jan. 15 in the journal Molecular Cell.

Lucks is an associate professor of chemical and biological engineering at Northwestern’s McCormick School of Engineering and a member of Northwestern’s Center for Synthetic Biology. He co-led the work with Alan Chen, an associate professor of chemistry at the University of Albany.

Although videos of RNA folding do exist, the computer models that generate them are full of approximations and assumptions. Lucks’ team has developed a technology platform that captures data about RNA folding as the RNA is being made. His group then uses computational tools to mine and organize the data, revealing points where the RNA folds and what happens after it folds. Angela Yu, a former student of Lucks, inputted this data into computer models to generate accurate videos of the folding process.

“The information that we give the algorithms helps the computer models correct themselves,” Lucks said. “The model makes accurate simulations that are consistent with the data.”

Lucks and his collaborators used this strategy to model the folding of an RNA called SRP, an ancient RNA found in all kingdoms of life. The molecule is well-known for its signature hairpin shape. When watching the videos, the researchers discovered that the molecule ties itself into a knot and unties itself very quickly. Then it suddenly flips into the correct hairpin-like structure using an elegant folding pathway called toehold mediated strand displacement.

“To the best of our knowledge, this has never been seen in nature,” Lucks said. “We think the RNA has evolved to untie itself from knots because if knots persist, it can render the RNA nonfunctional. The structure is so essential to life that it had to evolve to find a way to get out of a knot.”

The study, “Computationally reconstructing cotranscriptional RNA folding pathways from experimental data reveals rearrangement of non-native folding intermediates,” was supported by the National Institutes of Health (award numbers T32GM083937, 1DP2GM110838 and GM120582), the National Science Foundation (award numbers MCB1651877 and 1914567) and the Searle Funds at The Chicago Community Trust.

Video: https://www.youtube.com/watch?v=2XTi9LG9NnU&feature=emb_logo

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Materials provided by Northwestern University. Original written by Amanda Morris. Note: Content may be edited for style and length.

“This beneficial effect remained, even after correcting for age, sex, race, obesity, and hypertension or chronic kidney disease and heart failure,” said Anath Shalev, M.D., director of UAB’s Comprehensive Diabetes Center and leader of the study.

“Since similar results have now been obtained in different populations from around the world — including China, France and a UnitedHealthcare analysis — this suggests that the observed reduction in mortality risk associated with metformin use in subjects with Type 2 diabetes and COVID-19 might be generalizable,” Shalev said.

How metformin improves prognosis in the context of COVID-19 is not known, Shalev says. The UAB findings suggest that the mechanisms may go beyond any expected improvement in glycemic control or obesity, since neither body mass index, blood glucose nor hemoglobin A1C were lower in the metformin users who survived as compared to those who died.

“The mechanisms may involve metformin’s previously described anti-inflammatory and anti-thrombotic effects,” Shalev said.

The study — first made available in MedRxiv and now published in the peer-reviewed journal Frontiers in Endocrinology — included 25,326 patients tested for COVID-19 at the tertiary care UAB Hospital between Feb. 25 and June 22 of last year. Of the 604 patients found to be COVID-19-positive, 311 were African Americans.

The primary outcome in the study was mortality in COVID-19-positive subjects, and the potential association with subject characteristics or comorbidities was analyzed.

Researchers found that Blacks, who are only 26 percent of Alabama’s population, were 52 percent of those who tested positive for COVID-19, and only 30 percent of those who tested negative. In contrast, only 36 percent of the COVID-19-positive subjects were white, while whites made up 56 percent of those who tested negative, further underlining the racial disparity. Once COVID-19-positive though, no significant racial difference in mortality was observed.

“In our cohort,” Shalev said, “being African American appeared to be primarily a risk factor for contracting COVID-19, rather than for mortality. This suggests that any racial disparity observed is likely due to exposure risk and external socioeconomic factors, including access to proper health care.”

Overall mortality for COVID-19-positive patients was 11 percent. The study found that 93 percent of deaths occurred in subjects over the age of 50, and being male or having high blood pressure was associated with a significantly elevated risk of death. Diabetes was associated with a dramatic increase in mortality, with an odds ratio of 3.62. Overall, 67 percent of deaths in the study occurred in subjects with diabetes.

The researchers looked at the effects of diabetes treatment on adverse COVID-19 outcomes, focusing on insulin and metformin as the two most common medications for Type 2 diabetes. They found that prior insulin use did not affect mortality risk.

However, prior metformin use was a different matter. Metformin use significantly reduced the odds of dying, and the 11 percent mortality for metformin users was not only comparable to that of the general COVID-19-positive population, it was dramatically lower than the 23 percent mortality for diabetes patients not on metformin.

After controlling for other covariates, age, sex and metformin use emerged as independent factors affecting COVID-19-related mortality. Interestingly, even after controlling for all these other covariates, death was significantly less likely — with an odds ratio of 0.33 — for Type 2 diabetes subjects taking metformin, compared with those who did not take metformin.

“These results suggest that, while diabetes is an independent risk factor for COVID-19-related mortality,” Shalev said, “this risk is dramatically reduced in subjects taking metformin — raising the possibility that metformin may provide a protective approach in this high-risk population.”

The researchers say future studies will need to explore how metformin is protective, as well as assess the risks and benefits of metformin treatment and the indications for its use in the face of the ongoing COVID-19 pandemic.

This study is part of a new Precision Diabetes Program, a collaboration between the UAB Comprehensive Diabetes Center and the Hugh Kaul Precision Medicine Institute at UAB.

Co-authors with Shalev for the paper, “Metformin use is associated with reduced mortality in a diverse population with COVID-19 and diabetes,” are Andrew B. Crouse and Matthew Might, the Hugh Kaul Precision Medicine Institute at UAB; Tiffany Grimes and Fernando Ovalle, the Comprehensive Diabetes Center and the Department of Medicine Division of Endocrinology, Diabetes and Metabolism at UAB; and Peng Li, UAB School of Nursing.

Support came from National Institutes of Health grants DK078752, DK120379 and TR001417.

Shalev is a professor in the UAB Department of Medicine Division of Endocrinology, Diabetes and Metabolism, and she holds the Nancy R. and Eugene C. Gwaltney Family Endowed Chair in Juvenile Diabetes Research.

The researchers project that, due to the pandemic deaths last year, life expectancy at birth for Americans will shorten by 1.13 years to 77.48 years, according to their study published Thursday in the Proceedings of the National Academy of Sciences.

That is the largest single-year decline in life expectancy in at least 40 years and is the lowest life expectancy estimated since 2003.

The declines in life expectancy are likely even starker among minority populations. For Blacks, the researchers project their life expectancy would shorten by 2.10 years to 72.78 years, and for Latinos, by 3.05 years to 78.77 years.

Whites are also impacted, but their projected decline is much smaller — 0.68 years — to a life expectancy of 77.84 years.

Overall, the gap in life expectancy between Blacks and whites is projected to widen by 40%, from 3.6 to more than 5 years — further evidence of the disease’s disparate impact on disadvantaged populations.

“Our study analyzes the effect of this exceptional number of deaths on life expectancy for the entire nation, as well as the consequences for marginalized groups,” said study author Theresa Andrasfay, a postdoctoral fellow at the USC Leonard Davis School of Gerontology. “The COVID-19 pandemic’s disproportionate effect on the life expectancy of Black and Latino Americans likely has to do with their greater exposure through their workplace or extended family contacts, in addition to receiving poorer health care, leading to more infections and worse outcomes.”

COVID-19 appears to have eliminated many of the gains made in closing the Black-white life expectancy gap since 2006. Latinos, who have consistently experienced lower mortality than whites — a phenomenon known as the “Latino paradox” — would see their more than three-year survival advantage over whites reduced to less than one year.

“The huge decline in life expectancy for Latinos is especially shocking given that Latinos have lower rates than the white and Black populations of most chronic conditions that are risk factors for COVID-19,” said study co-author Noreen Goldman, the Hughes-Rogers Professor of Demography and Public Affairs at the Princeton School of Public and International Affairs. “The generally good health of Latinos prior to the pandemic, which should have protected them from COVID-19, has laid bare the risks associated with social and economic disadvantage.”

The study’s authors estimated life expectancy at birth and at age 65 for 2020 for the total U.S. population and by race and ethnicity. They used four scenarios of deaths — one in which the COVID-19 pandemic had not occurred and three others that include COVID-19 mortality projections by the Institute for Health Metrics and Evaluation, an independent global health research center at the University of Washington.

“The bigger reductions in life expectancy for the Black and Latino populations result in part from a disproportionate number of deaths at younger ages for these groups,” Goldman said. “These findings underscore the need for protective behaviors and programs to reduce potential viral exposure among younger individuals who may not perceive themselves to be at high risk.”

Life expectancy as an indicator of population health

Of the analyzed deaths for which race and ethnicity have been reported to the National Center for Health Statistics, 21% were Black and 22% Latino. Black and Latino Americans have experienced a disproportionate burden of coronavirus infections and deaths, reflecting persistent structural inequalities that heighten risk of exposure to and death from COVID-19.

The researchers say life expectancy is an important indicator of a population’s health and an informative tool for examining the impact of COVID-19 on survival.

In the decades before the COVID-19 pandemic, annual improvements in U.S. life expectancy had been small but overall life expectancy had rarely declined. An exception was the annual reduction of 0.1 year for three consecutive years — 2015, 2016, and 2017 — which were attributed in part to increases in so-called “deaths of despair” among middle-aged whites related to drug overdoses, including opioids, as well as alcohol-related liver disease and suicide.

The projected pandemic-related drop in life expectancy is about 10 times as large as the declines seen in recent years.

The last major pandemic to significantly reduce life expectancy in a short period of time was the 1918 influenza pandemic, which research indicates reduced life expectancy by an extraordinary 7-12 years.

As of Wednesday, more than 10 million Americans had received their first COVID-19 vaccination dose, according to the U.S. Centers for Disease Control and Prevention. But the vaccines may not be enough to immediately reverse the impact of the disease on U.S. life expectancy.

“While the arrival of effective vaccines is hopeful, the U.S. is currently experiencing more daily COVID-19 deaths than at any other point in the pandemic,” Andrasfay said. “Because of that, and because we expect there will be long-term health and economic effects that may result in worse mortality for many years to come, we expect there will be lingering effects on life expectancy in 2021.”

“That said,” she added, “no cohort may ever experience a reduction in life expectancy of the magnitude attributed to COVID-19 in 2020.”

The study authors say they are now studying occupational exposures to COVID-19 by race and ethnicity to further comprehend its disproportionate impact.

The research was supported by the National Institute on Aging (grant number T32AG000037).

Many plants produce chemical defenses to protect themselves against being eaten. Still little is known about what makes these substances toxic to their consumers. Researchers at the Max Planck Institute for Chemical Ecology and the University of Münster have now investigated how plants produce toxins and store them in their tissues without harming themselves. In particular, they wanted to know whether the mechanisms of autotoxicity and its prevention share similar mechanisms as the toxic characteristics that provide defense against herbivores.

Autotoxicity and defense

For their experiments, they chose diterpene glycosides from Nicotiana attenuata plants, a wild tobacco species. “These substances occur at very high concentrations in the leaves of tobacco plants. But we had no idea why they were such effective defenses or why they could be so toxic to produce. So the situation was completely different from the other very abundant toxin that this plant produces, namely, nicotine. Nicotine is a specific neurotoxin. Since plants lack nerves and muscles, they offer no target for the toxin. So producing and storing nicotine does not harm plants,” says Ian Baldwin from the Department of Molecular Ecology at the Jena Max Planck Institute, where the study was carried out.

To their surprise, the researchers found that tobacco plants which had been transformed so they could no longer produced two proteins involved in the biosynthesis of the diterpene glycosides and thus also not form the defensive substances otherwise stored in the leaves in large amounts, showed conspicuous symptoms of self-poisoning: they were sick, unable to grow normally, and could no longer reproduce. Further experiments revealed that certain components of the cell membrane, so-called sphingolipids, had been attacked.

Targeting the cell membrane

Sphingolipids are substances found in all animals and plants, including the enemies of wild tobacco, the larvae of the tobacco hawkmoth Manduca sexta. The researchers therefore asked whether the sphingolipid metabolism could be the target of the diterpene glycosides. In fact, Manduca sexta caterpillars, which had fed on plants without diterpene glycosides, grew significantly better than larvae, which had fed on controls that contained the defensive chemicals. Analyses of the frass of Manduca sexta larvae, which had ingested diterpene glycosides with their food, provided further insights, as the degradation of the plant toxins during larval digestion is more or less in reverse order to the synthesis of the substances in the plant. Plants prevent self-harm by storing the defensive substances in a non-toxic form. However, when insects feed on the plant, a part of the non-toxic molecule is cleaved off and the chemical becomes activated or “armed.” “Interestingly, in both cases, in plants with incomplete diterpene glycoside biosynthesis and in feeding caterpillars, the target of the toxins is the sphingolipid metabolism,” says first author Jiancai Li.

Sphingolipids are mediators in many physiological processes. This makes the effect of diterpene glycosides on sphingolipid metabolism so intriguing. “Diterpene glycosides and their derivatives can have broad defensive functions against many agricultural pests and pathogenic fungi. At the same time, many human diseases, such as diabetes, cancers and some neurodegenerative diseases are also associated with elevated sphingolipid metabolisms,” says Shuqing Xu from the Institute for Evolution and Biodiversity at the University of Münster, who is one of the senior authors of the study. Physicians have been searching for effective substances to treat these diseases by inhibiting the sphingolipid metabolism. The diterpene glycosides studied here could be potential candidates for further investigations.

“Frassomics” — a new powerful tool to study interactions between organisms

The analysis of larval frass proved to be the key to success in this study. The scientists call this new approach “frassomics”: a combination of frass (larval droppings) and metabolomics — the analysis of all metabolites in an organism. “From this work, we realized that frassomics can be a very powerful research tool. The analysis of larval frass can provide metabolic clues about how what one organism produces is metabolized by consumer organisms,” says Ian Baldwin.

The scientists plan to gain more insights into the “digestive duets” that occur between plants and insects, in order to better understand ecological interactions between plants, insects and microorganisms.