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Cryo-microscopy reveals nano-sized copy machine implicated in origin of life
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RNA is thought to have sparked the origin of life by self-copying. Researchers from Aarhus University, Denmark, and MRC LMB Cambridge, England, have revealed the atomic structure of an “RNA copy machine” through cryo-EM. This breakthrough sheds light on a primordial RNA world and fuels advancements in RNA nanotechnology and medicine.
Structure of an ice-loving RNA replicase
In a research paper published in PNAS, a team of researchers now report the first atomic structure of an RNA replicase using cryogenic electron microscopy (cryo-EM). The RNA replicase being studied was developed by the Holliger lab (MRC LMB Cambridge, UK) to be efficient at copying long templates using nucleotide triplets in the eutectic ice phase (similar to slush-ice). Returning from postdoctoral studies in the Holliger lab, Emil L. Kristoffersen, currently assistant professor at Aarhus University, facilitated a collaboration with the Andersen lab (Aarhus University, Denmark) to determine the structure of the RNA replicase by cryo-EM. Interestingly, the structure shows striking similarities to protein-based polymerases with domains for template binding, polymerization, and substrate discrimination arranged in a molecular shape resembling an open hand.
“It was surprising to find that a ribozyme that we evolved artificially in the test tube would display features of naturally occurring protein polymerases. This indicates that evolution can discover convergent molecular solutions no matter if the material is RNA or protein,” explains Philipp Holliger, program leader at MRC LMB Cambridge, UK.
Model for RNA synthesis in an RNA world
To better understand how the RNA replicase works, the researchers did a comprehensive mutational study to highlight the crucial elements of the RNA structure. This analysis confirmed features of the catalytic site but also revealed the importance of two so-called kissing-loop interactions, which bind the scaffolding and the catalytic subunits together, as well as the importance of a specific RNA domain for fidelity, that is the accuracy with which the replicase copies RNA strands. While the researchers could not determine the structure of the replicase “in-action” while actively copying RNA, it was possible to build a model for RNA-based RNA copying that is consistent with all experimental data.
“Cryo-EM is a powerful method for studying the structure and dynamical features of RNA molecules. By combing cryo-EM data with experiments, we were able to build a model of the inner workings of this complex RNA machine,” tells Ewan McRae, who did the cryo-EM work as a postdoc in the Andersen lab at Aarhus University but has now started his own research group at Houston Methodist Research Institute, Texas, USA.
Inspiration for RNA nanotechnology and medicine
The study provides an exciting first glimpse of an RNA replicase thought to reside at the very root of the tree of life. The currently developed RNA-based replicases are however very inefficient (as compared to protein-based polymerases) and cannot yet sustain their own replication and evolution. The structural insight provided by the reported study may help in designing more efficient replication mechanisms and thus get us closer to developing RNA world scenarios in the test tube.
“The properties of RNA replicases may be further improved by using chemical modifications that could exist in an RNA world. In addition, research into the origin of life leads to the discovery of several novel RNA building blocks that may be used in the emerging field of RNA nanotechnology and medicine,” explains Ebbe Sloth Andersen, associate professor at Aarhus University, Denmark.
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New understanding of fly behavior has potential application in robotics, public safety
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Why do flies buzz around in circles when the air is still? And why does it matter?
“We don’t currently have robotic systems to track odor or chemical plumes,” van Breugel said. “We don’t know how to efficiently find the source of a wind-borne chemical. But insects are remarkably good at tracking chemical plumes, and if we really understood how they do it, maybe we could train inexpensive drones to use a similar process to find the source of chemicals and chemical leaks.”
A fundamental challenge in understanding how insects track chemical plumes — basically, how does the fly find the banana in your kitchen? — is that wind and odors can’t be independently manipulated.
To address this challenge, van Breugel and Stupski used a new approach that makes it possible to remotely control neurons — specifically the “smell” neurons — on the antennae of flying fruit flies by genetically introducing light-sensitive proteins, an approach called optogenetics. These experiments, part of a $450,000 project funded through the Air Force Office of Scientific Research, made it possible to give flies identical virtual smell experiences in different wind conditions.
What van Breugel and Stupski wanted to know: how do flies find an odor when there’s no wind to carry it? This is, after all, likely the wind experience of a fly looking for a banana in your kitchen. The answer is in the Current Biology article, “Wind Gates Olfaction Driven Search States in Free Flight.” The print version will appear in the Sept. 9 issue.
Flies use environmental cues to detect and respond to air currents and wind direction to find their food sources, according to van Breugel. In the presence of wind, those cues trigger an automatic “cast and surge” behavior, in which the fly surges into the wind after encountering a chemical plume (indicating food) and then casts — moves side to side — when it loses the scent. Cast-and-surge behavior long has been understood by scientists but, according to van Breugel, it was fundamentally unknown how insects searched for a scent in still air.
Through their work, van Breugel and Stupski uncovered another automatic behavior, sink and circle, which involves lowering altitude and repetitive, rapid turns in a consistent direction. Flies perform this innate movement consistently and repetitively, even more so than cast-and-surge behavior.
According to van Breugel, the most exciting aspect of this discovery is that it shows flying flies are clearly able to assess the conditions of the wind — its presence, and direction — before deploying a strategy that works well under these conditions. The fact that they can do this is actually quite surprising — can you tell if there is a gentle breeze if you stick your head out of the window of a moving car? Flies aren’t just reacting to an odor with the same preprogrammed response every time like a simple robot, they are responding in context-appropriate manner. This knowledge potentially could be applied to train more sophisticated algorithms for scent-detecting drones to find the source of chemical leaks.
So, the next time you try to swat a fly in your home, consider the fact that flies might actually be a little more aware of some of their natural surroundings than you are. And maybe just open a window to let it out.
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New drug shows promise in clearing HIV from brain
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An experimental drug originally developed to treat cancer may help clear HIV from infected cells in the brain, according to a new Tulane University study.
Published in the journal Brain, this discovery marks a significant step toward eliminating HIV from hard-to-reach reservoirs where the virus evades otherwise effective treatment.
“This research is an important step in tackling brain-related issues caused by HIV, which still affect people even when they are on effective HIV medication,” said lead study author Woong-Ki Kim, PhD, associate director for research at Tulane National Primate Research Center. “By specifically targeting the infected cells in the brain, we may be able to clear the virus from these hidden areas, which has been a major challenge in HIV treatment.”
Antiretroviral therapy (ART) is an essential component of successful HIV treatment, maintaining the virus at undetectable levels in the blood and transforming HIV from a terminal illness into a manageable condition. However, ART does not completely eradicate HIV, necessitating lifelong treatment. The virus persists in “viral reservoirs” in the brain, liver, and lymph nodes, where it remains out of reach of ART.
The brain has been a particularly challenging area for treatment due to the blood-brain barrier — a protective membrane that shields it from harmful substances but also blocks treatments, allowing the virus to persist. In addition, cells in the brain known as macrophages are extremely long-lived, making them difficult to eradicate once they become infected.
Infection of macrophages is thought to contribute to neurocognitive dysfunction, experienced by nearly half of those living with HIV. Eradicating the virus from the brain is critical for comprehensive HIV treatment and could significantly improve the quality of life for those with HIV-related neurocognitive problems.
Researchers focused on macrophages, a type of white blood cell that harbors HIV in the brain. By using a small molecule inhibitor to block a receptor that increases in HIV-infected macrophages, the team successfully reduced the viral load in the brain. This approach essentially cleared the virus from brain tissue, providing a potential new treatment avenue for HIV.
The small molecule inhibitor used, BLZ945, has previously been studied for therapeutic use in amyotrophic lateral sclerosis (ALS) and brain cancer, but never before in the context of clearing HIV from the brain.
The study, which took place at the Tulane National Primate Research Center, utilized three groups to model human HIV infection and treatment: an untreated control group, and two groups treated with either a low or high dose of the small molecule inhibitor for 30 days. The high-dose treatment lead to a notable reduction in cells expressing HIV receptor sites, as well as a 95-99% decrease in viral DNA loads in the brain .
In addition to reducing viral loads, the treatment did not significantly impact microglia, the brain’s resident immune cells, which are essential for maintaining a healthy neuroimmune environment. It also did not show signs of liver toxicity at the doses tested.
The next step for the research team is to test this therapy in conjunction with ART to assess its efficacy in a combined treatment approach. This could pave the way for more comprehensive strategies to eradicate HIV from the body entirely.
This research was funded by the National Institutes of Health, including grants from the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke, and was supported with resources from the Tulane National Primate Research Center base grant of the National Institutes of Health, P51 OD011104.
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Chemical analyses find hidden elements from renaissance astronomer Tycho Brahe’s alchemy laboratory
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In the Middle Ages, alchemists were notoriously secretive and didn’t share their knowledge with others. Danish Tycho Brahe was no exception. Consequently, we don’t know precisely what he did in the alchemical laboratory located beneath his combined residence and observatory, Uraniborg, on the now Swedish island of Ven.
However, during an excavation in 1988-1990, some pottery and glass shards were found in Uraniborg’s old garden. These shards were believed to originate from the basement’s alchemical laboratory. Five of these shards — four glass and one ceramic — have now undergone chemical analyses to determine which elements the original glass and ceramic containers came into contact with.
The chemical analyses were conducted by Professor Emeritus and expert in archaeometry, Kaare Lund Rasmussen from the Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark. Senior researcher and museum curator Poul Grinder-Hansen from the National Museum of Denmark oversaw the insertion of the analyses into historical context.
Enriched levels of trace elements were found on four of them, while one glass shard showed no specific enrichments. The study has been published in the journal Heritage Science.
“Most intriguing are the elements found in higher concentrations than expected — indicating enrichment and providing insight into the substances used in Tycho Brahe’s alchemical laboratory,” said Kaare Lund Rasmussen.
The enriched elements are nickel, copper, zinc, tin, antimony, tungsten, gold, mercury, and lead, and they have been found on either the inside or outside of the shards.
Most of them are not surprising for an alchemist’s laboratory. Gold and mercury were — at least among the upper echelons of society — commonly known and used against a wide range of diseases.
“But tungsten is very mysterious. Tungsten had not even been described at that time, so what should we infer from its presence on a shard from Tycho Brahe’s alchemy workshop?,” said Kaare Lund Rasmussen.
Tungsten was first described and produced in pure form more than 180 years later by the Swedish chemist Carl Wilhelm Scheele. Tungsten occurs naturally in certain minerals, and perhaps the element found its way to Tycho Brahe’s laboratory through one of these minerals. In the laboratory, the mineral might have undergone some processing that separated the tungsten, without Tycho Brahe ever realizing it.
However, there is also another possibility that Professor Kaare Lund Rasmussen emphasizes has no evidence whatsoever — but which could be plausible.
Already in the first half of the 1500s, the German mineralogist Georgius Agricola described something strange in tin ore from Saxony, which caused problems when he tried to smelt tin. Agricola called this strange substance in the tin ore “Wolfram” (German for Wolf’s froth, later renamed to tungsten in English).
“Maybe Tycho Brahe had heard about this and thus knew of tungsten’s existence. But this is not something we know or can say based on the analyses I have done. It is merely a possible theoretical explanation for why we find tungsten in the samples,” said Kaare Lund Rasmussen.
Tycho Brahe belonged to the branch of alchemists who, inspired by the German physician Paracelsus, tried to develop medicine for various diseases of the time: plague, syphilis, leprosy, fever, stomach aches, etc. But he distanced himself from the branch that tried to create gold from less valuable minerals and metals.
In line with the other medical alchemists of the time, he kept his recipes close to his chest and shared them only with a few selected individuals, such as his patron, Emperor Rudolph II, who allegedly received Tycho Brahe’s prescriptions for plague medicine.
We know that Tycho Brahe’s plague medicine was complicated to produce. It contained theriac, which was one of the standard remedies for almost everything at the time and could have up to 60 ingredients, including snake flesh and opium. It also contained copper or iron vitriol (sulphates), various oils, and herbs.
After various filtrations and distillations, the first of Brahe’s three recipes against plague was obtained. This could be made even more potent by adding tinctures of, for example, coral, sapphires, hyacinths, or potable gold.
“It may seem strange that Tycho Brahe was involved in both astronomy and alchemy, but when one understands his worldview, it makes sense. He believed that there were obvious connections between the heavenly bodies, earthly substances, and the body’s organs. Thus, the Sun, gold, and the heart were connected, and the same applied to the Moon, silver, and the brain; Jupiter, tin, and the liver; Venus, copper, and the kidneys; Saturn, lead, and the spleen; Mars, iron, and the gallbladder; and Mercury, mercury, and the lungs. Minerals and gemstones could also be linked to this system, so emeralds, for example, belonged to Mercury,” explained Poul Grinder-Hansen.
Kaare Lund Rasmussen has previously analyzed hair and bones from Tycho Brahe and found, among other elements, gold. This could indicate that Tycho Brahe himself had taken medicine that contained potable gold.
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