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A trillion scents, one nose

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A trillion scents, one nose


The mammalian nose is a work of evolutionary art. Its millions of nerve cells, each tailored with just one of thousands of specific odor-chemical receptors encoded in the genome, can collectively distinguish a trillion distinct scents. Those sensations, in turn, inform many behaviors, from assessing food options to discerning friends from foes to sparking memories.

Today, in the journal Nature, a research team led by scientists at Columbia’s Zuckerman Institute describes a previously undetected mechanism in mice — starring the genetic molecule RNA — that could explain how each sensory cell, or neuron, in mammalian noses becomes tailored to detect a specific odor chemical.

For example, there are sensory neurons in our noses that bear receptors uniquely tuned to detect ethyl vanillin, the main odorant in vanilla, and other cells with receptors for limonene, lemon’s signature odorant.

“How sensory cells in the nose make their receptor choices has been one of the most vexing mysteries about olfaction,” said Stavros Lomvardas, PhD, a Roy and Diana Vagelos Professor and Chair of Biochemistry and Molecular Biophysics and Herbert and Florence Irving Professor of Neuroscience at Columbia’s Zuckerman Institute and the Vagelos College of Physicians and Surgeons, and corresponding author on the paper. “Now, the story behind our sense of smell, or olfaction, is becoming clearer, and also more dramatic.”

The sense-refining drama he is referring to unfolds entirely within the minuscule confines of each olfactory neuron’s nucleus, where the cell’s chromosomes and genes reside. There, in a Squid Games-style, winner-takes-all competition, a developing cell’s myriad olfactory receptor genes vie with each other in a process that winnow them down, in stages, first to handful of finalists and then to a single winner. The prevailing gene is the one that determines the cell’s odorant sensitivity. In their study, Dr. Lomvardas and his team uncover details of the final stage of this process when the winner emerges from the finalist genes.

“It’s basically a battle between a 1000 contenders,” said Ariel Pourmorady, the paper’s first author and an M.D.-Ph.D. candidate at the Zuckerman Institute in the Lomvardas lab.

The action is exceedingly complex and involves a dizzying cast of molecular characters. Playing roles that either dial up or down each gene’s ability to produce olfactory receptors are a variety of gene-regulating molecules. By gathering into various alliances within the genome, these molecular players help turn specific genes on or off.

Also in the fray is another set of molecular hubs that reshape portions of the genome in ways that favor specific receptor genes. When his team first observed these in the genome in 2014, Dr. Lomvardas dubbed them “Greek Islands” because they reminded him of islands in the Aegean Sea.

“It turns out that the genome has a certain spatial organization in the nucleus and changes in this structure are pivotal when it comes to which genes are expressed into proteins, like olfactory receptors,” said Pourmorady. “We are learning just how important this process is within maturing olfactory cells.”

In their new Nature paper, the researchers summon a trove of data from mouse studies pointing toward RNA as the linchpin molecule in the olfactory system’s gene-choosing mechanism. RNA is most known as the go-between molecule that translates the genetic code embodied in DNA into protein molecules with specific cellular jobs, like detecting odorants. Using sophisticated techniques for analyzing changes in genome structure as cells mature, however, the researchers say their evidence points to a pivotal second role for the RNA.

“It looks like the RNA the cell makes during gene expression also is altering the genome’s architecture in ways that bolster the expression of one olfactory receptor gene while also shutting down all the others,” Pourmorady said.

Big gaps in this genome-controlling story remain, but the researchers say the outline

is becoming more defined. It starts with maturing olfactory cells, which initially express many receptor genes at those genomic hubs where gene-regulating molecules and complexes, including Greek Islands, converge.

Then the RNA winnows the contending olfactory-receptor genes down to one. The particular hub in each cell where the molecular stars align to produce the highest amount of RNA wins the competition. At this hub, receptor-gene expression soars. But, like a slinky saboteur, RNA from that same hub may wind its way to all the other hubs. In those locations, the RNA causes shape changes in the genome that shut down gene expression. The result is a nose’s worth of mature olfactory neurons, each of which bears on its surface only one odorant receptor.

“We are reaching the edge of science fiction when it comes to the molecular and genomic details we now can observe inside a single cell’s nucleus,” said Dr. Lomvardas. “We need to keep going back in to figure out the rest of this olfaction puzzle.”



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New understanding of fly behavior has potential application in robotics, public safety

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A trillion scents, one nose


Why do flies buzz around in circles when the air is still? And why does it matter?

In a paper published online July 26, 2024 by the scientific journal Current Biology, University of Nevada, Reno Assistant Professor Floris van Breugel and Postdoctoral Researcher S. David Stupski respond to this up-until-now unanswered question. And that answer could hold a key to public safety — specifically, how to better train robotic systems to track chemical leaks.

“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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A trillion scents, one nose


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.

For the first time, researchers at Tulane National Primate Research Center found that a cancer drug significantly reduced levels of SIV, the nonhuman primate equivalent of HIV, in the brain by targeting and depleting certain immune cells that harbor the virus.

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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A trillion scents, one nose


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.

Only a few of his alchemical recipes have survived, and today, there are very few remnants of his laboratory. Uraniborg was demolished after his death in 1601, and the building materials were scattered for reuse.

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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