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Biochemistry

Unlocking Cellular Secrets: New Technique Expands Tissues for Mass Spectrometry Imaging

A new tissue expansion method enables scientists to use mass spectrometry imaging to simultaneously detect hundreds of molecules at the single cell level in their native locations.

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Unlocking Cellular Secrets: New Technique Expands Tissues for Mass Spectrometry Imaging

For biologists, seeing is believing. But sometimes biologists face a daunting challenge: visualizing the intricate world within intact tissue samples, down to the level of single cells. Detecting hundreds or thousands of biomolecules – from lipids to metabolites to proteins – in their native environment allows researchers to better understand their functions and interactions.

Traditional imaging methods, including most types of microscopy, provide a view of molecules inside cells but can only track a select handful at one time. Other methods, like regular mass spectrometry, can detect hundreds of molecules but don’t work on intact samples, so researchers can’t see how the biomolecules are oriented.

One promising technique – mass spectrometry imaging – overcomes some of these challenges. It allows researchers to see hundreds of molecules at once in intact tissues. However, it doesn’t have high enough resolution to allow detection at the single cell level.

This was the problem Janelia Senior Group Leader Meng Wang faced. Wang and her team study the fundamental mechanisms behind aging and longevity, and they wanted to detect many different biomolecules in intact tissues to understand how the components change as tissues age.

“Knowing at each specific location what molecules are there and what is in the neighboring cells is very important for any kind of biological question,” Wang says.

Luckily, Wang’s lab is down the hall from Janelia Principal Scientist Paul Tillberg. Tillberg co-invented expansion microscopy as a graduate student at MIT. The method uses a swellable hydrogel material to expand samples uniformly in all directions to a point where fine details, like sub-organelle structure, can be detected with a conventional microscope.

Now a decade old, the expansion process is being applied to other methods outside traditional microscopy. Wang, Tillberg, and their collaborators at Janelia and the University of Wisconsin-Madison wanted to see if they could use expansion to overcome mass spectrometry imaging’s spatial resolution problem.

The result is a new method that expands tissue samples gradually without having to degrade them at the molecular level, as happens in the original expansion process. By expanding the intact samples in all directions, researchers can use mass spectrometry imaging to simultaneously detect hundreds of molecules at the single cell level in their native locations.

“This lets you have an untargeted look in the molecular space, and we are trying to bring it closer to what microscopy can do in terms of spatial resolution,” Tillberg says.

The team used the new technique to delineate the specific spatial patterns of small molecules in different layers of the cerebellum. They found that these molecules – including lipids, peptides, proteins, metabolites, and glycans – are not uniformly distributed, as previously thought. Moreover, they found that each specific layer of the cerebellum has its own signature of lipids, metabolites, and proteins.

The team was also able to detect biomolecules in kidney, pancreas, and tumor tissues, demonstrating that the method can be adapted for many different tissue types. In tumor tissues, they were able to visualize large variations in biomolecules, which could be useful for understanding the molecular mechanisms of tumors and potentially aid in drug development.

“When you can see these biomolecules, then you can start to understand why they have such patterns and how that is related to function,” says Wang. She believes the new technology will allow researchers to track these patterns during development, aging, and disease to understand how different molecules contribute to these processes.

Because the new method doesn’t require adding hardware to an existing mass spec imaging system, and the expansion technique is relatively easy to learn, the team hopes it will be used by many labs around the world. They also hope the new technique will make mass spectrometry imaging a more useful tool for biologists and have laid out a detailed description of the new method and a roadmap for adapting it to other tissue types.

“We wanted to develop something that did not require specialized instruments or procedures, but can be broadly adopted,” Wang says.

Air Quality

New Computer Language Unlocks Hidden Pollutants in Environmental Data

Biologists and chemists have a new programming language to uncover previously unknown environmental pollutants at breakneck speed — without requiring them to code.

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New Computer Language Unlocks Hidden Pollutants in Environmental Data

In a breakthrough for environmental science, researchers at UC Riverside have developed a programming language called Mass Query Language (MassQL) that enables biologists and chemists to quickly identify previously unknown pollutants in massive chemical datasets. This innovative tool has already helped scientists discover toxic compounds hidden in plain sight.

The power of MassQL lies in its ability to function like a search engine for mass spectrometry data, which is akin to a chemical fingerprint. By making it easier to search these vast datasets, the language allows researchers to find patterns that would otherwise require advanced programming skills. This has significant implications for environmental science, as scientists can now quickly identify pollutants in water, air, and other samples.

Developed by Mingxun Wang, an assistant professor of computer science at UC Riverside, MassQL was created to empower chemists and biologists without extensive coding experience to mine their data exactly how they want. This user-friendly approach has the potential to revolutionize environmental research, enabling scientists to quickly identify pollutants and develop strategies for removal.

One notable example of MassQL’s effectiveness is its use by Nina Zhao, a UCR postdoctoral student now at UC San Diego. She employed the language to sift through the entire world’s mass spectrometry data on water samples, searching for organophosphate esters – compounds commonly found in flame retardants. The results were staggering: MassQL pulled out thousands of measurements, including some chemicals that have not been previously described or catalogued.

These findings highlight the importance of MassQL in environmental science. By providing a powerful tool for identifying pollutants, researchers can now develop strategies to address these toxic compounds and protect human and animal health.

MassQL’s development was made possible by a collaborative effort involving over 70 scientists from various fields. This consensus-driven approach ensured that the language would be useful across multiple disciplines and real-life situations.

The potential applications of MassQL are vast, ranging from detecting fatty acids as markers of alcohol poisoning to identifying new drugs to combat antibiotic resistance. The research team has demonstrated the effectiveness of the language in a variety of scenarios, including finding forever chemicals on playgrounds.

As Wang notes, “I wanted to create one language that could handle multiple kinds of queries. And now we have. I’m excited to hear about the discoveries that could come from this.”

With MassQL, researchers can now quickly identify pollutants and develop strategies for removal, paving the way for a cleaner, healthier environment for all.

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Batteries

“Unlocking the Secrets of Influenza Viruses: How Scientists Are Studying the Interaction between Viruses and Host Cells”

Influenza viruses are among the most likely triggers of future pandemics. A research team has developed a method that can be used to study the interaction of viruses with host cells in unprecedented detail. With the help of their new development, they have also analyzed how novel influenza viruses use alternative receptors to enter target cells.

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The threat of future pandemics has been heightened by the emergence of new influenza viruses. In recent years, researchers from the Helmholtz Centre for Infection Research (HZI) and the Medical Center — University of Freiburg have made significant progress in understanding how these viruses interact with host cells.

Led by Professor Christian Sieben’s team at HZI, scientists have developed a novel method to study the initial contact between influenza viruses and host cells. This breakthrough allows researchers to investigate the complex process of viral entry in unprecedented detail.

The researchers immobilized individual viruses on microscopy glass surfaces and then seeded cells on top. This innovative “upside-down” experimental setup enables scientists to analyze the critical moment when viruses interact with cells but do not enter them, stabilizing the initial cell contact for further investigation.

Using high-resolution and super-resolution microscopy, the team demonstrated that contact between the virus and the cell surface triggers a cascade of cellular reactions. The accumulation of local receptors at the binding site, the recruitment of specific proteins, and the dynamic reorganization of the actin cytoskeleton are just some of the processes observed in this study.

What’s more remarkable is that researchers applied their method not only to an established influenza A model but also to a novel strain found in bats. The H18N11 virus, which targets MHC class II complexes rather than glycans on the cell surface, was shown to cluster specific MHCII molecules upon contact with the cell.

This groundbreaking research has significant implications for understanding alternative receptors used by new and emerging influenza viruses. The findings provide a critical basis for investigating potential pandemic pathogens in a more targeted manner, identifying new targets for antiviral therapies, and ultimately developing effective treatments against future pandemics.

The EU project COMBINE, launched in 2025 and coordinated by Professor Sieben’s team at HZI, aims to investigate the virus entry process of newly emerging viruses. This research has far-reaching implications for understanding and combating infectious diseases, making it a significant contribution to the global fight against pandemics.

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Biochemistry

A Breakthrough in Brain Research: The Iontronic Pipette Revolutionizes Neurological Studies

Researchers have developed a new type of pipette that can deliver ions to individual neurons without affecting the sensitive extracellular milieu. Controlling the concentration of different ions can provide important insights into how individual brain cells are affected, and how cells work together. The pipette could also be used for treatments.

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The development of an iontronic pipette at Linköping University has opened up new avenues for neurological research. This innovative tool allows researchers to deliver ions directly to individual neurons without affecting the surrounding extracellular milieu. By controlling the concentration of various ions, scientists can gain valuable insights into how brain cells respond to different stimuli and interact with each other.

The human brain consists of approximately 85-100 billion neurons, supported by a similar number of glial cells that provide essential functions such as nutrition, oxygenation, and healing. The extracellular milieu, a fluid-filled space between the cells, plays a crucial role in maintaining cell function. Changes in ion concentration within this environment can activate or inhibit neuronal activity, making it essential to study how local changes affect individual brain cells.

Previous attempts to manipulate the extracellular environment involved pumping liquid into the area, disrupting the delicate biochemical balance and making it difficult to determine whether the substances themselves or the changed pressure were responsible for the observed effects. To overcome this challenge, researchers at the Laboratory of Organic Electronics developed an iontronic micropipette measuring only 2 micrometers in diameter.

This tiny pipette can deliver ions such as potassium and sodium directly into the extracellular milieu, allowing scientists to study how individual neurons respond to these changes. Glial cell activity is also monitored, providing a more comprehensive understanding of brain function.

Theresia Arbring Sjöström, an assistant professor at LOE, highlighted that glial cells are critical components of the brain’s chemical environment and can be precisely activated using this technology. In experiments conducted on mouse hippocampus tissue slices, it was observed that neurons responded dynamically to changes in ion concentration only after glial cell activity had saturated.

This research has significant implications for neurological disease treatment. The iontronic pipette could potentially be used to develop extremely precise treatments for conditions such as epilepsy, where brain function can be disrupted by localized imbalances in ion concentrations.

Researchers are now continuing their studies on chemical signaling in healthy and diseased brain tissue using the iontronic pipette. They also aim to adapt this technology to deliver medical drugs directly to affected areas of the brain, paving the way for more targeted treatments for neurological disorders.

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