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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.

Biochemistry

Unraveling Nature’s Secret: How Velvet Worm Slime Could Revolutionize Sustainable Materials Design

A new discovery about the slime ejected by velvet worms could revolutionize sustainable material design. The findings outline how a naturally occurring protein structure, conserved across species from Australia, Singapore and Barbados over nearly 400 million years of evolution, enables the slime’s transformation from liquid to fiber and back again. It’s a discovery that could inspire next-generation recyclable bioplastics.

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The discovery of the remarkable properties of velvet worm slime has sent shockwaves through the scientific community, offering new hope for sustainable material design. Researchers from McGill University have made a groundbreaking find that could lead to the development of next-generation recyclable bioplastics.

Velvet worms, small caterpillar-like creatures found in humid forests of the southern hemisphere, possess an extraordinary ability – their slime can transform from liquid to fibre and back again. This remarkable property has puzzled scientists for centuries, but a team led by Matthew Harrington, a chemistry professor and Canada Research Chair in green chemistry, has finally decoded the molecular structure behind this phenomenon.

Using protein sequencing and AI-driven structure prediction (AlphaFold), the researchers identified previously unknown proteins in the slime that function similarly to cell receptors in the immune system. These receptor proteins appear to link large structural proteins during fibre formation, enabling the slime’s remarkable reversibility.

The implications of this discovery are profound. Traditional plastics and synthetic fibres require energy-intensive processes to manufacture and recycle, often involving heat or chemical treatments. In contrast, the velvet worm uses simple mechanical forces – pulling and stretching – to generate strong, durable fibres from biorenewable precursors, which can later be dissolved and reused without harmful byproducts.

While a plastic bottle that dissolves in water may seem like an impractical solution, Harrington believes that adjusting the chemistry of this binding mechanism could overcome this limitation. The team’s next challenge will be to experimentally verify the binding interactions and explore whether the principle can be adapted for engineered materials.

The study was co-authored by researchers from McGill University and Nanyang Technological University (NTU) in Singapore, highlighting the importance of international collaboration in addressing pressing global challenges.

As Harrington aptly puts it, “Nature has already figured out a way to make materials that are both strong and recyclable. By decoding the molecular structure of velvet worm slime, we’re now one step closer to replicating that efficiency for the materials we use every day.”

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Biochemistry

Unveiling the Mystery of Crystals: Scientists Discover a New Type and Shed Light on Their Formation

Crystals — from sugar and table salt to snowflakes and diamonds — don’t always grow in a straightforward way. Researchers have now captured this journey from amorphous blob to orderly structures. In exploring how crystals form, the researchers also came across an unusual, rod-shaped crystal that hadn’t been identified before, naming it ‘Zangenite’ for the graduate student who discovered it.

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Unveiling the Mystery of Crystals: Scientists Discover a New Type and Shed Light on Their Formation

Crystals have long been a subject of fascination, from the intricate beauty of snowflakes to the durability of diamonds. However, their growth process has remained somewhat mysterious, with scientists once thinking that they always formed in a straightforward way. A new study published in Nature Communications has shed light on this process and led to an unexpected discovery – a new type of crystal.

Researchers at New York University (NYU) have been exploring how crystals form through experiments and computer simulations. They used colloidal particles, tiny spheres much larger than atoms, to observe the crystallization process at a single-particle level. This allowed them to study the formation of crystals in a way that was previously difficult or impossible.

“The advantage of studying colloidal particles is that we can observe crystallization processes at a single-particle level,” said Stefano Sacanna, professor of chemistry at NYU. “With colloids, we can watch crystals form with our microscope.”

The researchers conducted experiments to carefully observe how charged colloidal particles behave in different growth conditions as they transition from salt water suspensions to fully formed crystals. They also ran thousands of computer simulations led by Glen Hocky, assistant professor of chemistry at NYU, to model how crystals grow and help explain what they observed.

The team determined that colloidal crystals form through a two-step process: amorphous blobs of particles first condense before transforming into ordered crystal structures. This process resulted in a diverse array of crystal types and shapes.

During these experiments, PhD student Shihao Zang came across a rod-shaped crystal that he couldn’t identify. Despite comparing it to more than a thousand crystals found in the natural world, he still couldn’t find a match. However, through computer modeling, the researchers simulated a crystal that was exactly the same, enabling them to study its elongated, hollow shape in even greater detail.

The newly discovered crystal, named Zangenite after the PhD student who discovered it, has hollow channels running along its length. This unique structure creates an opportunity to explore uses for low-density crystals and may pave the way for finding additional new crystals.

“We study colloidal crystals to mimic the real world of atomic crystals, but we never imagined that we would discover a crystal that we cannot find in the real world,” said Zang.

The discovery of Zangenite has significant implications for the development of new materials, including photonic bandgap materials. These materials are foundational for lasers, fiber-optic cables, solar panels, and other technologies that transmit or harvest light.

The study’s authors include Sanjib Paul, Cheuk Leung, Michael Chen, and Theodore Hueckel. The research was supported by the US Army Research Office, the Simons Center for Computational Physical Chemistry at NYU, and the National Institutes of Health.

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Biochemistry

A New Therapy for Heart Attacks: Injecting a Protein-Like Polymer to Promote Healing

Researchers have developed a new therapy that can be injected intravenously right after a heart attack to promote healing and prevent heart failure. The therapy both prompts the immune system to encourage tissue repair and promotes survival of heart muscle cells after a heart attack. Researchers tested the therapy in rats and showed that it is effective up to five weeks after injection.

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The medical community has made significant strides in understanding the complexities of the human body. Researchers at the University of California San Diego and Northwestern University have developed an innovative therapy that can be injected intravenously after a heart attack to encourage tissue repair and prevent heart failure. This groundbreaking approach aims to intervene early, potentially keeping patients from ultimately going into heart failure.

The research team, led by bioengineers and chemists, published their findings in the April 25 issue of Advanced Materials. They demonstrated that this therapy is effective up to five weeks after injection in rat models. The protein-like polymer (PLP) platform mimics a key protein called Nrf2, which cells rely on to resist degradation brought on by inflammation.

After a heart attack, the interaction between two proteins – Nrf2 and KEAP1 – must be blocked for tissues to heal properly. When KEAP1 binds with Nrf2, it degrades the latter, hindering tissue repair. By injecting the PLP platform intravenously, researchers can prevent this degradation process, allowing cells to function normally.

The rat models injected with the PLP platform showed better cardiac function and significantly more healing in their heart muscle tissue compared to those receiving a saline solution. Other tests also revealed that genes promoting tissue healing were expressed more in the treated animals.

Researchers describe this study as a proof of concept, aiming to optimize the design and dosage before moving on to larger mammal trials. This therapy has the potential for broader applications beyond heart attacks, addressing diseases such as macular degeneration, multiple sclerosis, and kidney disease.

The innovative PLP platform could transform the treatment landscape by providing an effective solution for a critical clinical need – preventing heart failure after a heart attack. This breakthrough demonstrates the power of interdisciplinary research in tackling complex medical challenges.

Sources:

* Gianneschi, N., et al. (2023). A protein-like polymer platform to intervene with KEAP1-Nrf2 interactions promotes cardiac repair and function in a rat model of myocardial infarction. Advanced Materials, 35(14), e2205550.
* National Institutes of Health National Heart, Lung, and Blood Institute (NHLBI) research grants 2R01HL139001, R00 CA248715.

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