Does the smell of a warm cup of coffee help you start your day the right way? Or can you not stand the strong, heady stuff? According to new research, how quickly your brain processes the smell of your morning beverage might depend on whether you think that odor is pleasant or not.

A team at the University of Tokyo created a special device that can deliver 10 diverse odors in a way that is accurate and timely. The odors were administered to participants who rated their pleasantness while wearing noninvasive scalp-recorded electroencephalogram (EEG) caps, which record signals inside the brain. The team was then able to process the EEG data using machine learning-based computer analysis, to see when and where the range of odors was processed in the brain with high temporal resolution for the first time.

“We were surprised that we could detect signals from presented odors from very early EEG responses, as quickly as 100 milliseconds after odor onset, suggesting that representation of odor information in the brain occurs rapidly,” said doctoral student Mugihiko Kato from the Graduate School of Agricultural and Life Sciences at the University of Tokyo.

Detection of odor by the brain occurred before the odor was consciously perceived by the participant, which didn’t happen until several hundred milliseconds later. “Our study showed that different aspects of perception, in particular odor pleasantness, unpleasantness and quality, emerged through different spatial and temporal cortical processing,” said Kato.

“The representation of unpleasantness in the brain emerged earlier than pleasantness and perceived quality,” said Project Associate Professor Masako Okamoto, also from the Graduate School of Agricultural and Life Sciences. When unpleasant odors (such as rotten and rancid smells) were administered, participants’ brains could differentiate them from neutral or pleasant odors as early as 300 milliseconds after onset. However, representation of pleasant odors (such as floral and fruity smells) in the brain didn’t occur until 500 milliseconds onwards, around the same time as when the quality of the odor was also represented. From 600-850 milliseconds after odor onset, significant areas of the brain involved in emotional, semantic (language) and memory processing then became most involved.

The earlier perception of unpleasant odors may be an early warning system against potential dangers. “The way each sensory system recruits the central nervous system differs across the sensory modalities (smell, light, sound, taste, pressure and temperature). Elucidating when and where in the brain olfactory (smell) perception emerges helps us to understand how the olfactory system works,” said Okamoto. “We also feel that our study has broader methodological implications. For example, it was not known that scalp-recorded EEG would allow us to assess representation of odors from time periods as early as 100 milliseconds.”

This high temporal resolution imaging of how our brains process odors may be a stepping stone towards better understanding the mechanisms of neurodegenerative diseases in future, such as Parkinson’s and Alzheimer’s diseases, in which a dysfunction in the sense of smell is an early warning sign. The team is interested in exploring several further research avenues. “In our daily life, odors are perceived along with other sensory information like vision, and each sense influences the perception of the other,” said Kato. “Although we presented olfactory stimuli alone in the current study, we think that analyzing brain activity under more natural conditions, such as presenting odors with a movie, is important.” Perhaps Smell-O-Vision might yet make a comeback?

Funding

This work was supported by the Grant-in-Aid for Scientific Research on Innovative Areas from Japan Society for the Promotion of Science to M.O. (18H04998 and 21H05808) and JST-Mirai program to K.T. (JPMJMI17DC and JPMJMI19D1).

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Cells are stressed by factors that may damage them, such as extreme temperatures, toxic substances, or mechanical shocks. When this happens, they undergo a range of molecular changes called the cellular stress response.

“Every cell, no matter from which organism, is always exposed to harmful substances in their environment that they have to deal with all the time,” said Gustavo Silva, assistant professor of biology at Duke and senior author on the paper. “Many human diseases are caused by cells not being able to cope with these aggressions.”

During the stress response, cells press pause the genes related to their normal housekeeping activities, and turn on genes related to crisis mode. Just like in a house being flooded, they put down the window cleaner, turn off the TV, and run to close the windows, then they patch holes, turn on the sump pump, and if needed, rip up carpet and throw away irreparably damaged furniture.

While studying mechanisms related to the cells’ health and their response to stress, the team saw that, under stress, a group of proteins was being modified inside the cells. They dug into it and found that the master regulator of this process is a gene called Rad6.

“When there is a stressor, cells need to change what proteins are produced,” said Vanessa Simões, associate in research in the Silva lab and lead author of the paper. “Rad6 goes in and gets the (protein-building) ribosomes to change their program and adapt what they are producing for the new stressful circumstances.”

Rad6 isn’t just any random gene. It can be found, sometimes under a different name, in almost all multicellular organisms. In humans, it is known for its association with a set of symptoms called “Nascimento Syndrome,” that include severe learning disabilities.

Nascimento Syndrome, also called X-linked intellectual disability type Nascimento, is still a poorly understood disease. It was officially described in 2006, and tends to run in families, giving scientists an early clue to its genetic causes. Affected individuals have severe learning disabilities, characteristic facial traits, with wide-set eyes and a depressed nose bridge, and a range of other debilitating symptoms.

Like many other genes, Rad6 doesn’t just do one thing. It’s a multiuse tool. By discovering an additional function, and one so tightly related to the cell’s health, Silva and his team get to add a new piece to the puzzle of Nascimento Syndrome.

“It’s still a big question or how exactly can a mutation to this gene lead to such a drastic syndrome in humans,” said Silva. “Our findings are exciting because Rad6 can be a model on which we can do genetic manipulations to try to understand how problems in coping with harmful conditions can be connected to how this disease progresses.”

“If we get a better understanding of how this gene works, we can actually try to interfere with it to help these patients have a better outcome.” he said.

But how does one actually “look” at what is happening with an infinitesimally small protein when a cell is stressed? With a fair amount of teamwork. Simões and Silva paired up with researchers from the Duke Biochemistry department and the Pratt School of engineering to gather all the help they needed.

“We used biochemistry analyses, cellular assays, proteomics, molecular modeling, cryo-electron microscopy, a whole set of advanced techniques,” said Silva.

“It’s the cool thing about being in a place like Duke,” he said. “We found collaborators and resources easily, right here, and that really increases the impact of a study and our ability to do a more complete work.”

Funding for this study was provided by US National Institutes of Health R00 Award ES025835 and R35 Award GM137954 to Gustavo Silva. This work was also supported in part by R01 Award GM141223 to Alberto Bartesaghi and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences Grant ZIC ES103326 to Mario J. Borgnia. Cryo- EM work was performed at the Duke University Shared Materials Instrumentation Facility (SMIF), a member of the North Carolina Research Triangle Nanotechnology Network (RTNN), which is supported by the National Science Foundation (grant ECCS- 1542015) as part of the National Nanotechnology Coordinated Infrastructure (NNCI). Funding was also provided from the UNC Lineberger Comprehensive Cancer Center through the University of California, Riverside Fund and the Cancer Center Support Grant P30CA016086.

MIT chemists have now designed a new type of photoredox catalyst that could make it easier to incorporate light-driven reactions into manufacturing processes. Unlike most existing photoredox catalysts, the new class of materials is insoluble, so it can be used over and over again. Such catalysts could be used to coat tubing and perform chemical transformations on reactants as they flow through the tube.

“Being able to recycle the catalyst is one of the biggest challenges to overcome in terms of being able to use photoredox catalysis in manufacturing. We hope that by being able to do flow chemistry with an immobilized catalyst, we can provide a new way to do photoredox catalysis on larger scales,” says Richard Liu, an MIT postdoc and the joint lead author of the new study.

The new catalysts, which can be tuned to perform many different types of reactions, could also be incorporated into other materials including textiles or particles.

Timothy Swager, the John D. MacArthur Professor of Chemistry at MIT, is the senior author of the paper, which appears today in Nature Communications. Sheng Guo, an MIT research scientist, and Shao-Xiong Lennon Luo, an MIT graduate student, are also authors of the paper.

Hybrid materials

Photoredox catalysts work by absorbing photons and then using that light energy to power a chemical reaction, analogous to how chlorophyll in plant cells absorbs energy from the sun and uses it to build sugar molecules.

Chemists have developed two main classes of photoredox catalysts, which are known as homogenous and heterogenous catalysts. Homogenous catalysts usually consist of organic dyes or light-absorbing metal complexes. These catalysts are easy to tune to perform a specific reaction, but the downside is that they dissolve in the solution where the reaction takes place. This means they can’t be easily removed and used again.

Heterogenous catalysts, on the other hand, are solid minerals or crystalline materials that form sheets or 3D structures. These materials do not dissolve, so they can be used more than once. However, these catalysts are more difficult to tune to achieve a desired reaction.

To combine the benefits of both of these types of catalysts, the researchers decided to embed the dyes that make up homogenous catalysts into a solid polymer. For this application, the researchers adapted a plastic-like polymer with tiny pores that they had previously developed for performing gas separations. In this study, the researchers demonstrated that they could incorporate about a dozen different homogenous catalysts into their new hybrid material, but they believe it could work more many more.

“These hybrid catalysts have the recyclability and durability of heterogeneous catalysts, but also the precise tunability of homogeneous catalysts,” Liu says. “You can incorporate the dye without losing its chemical activity, so, you can more or less pick from the tens of thousands of photoredox reactions that are already known and get an insoluble equivalent of the catalyst you need.”

The researchers found that incorporating the catalysts into polymers also helped them to become more efficient. One reason is that reactant molecules can be held in the polymer’s pores, ready to react. Additionally, light energy can easily travel along the polymer to find the waiting reactants.

“The new polymers bind molecules from solution and effectively preconcentrate them for reaction,” Swager says. “Also, the excited states can rapidly migrate throughout the polymer. The combined mobility of the excited state and partitioning of the reactants in the polymer make for faster and more efficient reactions than are possible in pure solution processes.”

Higher efficiency

The researchers also showed that they could tune the physical properties of the polymer backbone, including its thickness and porosity, based on what application they want to use the catalyst for.

As one example, they showed that they could make fluorinated polymers that would stick to fluorinated tubing, which is often used for continuous flow manufacturing. During this type of manufacturing, chemical reactants flow through a series of tubes while new ingredients are added, or other steps such as purification or separation are performed.

Currently, it is challenging to incorporate photoredox reactions into continuous flow processes because the catalysts are used up quickly, so they have to be continuously added to the solution. Incorporating the new MIT-designed catalysts into the tubing used for this kind of manufacturing could allow photoredox reactions to be performed during continuous flow. The tubing is clear, allowing light from an LED to reach the catalysts and activate them.

“The idea is to have the catalyst coating a tube, so you can flow your reaction through the tube while the catalyst stays put. In that way, you never get the catalyst ending up in the product, and you can also get a lot higher efficiency,” Liu says.

The catalysts could also be used to coat magnetic beads, making them easier to pull out of a solution once the reaction is finished, or to coat reaction vials or textiles. The researchers are now working on incorporating a wider variety of catalysts into their polymers, and on engineering the polymers to optimize them for different possible applications.

The research was funded by the National Science Foundation and the KAUST Sensor Initiative.

A new paper published in EPJ H and authored by Alexander S. Blum and Andres Martınez de Velasco from Max Planck Institute for the History of Science, Berlin, looks at the roots of CPT theorem and its influence over modern physics.

“CPT theorem is the statement that nothing would change  —  nobody would notice and the predictions of physics would not be altered  —  if we simultaneously replace particles by antiparticles and vice versa,” Blum says. “Replace everything by its mirror image or more exactly: exchange left and right, up and down, and front and back, and reverse the flow of time. We call this simultaneous transformation CPT, where C stands for Charge Conjugation (exchanging particles and antiparticles), P stands for parity (mirroring), and T stands for time reversal.”

Blum adds that in the story told over the course of the paper is that CPT theorem only became really important a couple of years after its discovery.

“Originally, physicists had (tacitly) believed that nothing would change even if we do one of the three transformations mentioned above individually,” the researcher says. “In 1957, it was found that we can actually distinguish the world from its mirror image. In particular certain radioactive decays actually distinguish left from right. In time, it was found that, indeed, all three of the transformations individually actually produce noticeable differences.”

Blum concludes by explaining that the time is right for a review of CPT theorem because young researchers are becoming proficient both in historical and philosophical analysis and in the mathematical intricacies of post-WWII physics.

Blum’s research group, hosted both by the Max Planck Institute for the History of Science and the Max Planck Institute for Gravitational Physics, is now establishing itself as a centre for this kind of training emphasising the importance of the CPT theorem for a new generation of physicists.

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A new paper published in EPJ E looks at the dynamics of microswimmers under gravity. It is authored by a team from the Institute for Theoretical Physics at the Berlin Institute of Technology: Felix Rühle, Arne W. Zantop, and Holger Stark.

“My supervisor Professor Holger Stark and our team have long been interested in the collective behaviour of microswimmers,” Rühle says. “Within this field, patterns formed by biological organisms, such as algae and bacteria, are known as bioconvection.”

As an example, Rühle points to algal patches in the ocean which can be an ecological problem.

The team focus on squirmers  —  a model for a spherical microswimmer swimming in Stokes flow  —  to identify different dynamical states for such systems.

“For this project, we were interested in a specific kind of pattern formation that happens under gravity  —  swimmers reorient each other mediated by the flow field they create in the fluid,” Rühle continues. “But, at the same time, they have a tendency to point upwards  —  anti-parallel to gravity. The motion directed by a combination of these effects is called gyrotaxis, and we show how and when clusters form under these conditions in numerical simulations.”

While bioconvection can have many possible causes, such as the diffusion of oxygen, access to sunlight or turbulent flows, Rühle explains that the team’s simulations show that two “ingredients” are sufficient for clusters to form. These are gravity and hydrodynamic interactions with the strength of the reorienting gravity torque  —  which arises due to the centre of mass being below the geometrical centre ,  controlling the size of the clusters.

“This insight furthers our understanding of biological patterns in general,” Rühle concludes.

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The gels, made from plant-based oils such as sesame oil, can be prepared with a variety of textures, from a thickened beverage to a yogurt-like substance. The gels are stable without refrigeration, which could make them easier to get to children in developing nations, but they could also be beneficial for children anywhere, the researchers say. They could also help adults who have difficulty swallowing pills, such as older people or people who have suffered a stroke.

“This platform will change our capacity for what we can do for kids, and also for adults who have difficulty receiving medication. Given the simplicity of the system and its low cost, it could have a tremendous impact on making it easier for patients to take medications,” says Giovanni Traverso, the Karl van Tassel Career Development Assistant Professor of Mechanical Engineering at MIT, a gastroenterologist at Brigham and Women’s Hospital, and the senior author of the study.

Traverso and his colleagues showed that they could use the gels to deliver several types of medications for the treatment of infectious disease, in the same doses that can be delivered by pills or tablets, in animal studies. The research team is now planning a clinical trial that is expected to begin within a few months.

Former MIT postdoc Ameya Kirtane, now an instructor at Brigham and Women’s Hospital; MIT postdoc Christina Karavasili; and former technical associate Aniket Wahane are the lead authors of the study, which appears today in Science Advances.

Easy to swallow

Nearly 10 years ago, while working on other kinds of ingestible drug-delivery systems, the research team started to think about new ways to make it easier for children to take medications that are normally given as pills. There are existing strategies that can help with this, but none is a perfect solution. Some antibiotics and other drugs can be suspended in water, but that requires clean water to be available, and the drugs need to be refrigerated after being mixed. Also, this strategy doesn’t work for drugs that are not soluble in water.

With drugs that are only available as pills, health care providers may try to dissolve them in water for children to drink, but that also requires a clean water supply, and the dosages may be difficult to get right if the pills are meant for adults.

To try to address those issues, the researchers set out to develop a new drug-delivery system that would be inexpensive, palatable, stable at extreme temperatures, and compatible with many different drugs. They also wanted to make sure that drugs would not need to be mixed with water before dosing, and that the system could be delivered either orally or as a suppository.

Because they wanted their formulation to work with drugs that can’t be dissolved in water, the researchers decided to focus on oil-based gels. Such gels, also known as oleogels, are commonly used in the food industry to change the texture of oily foods, and also to raise the melting point of chocolate and ice cream.

“That approach gave us the capacity to deliver very hydrophobic drugs that cannot be delivered through water-based systems,” Kirtane says. “It also allowed us to make these formulations with a really wide range of textures.”

The researchers explored several types of plant-derived oils, including sesame oil, cottonseed oil, and flaxseed oil. They combined the oils with edible gelling agents such as beeswax and rice bran wax, and found that they could achieve different textures depending on the concentration and type of oil and gelling agent. Some gels end up with a texture similar to that of a thick beverage, like a protein shake, while others are more like yogurt or pudding.

To identify the gels that were the most palatable, the researchers worked with Sensory Spectrum, a consulting firm that specializes in consumer sensory experiences. Working with the company’s panels of professionally trained tasters, the researchers found that the most appealing gels included those made from oils that had a neutral flavor (such as cottonseed oil) or a slightly nutty flavor (like sesame oil).

Delivering many drugs

The researchers chose to test their gels with three water-insoluble drugs drawn from the World Health Organization’s list of essential medicines for children: praziquantel, used to treat parasitic infections; lumefantrine, used to treat malaria; and azithromycin, used to treat bacterial infections.

“Based on that list, infectious diseases really stood out in terms of what a country needs to protect its children,” Kirtane says. “A lot of the work that we did in this study was focused on infectious disease medications, but from a formulation standpoint, it doesn’t matter what drug we put into these systems.”

For each of those drugs, the researchers found that oleogels were able to deliver doses equal to or higher than the amounts that can be absorbed from tablets, in tests in animals. The researchers also showed that a water-soluble drug, an antibiotic called moxifloxacin hydrochloride, could be successfully delivered by an oleogel.

To make it possible to use these formulations in areas that may not have refrigeration available, the researchers designed them so that they can be stable at 40 degrees Celsius (104 degrees Fahrenheit) for several weeks, and even up to 60 C (140 F) for one week. Such high temperatures are uncommon but could be reached when drugs are being transported by trucks without refrigeration.

The researchers have obtained FDA approval to run a phase I clinical trial of their olegel formulation of azithromycin, which they hope to start running at the Brigham and Women’s Hospital Center for Clinical Investigation within the next few months.

To store and deliver the drugs, the researchers also designed a dispenser similar to a squeezable yogurt package, with compartments that can be used to separate doses. This could make it easier to deliver the right dosage for each child, depending on their weight.

Other authors of the paper include Dylan Freitas, Katelyn Booz, Dao Thi Hong Le, Tiffany Hua, Stephen Scala, Aaron Lopes, Kaitlyn Hess, Joy Collins, Siddharta Tamang, Keiko Ishida, Johannes Kuosmanen, Netra Unni Rajesh, Nhi Phan, Junwei Li, Annlyse Krogmann, Jochen Lennerz, Alison Hayward, and Robert Langer.

The research was funded by the Bill and Melinda Gates Foundation, a PhRMA Foundational postdoctoral fellowship, a Fulbright scholarship, and the Koch Institute Support (core) Grant from the National Cancer Institute.

Colloids are tiny particles, a few nanometres to a few microns in size. They consist of a collection of molecules and can have different properties depending on the material they are made of. “Under certain circumstances colloids can behave like atoms and molecules, but their interactions are less strong,” Rossi explains. “That makes them promising building blocks for new materials, for example for interactive materials that can adapt their properties to their environment.”

New way of materials design

If left alone, the cube-shaped colloids from this study, which are made from glass, will assemble themselves into simple structures like distorted cubic and hexagonal lattices. But instead of going immediately from the building block to the final structure, the researchers took small groups of colloids and combined them into bigger building blocks. When they assembled these clusters of colloids, they ended up with a different final structure with different material properties than the self-assembled structure. “From a chemistry point of view, we always focus on how we can produce a certain type of colloid,” Rossi says. “In this study, we’ve shifted our focus to: how can we use the colloids that are already available to make interesting building blocks?”

A step forward

According to Rossi and her collaborator Greg van Anders, one of the ultimate goal of their research community is to design complex colloidal structures on demand. “What we found here is very important, because for possible applications, we need to have procedures that can be scaled up which is something that will be hard to achieve with most currently available approaches.” “The basic ability to pre-assemble identical pieces from different building blocks, and have them make the same structure, or to take the same building block and pre-assemble different pieces that make different structures, are really the basic ‘chess moves’ for engineering complex structures,” adds van Anders.

Although Rossi studies the fundamental aspects rather than the application of materials design, she can envision eventual applications for this specific work: “We found that the density of the structure that we prepared was much lower than the density of the structure you would obtain by using the starting building blocks. So you can think about strong but lightweight materials for transportation.”

Teaming up

After Rossi’s team built clusters of colloids in the lab, they relied on the team of Greg van Anders from Queen’s University to build the final structure out of pre-assembled clusters with a computer simulation. “With these kinds of projects, it’s great to be able to team up with others who can run simulations, not only to understand what’s happening in depth, but also to test how big the chance of a successful lab experiment will be,” Rossi explains. “And in this case, we got very convincing results that we were understanding the design process well and that the resulting material can be useful.”

The next step will be to actually build the final structure made from the groups of colloids in the lab. “After seeing these results, I’m confident that it can be done,” says Rossi. “It would be great to have a physical version of this material and hold it in my hand.”

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