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New Tech Assigns More Accurate “time of Death” to Cells

Carly Russell

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SAN FRANCISCO, CA–December 8, 2021–It’s surprisingly hard to tell when a brain cell is dead. Neurons that appear inactive and fragmented under the microscope can persist in a kind of life-or-death limbo for days, and some suddenly begin signaling again after appearing inert. For researchers who study neurodegeneration, this lack of a precise “time of death” declaration for neurons makes it hard to pin down what factors lead to cell death and to screen drugs that might save aging cells from dying.

SAN FRANCISCO, CA–December 8, 2021–It’s surprisingly hard to tell when a brain cell is dead. Neurons that appear inactive and fragmented under the microscope can persist in a kind of life-or-death limbo for days, and some suddenly begin signaling again after appearing inert. For researchers who study neurodegeneration, this lack of a precise “time of death” declaration for neurons makes it hard to pin down what factors lead to cell death and to screen drugs that might save aging cells from dying.

Now, researchers at Gladstone Institutes have developed a new technology that lets them track thousands of cells at a time and determine the precise moment of death for any cell in the group. The team showed, in a paper published in the journal Nature Communications, that the approach works in rodent and human cells as well as within live zebrafish, and can be used to follow the cells over a period of weeks to months.

“Getting a precise time of death is very important for unraveling cause and effect in neurodegenerative diseases,” says Steve Finkbeiner, MD, PhD, director of the Center for Systems and Therapeutics at Gladstone and senior author of both new studies. “It lets us figure out which factors are directly causing cell death, which are incidental, and which might be coping mechanisms that delay death.”

In a companion paper published in the journal Science Advances, the researchers combined the cell sensor technology with a machine learning approach, teaching a computer how to distinguish live and dead cells 100 times faster and more accurately than a human.

“It took college students months to analyze these kind of data by hand, and our new system is nearly instantaneous–it actually runs faster than we can acquire new images on the microscope,” says Jeremy Linsley, PhD, a scientific program leader in Finkbeiner’s lab and the first author of both new papers.

Teaching an Old Sensor New Tricks

When cells die–whatever the cause or mechanism–they eventually become fragmented and their membranes degenerate. But this degradation process takes time, making it difficult for scientists to distinguish between cells that have long since stopped functioning, those that are sick and dying, and those that are healthy.

Researchers typically use fluorescent tags or dyes to follow diseased cells with a microscope over time and try to diagnose where they are within this degradation process. Many indicator dyes, stains, and labels have been developed to distinguish the already dead cells from those that are still alive, but they often only work over short periods of time before fading and can also be toxic to the cells when they are applied.

“We really wanted an indicator that lasts for a cell’s whole lifetime–not just a few hours–and then gives a clear signal only after the specific moment the cell dies,” says Linsley.

Linsley, Finkbeiner, and their colleagues co-opted calcium sensors, originally designed to track levels of calcium inside a cell. As a cell dies and its membranes become leaky, one side effect is that calcium rushes into the cell’s watery cytosol, which normally has relatively low levels of calcium.

So, Linsley engineered the calcium sensors to reside in the cytosol, where they would fluoresce only when calcium levels increased to a level that indicates cell death. The new sensors, known as genetically encoded death indicator (GEDI, pronounced like Jedi in Star Wars), could be inserted into any type of cell and signal that the cell is alive or dead over the cell’s entire lifetime.

To test the utility of the redesigned sensors, the group placed large groups of neurons–each containing GEDI–under the microscope. After visualizing more than a million cells, in some cases prone to neurodegeneration and in others exposed to toxic compounds, the researchers found that the GEDI sensor was far more accurate than other cell death indicators: there wasn’t a single case where the sensor was activated and a cell remained alive. Moreover, in addition to that accuracy, GEDI also seemed to detect cell death at an earlier stage than previous methods–close to the “point of no return” for cell death.

“This allows you to separate live and dead cells in a way that’s never been possible before,” says Linsley.

Superhuman Death Detection

Linsley mentioned GEDI to his brother–Drew Linsley, PhD, an assistant professor at Brown University who specializes in applying artificial intelligence to large-scale biological data. His brother suggested that the researchers use the sensor, coupled with a machine learning approach, to teach a computer system to recognize live and dead brain cells based only on the form of the cell.

The team coupled results from the new sensor with standard fluorescence data on the same neurons, and they taught a computer model, called BO-CNN, to recognize the typical fluorescence patterns associated with what dying cells look like. The model, the Linsley brothers showed, was 96 percent accurate and better than what human observers can do, and was more than 100 times faster than previous methods of differentiating live and dead cells.

“For some cell types, it’s extremely difficult for a person to pick up on whether a cell is alive or dead–but our computer model, by learning from GEDI, was able to differentiate them based on parts of the images we had not previously known were helpful in distinguishing live and dead cells,” says Jeremy Linsley.

Both GEDI and BO-CNN will now allow the researchers to carry out new, high-throughput studies to discover when and where brain cells die–a very important endpoint for some of the most important diseases. They can also screen drugs for their ability to delay or avoid cell death in neurodegenerative diseases. Or, in the case of cancer, they can search for drugs that hasten the death of diseased cells.

“These technologies are game changers in our ability to understand where, when, and why death occurs in cells,” says Finkbeiner. “For the first time, we can truly harness the speed and scale provided by advances in robot-assisted microscopy to more accurately detect cell death, and do so well in advance of the moment of death. We hope this can lead to more specific therapeutics for many neurodegenerative diseases that have been so far uncurable.”

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About the Studies

The paper “Genetically encoded cell-death indicators (GEDI) to detect an early irreversible commitment to neurodegeneration” was published by the journal Nature Communications on September 6, 2021. Other authors are Kevan Shah, Nicholas Castello, Michelle Chan, Dominic Haddad, Jay Mancini, Viral Oza, Shijie Wang, and Ashkan Javaherian of Gladstone; and David Kokel of UC San Francisco. The work at Gladstone was supported by the National Institutes of Health (U54 NS191046, R37 NS101996, RF1 AG058476, RF1 AG056151, RF1 AG058447, P01 AG054407, U01 MH115747), the National Library of Medicine (R01 LM013617), the Koret Foundation, the Taube/Koret Center for Neurodegenerative Research, and the National Center for Research Resources (RR18928).

The paper “Superhuman cell death detection with biomarker-optimized neural networks” was published by the journal Science Advances on December 8, 2021. Other authors are Josh Lamstein, Gennadi Ryan, Kevan Shah, Nicholas Castello, Viral Oza, Jaslin Kaira, Shijie Wang, Zachary Tokuno, and Ashkan Javaherian of Gladstone; and Drew Linsley and Thomas Serre of Brown University. The work at Gladstone was supported by the National Institutes of Health (U54 NS191046, R37 NS101996, RF1 AG058476, RF1 AG056151, RF1 AG058447, P01 AG054407, U01 MH115747), the National Library of Medicine (R01 LM013617), the Koret Foundation, the Taube/Koret Center for Neurodegenerative Research, the National Center for Research Resources (RR18928), the Target ALS Foundation, the Amyotrophic Lateral Sclerosis Association Neuro Collaborative, Mike Frumkin, and the Department of Defense (W81XWH-13-ALSRP-TIA).

About Gladstone Institutes

To ensure our work does the greatest good, Gladstone Institutes focuses on conditions with profound medical, economic, and social impact–unsolved diseases. Gladstone is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. It has an academic affiliation with the University of California, San Francisco.

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Original Post: bioengineer.org

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UNLV Research: No, the Human Brain Did Not Shrink 3,000 Years Ago

Carly Russell

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Did the 12th century B.C.E. — a time when humans were forging great empires and developing new forms of written text — coincide with an evolutionary reduction in brain size? Think again, says a UNLV-led team of researchers who refute a hypothesis that’s growing increasingly popular among the science community.

Did the 12th century B.C.E. — a time when humans were forging great empires and developing new forms of written text — coincide with an evolutionary reduction in brain size? Think again, says a UNLV-led team of researchers who refute a hypothesis that’s growing increasingly popular among the science community.

Last year, a group of scientists made headlines when they concluded that the human brain shrank during the transition to modern urban societies about 3,000 years ago because, they said, our ancestors’ ability to store information externally in social groups decreased our need to maintain large brains. Their hypothesis, which explored decades-old ideas on the evolutionary reduction of modern human brain size, was based on a comparison to evolutionary patterns seen in ant colonies.

Not so fast, said UNLV anthropologist Brian Villmoare and Liverpool John Moores University scientist Mark Grabowski.

In a new paper published last week in Frontiers in Ecology and Evolution, the UNLV-led team  analyzed the dataset that the research group from last year’s study used and dismissed their findings.

“We were struck by the implications of a substantial reduction in modern human brain size at roughly 3,000 years ago, during an era of many important innovations and historical events — the appearance of Egypt’s New Kingdom, the development of Chinese script, the Trojan War, and the emergence of the Olmec civilization, among many others,” Villmoare said. 

“We re-examined the dataset from DeSilva et al. and found that human brain size has not changed in 30,000 years, and probably not in 300,000 years,” Villmoare said. “In fact, based on this dataset, we can identify no reduction in brain size in modern humans over any time-period since the origins of our species.” 

Key Takeaways

The UNLV research team questioned several of the hypotheses that DeSilva et. al gleaned from a dataset of nearly 1,000 early human fossil and museum specimens, including:

The UNLV team says the rise of agriculture and complex societies occurred at different times around the globe — meaning there should be variation in timing of skull changes seen in different populations. However, DeSilva’s dataset sampled only 23 crania from the timeframe critical to the brain shrinkage hypothesis and lumped together specimens from locations including England, China, Mali, and Algeria. 
The dataset is heavily skewed because more than half of the 987 skulls examined represent only the last 100 years of a 9.8-million-year span of time — and therefore don’t give scientists a good idea of how much cranial size has changed over time. 
Multiple hypotheses on causes of reduction in modern human brain size need to be reassessed if human brains haven’t actually changed in size since the arrival of our species.

Publication Details

“Did the transition to complex societies in the Holocene drive a reduction in brain size? A reassessment of the DeSilva et al. (2021) hypothesis” was published July 29 in Frontiers in Ecology and Evolution.

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Growing Cereal Crops With Less Fertilizer

Carly Russell

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Researchers at the University of California, Davis, have found a way to reduce the amount of nitrogen fertilizers needed to grow cereal crops. The discovery could save farmers in the United States billions of dollars annually in fertilizer costs while also benefiting the environment.

Researchers at the University of California, Davis, have found a way to reduce the amount of nitrogen fertilizers needed to grow cereal crops. The discovery could save farmers in the United States billions of dollars annually in fertilizer costs while also benefiting the environment.

The research comes out of the lab of Eduardo Blumwald, a distinguished professor of plant sciences, who has found a new pathway for cereals to capture the nitrogen they need to grow.

The discovery could also help the environment by reducing nitrogen pollution, which can lead to contaminated water resources, increased greenhouse gas emissions and human health issues. The study was published in the journal Plant Biotechnology.

Nitrogen is key to plant growth, and agricultural operations depend on chemical fertilizers to increase productivity. But much of what is applied is lost, leaching into soils and groundwater. Blumwald’s research could create a sustainable alternative.

“Nitrogen fertilizers are very, very expensive,” Blumwald said. “Anything you can do to eliminate that cost is important. The problem is money on one side, but there are also the harmful effects of nitrogen on the environment.”

Blumwald’s research centers on increasing the conversion of nitrogen gas in the air into ammonium by soil bacteria — a process known as nitrogen fixation.

Legumes such as peanuts and soybeans have root nodules that can use nitrogen-fixing bacteria to provide ammonium to the plants. Cereal plants like rice and wheat don’t have that capability and must rely on taking in inorganic nitrogen, such as ammonia and nitrate, from fertilizers in the soil.

“If a plant can produce chemicals that make soil bacteria fix atmospheric nitrogen gas, we could modify the plants to produce more of these chemicals,” Blumwald said. “These chemicals will induce soil bacterial nitrogen fixation and the plants will use the ammonium formed, reducing the amount of fertilizer used.”

Blumwald’s team used chemical screening and genomics to identify compounds in rice plants that enhanced the nitrogen-fixing activity of the bacteria.

Then they identified the pathways generating the chemicals and used gene editing technology to increase the production of compounds that stimulated the formation of biofilms. Those biofilms contain bacteria that enhanced nitrogen conversion. As a result, nitrogen-fixing activity of the bacteria increased, as did the amount of ammonium in the soil for the plants.

“Plants are incredible chemical factories,” he said. “What this could do is provide a sustainable alternative agricultural practice that reduces the use of excessive nitrogen fertilizers.”

The pathway could also be used by other plants. A patent application on the technique has been filed by the University of California and is pending.  

Dawei Yan, Hiromi Tajima, Howard-Yana Shapiro, Reedmond Fong and Javier Ottaviani from UC Davis contributed to the research paper, as did Lauren Cline from Bayer Crop Science. Ottaviani is also a research associate at Mars Edge.

The research was funded by the Will W. Lester Endowment. Bayer Crop Science is supporting further research on the topic.

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Illinois Tech ‘spinout’ Startup Influit Energy Has Created the World’s First Rechargeable, Safe, Electric Fuel

Carly Russell

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CHICAGO, Aug. 5, 20222—It was only a matter of time—before Influit Energy would need to hire more scientists, before the 2,100-square-foot lab space that the company occupies in Chicago’s West Loop neighborhood would grow too small, and before the three co-founders of the startup whose history is inextricably linked to Illinois Institute of Technology would be ready to publicly disclose what they have created: the world’s first rechargeable, safe, electric fuel.

CHICAGO, Aug. 5, 20222—It was only a matter of time—before Influit Energy would need to hire more scientists, before the 2,100-square-foot lab space that the company occupies in Chicago’s West Loop neighborhood would grow too small, and before the three co-founders of the startup whose history is inextricably linked to Illinois Institute of Technology would be ready to publicly disclose what they have created: the world’s first rechargeable, safe, electric fuel.

“We have created a new type of flow battery that is predicated upon a composite material that we invented, which is a nanofluid where the nanoparticles are battery-active materials, which we called nanoelectrofuel, or NEF,” says John Katsoudas (M.S. PHYS ’03), co-founder and CEO of Influit Energy. “All of the technology has come together—we have a crystal-clear path before us.”

Katsoudas calls Influit Energy a “spinout” of Illinois Tech. Leading the company alongside him are two co-founders: Elena Timofeeva, chief operating officer, director of research and development, and a research associate professor of chemistry at Illinois Tech, and Carlo Segre, chief technology officer, chief financial officer, and a professor of physics at Illinois Tech. Segre is also director of the Center for Synchrotron Radiation Research and Instrumentation at Illinois Tech, which operates two sectors of the Advanced Photon Source at Argonne National Laboratory, a resource that Influit Energy occasionally utilizes.

“[Influit Energy’s research] started back in 2009 as a basic science investigation when we were at Illinois Tech and Argonne National Laboratory, and we have taken our technology from basic science development, to applied science, to building prototypes, and now our first product development,” Katsoudas says.

The United States government has also played a critical role in Influit Energy’s growth, awarding the company more than $10 million in contracts to fund the design and fabrication of NEF flow battery prototypes that will allow several agencies to utilize Influit Energy’s batteries in electric vehicles and aircraft.

“The unique high-energy density liquid format of the NEF flow batteries allows use of the same fluids in different devices, meaning fluid, charged at the recharging station from renewable energy sources or a grid, can be used to rapidly refuel vehicles, or for stationary storage and other large portable applications,” Timofeeva says. “Discharged fluid can be returned to a recharge/refuel station for recharging or be charged inside the device by plugging into the power source.”

The company’s current client roster includes NASA, the U.S. Department of Defense’s Defense Advanced Research Project Agency (DARPA), and two grant-awarding programs operated by the U.S. Air Force: AFWERX, a team of innovators fostering collaborations across the military, academia, and industry, and the Small Business Innovation Research program (AFRL SBIR).

“We are using multiple small business innovation grants to demonstrate different elements of this closed loop energy ecosystem,” Segre says. “It takes time when you’re trying to do something transformational and new like this, and you have to not overreach, but ultimately, we’re moving toward the same goal—to actually get technology commercialization.”

Five separate projects funded by the government have been strategically designed by Influit Energy to work together as components of a closed loop energy ecosystem that will one day be able to be commercialized more broadly.

“Everything we’re doing right now is geared toward the specific goal of developing what we call the closed-loop energy cycle, whereby your batteries are not solid materials, they are liquids. You can treat the battery as a fuel that gets pumped in to mobility devices—cars, trucks, airplanes, anything that needs to be electrified,” Katsoudas says. “Every one of our contracts is funding a different aspect of the totality development of that ecosystem.”

The fuel utilized by this new system can be charged using either renewable energy or an electrical grid.

“Components of such ecosystems are batteries for devices like cars and electric utility vehicles funded by DARPA as of now; a refueling nozzle and control system, funded by AFWERX; and a charger for fast charging of the fluids, funded by NASA,” Timofeeva says.

Influit Energy has two separate projects underway with DARPA. One is focused on demonstrating the effectiveness of the batteries in a utility electric vehicle, and the other is a study looking at how to optimize and scale up the manufacturing of the NEF batteries. The goal is to reduce the mass and volume of the batteries.

“The fifth project is related to the development of [second-generation nanoelectrofuel] and funded by AFRL SBIR funding,” Timofeeva says. “This new second generation of NEF chemistry in our unique and proprietary nanofluid format will ultimately provide a four-to-five-times increase in energy density compared to state-of-the art [lithium-ion] batteries and could meet Air Force needs and demand with significantly improved energy density, increased operating temperature range, no fire/explosion hazard, and are made of inexpensive, domestically sourced, Earth-abundant materials.”

Because the fluid in the batteries can be recharged in any location using whatever charging mechanisms are available in that market, Katsoudas envisions tremendous growth and opportunity for the use of Influit Energy’s batteries in the future.

“That in a nutshell is what Influit Energy is going after, and every one of the contracts that we have is geared toward,” he says. “[Each of our sponsors are] funding a different section of the vision. The neat thing is that, from Influit Energy’s perspective, they’re funding this complete vision, pieces of it. For [each of the funding agencies], they’re getting a specific pain point addressed that is specific to each of our sponsors, so it’s sort of a win-win-win. And effectively that’s why we’re going to win this—the complete and total electrification of transportation, the electrification of transportation that doesn’t crash the grid, and the distribution of energy that doesn’t cost us to have to rebuild trillions of dollars of infrastructure.”

In June of 2022, the Influit team successfully completed their first NEF flow battery testing for the electric utility vehicle, which was demonstrated at a commercialization partner site. Katsoudas also spoke at the South by Southwest festival and a few academic conferences earlier this year about Influit Energy’s work, and is now in conversation with venture capitalists regarding the future of Influit Energy. As contracts continue to accumulate, the company is hiring new scientists and is actively seeking to expand its square footage—from 2,100 square feet to 20,000—through the acquisition of a new lab space. Where the lab will be located remains to be seen. The co-founders hope to stay in Chicago, but say they are also considering opportunities in Austin, Texas.

ILLINOIS INSTITUTE OF TECHNOLOGY

Illinois Institute of Technology, also known as Illinois Tech, is a private, technology-focused research university. Illinois Tech is the only university of its kind in Chicago, and its Chicago location offers students access to the world-class resources of a great global metropolis. It offers undergraduate and graduate degrees in engineering, science, architecture, business, design, human sciences, applied technology, and law. One of 22 institutions that comprise the Association of Independent Technological Universities, Illinois Tech provides an exceptional education centered on active learning, and its graduates lead the state and much of the nation in economic prosperity. Illinois Tech uniquely prepares students to succeed in professions that require technological sophistication, an innovative mindset, and an entrepreneurial spirit. 

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