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Using fMRI, new vision study finds promising model for restoring cone function

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Using fMRI, new vision study finds promising model for restoring cone function


In the retinas of human eyes, the cones are photoreceptor cells responsible for color vision, daylight vision, and the perception of small details. As vision scientists from the Division of Experimental Retinal Therapies at the University of Pennsylvania School of Veterinary Medicine, Gustavo D. Aguirre and William A. Beltran have been working for decades to identify the basis of inherited retinal diseases. They previously showed they could recover missing cone function by reintroducing a copy of the normal gene in photoreceptor cells.

Both humans and dogs are affected by retinal disease, and a new study of daylight vision using a canine model offers a critical insight for evaluating “whether these cell replacements — where we are introducing cones into the retinas of these dogs — is a successful approach for restoring cone vision,” says Beltran, the Corinne R. and Henry Bower Endowed Professor of Ophthalmology.

He and Gustavo Aguirre teamed with researchers including cognitive neuroscientist Geoffrey K. Aguirre, a professor of neurology at the Perelman School of Medicine, bringing together knowledge on the retinal system and brain measurements. In dogs with three different kinds of naturally occurring retinal disease and in dogs with normal vision, the scientists used functional magnetic resonance imaging (fMRI) to assess brain responses to lights that stimulate only the cone cells.

The researchers found that fMRI can detect brain responses to daylight vision for black and white information as well as color information, and it can identify the area of the visual cortex that responds to stimulation of a region in the dog retina that is rich in cones and similar to the human fovea. They also found they can use fMRI to measure the relative degree of loss of daylight vision. Using this technique in animals with a retinal disease caused by a mutation in a gene called NPHP5, they demonstrated that gene augmentation therapy restored the response in the cortex to black and white stimulation. That makes this disease a promising one in which to study photoreceptor cell replacement as a treatment in the future.

Their findings were published in Translational Vision Science & Technology. The other co-authors are Huseyin O. Taskin, a former research specialist at Penn in the GKAguirre Lab and current graduate student at the University of Toronto, and Jacqueline Wivel, a veterinary technician.

“Canine models are useful for studying retinal diseases because they have a variety of different naturally occurring genetic disorders. The ultimate goal is to first demonstrate that these disorders can be treated in canines before translating it to human patients,” says Taskin, the first author. Gustavo Aguirre says, “The hope is that successful therapeutic approaches in people will then become available to veterinarians so that they can benefit man’s four-legged friend.”

Geoffrey Aguirre says, “The purpose of the study was to see, in different versions of these retinal diseases, how much information about daylight vision makes it to the visual system in these dogs.” This knowledge is particularly useful, he says, because figuring out whether a treatment for retinal disease has been effective requires knowing how much vision function was present prior to treatment.

Beltran says this paper shows that gene therapy can recover cone function because it looks at an animal model with no cone function and shows an improvement. He explains that, in the disease caused by the NPHP5 mutation, cones are present but not functional. Animals with this disease are born day-blind but initially have some night vision, though rods — photoreceptors that allow night vision — die over a period of months, making dogs fully blind within a year.

Previous research has measured responses to stimuli through electroretinography and visual behavior tests, which Beltran says can require weeks if not months of dog training. Geoffrey Aguirre says the use of fMRI in this study is significant because it is faster and easier than measuring behavior, and it is not invasive. Taskin also notes that neither visual behavior tests nor electroretinography provide certainty as to what happens in the visual cortex.

A prior study showed that retinal gene therapy in a type of blinding disorder called Leber congential amaurosis is associated with restoration of fMRI responses from the canine visual cortex, but the nature of that study meant that both rod and cone responses could have contributed to cortical activity. The new study furthers knowledge of retinal disease by specifically stimulating the cones.

Huseyin O. Taskin is a former research specialist in the Department of Neurology at the Perelman School of Medicine and a current doctoral candidate in medical sciences at the University of Toronto.

Jacqueline Wivel is a certified veterinary technician in the University of Pennsylvania School of Veterinary Medicine.

Gustavo D. Aguirre is professor of medical genetics and ophthalmology in Penn Vet’s Department of Clinical Sciences & Advanced Medicine.

William A. Beltran is the Corinne R. and Henry Bower Endowed Professor of Ophthalmology and director of the Division of Experimental Retinal Therapies in Penn Vet’s Department of Clinical Sciences & Advanced Medicine.

Geoffrey K. Aguirre is professor of neurology, associate director of the Penn Center for Neuroscience and Society, and associate director of neurology residency in the Department of Neurology at Penn Medicine.

This study was supported by the National Eye Institute (grants R24-EY029890, RO1-EY006855, RO1-EY017549, and P30-EY001583), Fighting Blindness Canada Vision 20/20, The Foundation Fighting Blindness, and the Low Vision Research Award from the Research to Prevent Blindness / Lions Clubs 25 International Foundation.



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Early dark energy could resolve cosmology’s two biggest puzzles

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A new study by MIT physicists proposes that a mysterious force known as early dark energy could solve two of the biggest puzzles in cosmology and fill in some major gaps in our understanding of how the early universe evolved.

One puzzle in question is the “Hubble tension,” which refers to a mismatch in measurements of how fast the universe is expanding. The other involves observations of numerous early, bright galaxies that existed at a time when the early universe should have been much less populated.

Now, the MIT team has found that both puzzles could be resolved if the early universe had one extra, fleeting ingredient: early dark energy. Dark energy is an unknown form of energy that physicists suspect is driving the expansion of the universe today. Early dark energy is a similar, hypothetical phenomenon that may have made only a brief appearance, influencing the expansion of the universe in its first moments before disappearing entirely.

Some physicists have suspected that early dark energy could be the key to solving the Hubble tension, as the mysterious force could accelerate the early expansion of the universe by an amount that would resolve the measurement mismatch.

The MIT researchers have now found that early dark energy could also explain the baffling number of bright galaxies that astronomers have observed in the early universe. In their new study, reported in the Monthly Notices of the Royal Astronomical Society, the team modeled the formation of galaxies in the universe’s first few hundred million years. When they incorporated a dark energy component only in that earliest sliver of time, they found the number of galaxies that arose from the primordial environment bloomed to fit astronomers’ observations.

You have these two looming open-ended puzzles,” says study co-author Rohan Naidu, a postdoc in MIT’s Kavli Institute for Astrophysics and Space Research. “We find that in fact, early dark energy is a very elegant and sparse solution to two of the most pressing problems in cosmology.”

The study’s co-authors include lead author and Kavli postdoc Xuejian (Jacob) Shen, and MIT professor of physics Mark Vogelsberger, along with Michael Boylan-Kolchin at the University of Texas at Austin, and Sandro Tacchella at the University of Cambridge.

Big city lights

Based on standard cosmological and galaxy formation models, the universe should have taken its time spinning up the first galaxies. It would have taken billions of years for primordial gas to coalesce into galaxies as large and bright as the Milky Way.

But in 2023, NASA’s James Webb Space Telescope (JWST) made a startling observation. With an ability to peer farther back in time than any observatory to date, the telescope uncovered a surprising number of bright galaxies as large as the modern Milky Way within the first 500 million years, when the universe was just 3 percent of its current age.

“The bright galaxies that JWST saw would be like seeing a clustering of lights around big cities, whereas theory predicts something like the light around more rural settings like Yellowstone National Park,” Shen says. “And we don’t expect that clustering of light so early on.”

For physicists, the observations imply that there is either something fundamentally wrong with the physics underlying the models or a missing ingredient in the early universe that scientists have not accounted for. The MIT team explored the possibility of the latter, and whether the missing ingredient might be early dark energy.

Physicists have proposed that early dark energy is a sort of antigravitational force that is turned on only at very early times. This force would counteract gravity’s inward pull and accelerate the early expansion of the universe, in a way that would resolve the mismatch in measurements. Early dark energy, therefore, is considered the most likely solution to the Hubble tension.

Galaxy skeleton

The MIT team explored whether early dark energy could also be the key to explaining the unexpected population of large, bright galaxies detected by JWST. In their new study, the physicists considered how early dark energy might affect the early structure of the universe that gave rise to the first galaxies. They focused on the formation of dark matter halos — regions of space where gravity happens to be stronger, and where matter begins to accumulate.

“We believe that dark matter halos are the invisible skeleton of the universe,” Shen explains. “Dark matter structures form first, and then galaxies form within these structures. So, we expect the number of bright galaxies should be proportional to the number of big dark matter halos.”

The team developed an empirical framework for early galaxy formation, which predicts the number, luminosity, and size of galaxies that should form in the early universe, given some measures of “cosmological parameters.” Cosmological parameters are the basic ingredients, or mathematical terms, that describe the evolution of the universe.

Physicists have determined that there are at least six main cosmological parameters, one of which is the Hubble constant — a term that describes the universe’s rate of expansion. Other parameters describe density fluctuations in the primordial soup, immediately after the Big Bang, from which dark matter halos eventually form.

The MIT team reasoned that if early dark energy affects the universe’s early expansion rate, in a way that resolves the Hubble tension, then it could affect the balance of the other cosmological parameters, in a way that might increase the number of bright galaxies that appear at early times. To test their theory, they incorporated a model of early dark energy (the same one that happens to resolve the Hubble tension) into an empirical galaxy formation framework to see how the earliest dark matter structures evolve and give rise to the first galaxies.

“What we show is, the skeletal structure of the early universe is altered in a subtle way where the amplitude of fluctuations goes up, and you get bigger halos, and brighter galaxies that are in place at earlier times, more so than in our more vanilla models,” Naidu says. “It means things were more abundant, and more clustered in the early universe.”

“A priori, I would not have expected the abundance of JWST’s early bright galaxies to have anything to do with early dark energy, but their observation that EDE pushes cosmological parameters in a direction that boosts the early-galaxy abundance is interesting,” says Marc Kamionkowski, professor of theoretical physics at Johns Hopkins University, who was not involved with the study. “I think more work will need to be done to establish a link between early galaxies and EDE, but regardless of how things turn out, it’s a clever — and hopefully ultimately fruitful — thing to try.”

We demonstrated the potential of early dark energy as a unified solution to the two major issues faced by cosmology. This might be an evidence for its existence if the observational findings of JWST get further consolidated,” Vogelsberger concludes. “In the future, we can incorporate this into large cosmological simulations to see what detailed predictions we get.”

This research was supported, in part, by NASA and the National Science Foundation.



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Plant-derived secondary organic aerosols can act as mediators of plant-plant interactions

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A new study published in Science reveals that plant-derived secondary organic aerosols (SOAs) can act as mediators of plant-plant interactions. This research was conducted through the cooperation of chemical ecologists, plant ecophysiologists and atmospheric physicists at the University of Eastern Finland.

It is well known that plants release volatile organic compounds (VOCs) into the atmosphere when damaged by herbivores. These VOCs play a crucial role in plant-plant interactions, whereby undamaged plants may detect warning signals from their damaged neighbours and prepare their defences. “Reactive plant VOCs undergo oxidative chemical reactions, resulting in the formation of secondary organic aerosols (SOAs). We wondered whether the ecological functions mediated by VOCs persist after they are oxidated to form SOAs,” said Dr. Hao Yu, formerly a PhD student at UEF, but now at the University of Bern.

The study showed that Scots pine seedlings, when damaged by large pine weevils, release VOCs that activate defences in nearby plants of the same species. Interestingly, the biological activity persisted after VOCs were oxidized to form SOAs. The results indicated that the elemental composition and quantity of SOAs likely determines their biological functions.

“A key novelty of the study is the finding that plants adopt subtly different defence strategies when receiving signals as VOCs or as SOAs, yet they exhibit similar degrees of resistance to herbivore feeding,” said Professor James Blande, head of the Environmental Ecology Research Group. This observation opens up the possibility that plants have sophisticated sensing systems that enable them to tailor their defences to information derived from different types of chemical cue.

“Considering the formation rate of SOAs from their precursor VOCs, their longer lifetime compared to VOCs, and the atmospheric air mass transport, we expect that the ecologically effective distance for interactions mediated by SOAs is longer than that for plant interactions mediated by VOCs,” said Professor Annele Virtanen, head of the Aerosol Physics Research Group. This could be interpreted as plants being able to detect cues representing close versus distant threats from herbivores.

The study is expected to open up a whole new complex research area to environmental ecologists and their collaborators, which could lead to new insights on the chemical cues structuring interactions between plants.



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Folded or cut, this lithium-sulfur battery keeps going

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Using fMRI, new vision study finds promising model for restoring cone function


Most rechargeable batteries that power portable devices, such as toys, handheld vacuums and e-bikes, use lithium-ion technology. But these batteries can have short lifetimes and may catch fire when damaged. To address stability and safety issues, researchers reporting in ACS Energy Letters have designed a lithium-sulfur (Li-S) battery that features an improved iron sulfide cathode. One prototype remains highly stable over 300 charge-discharge cycles, and another provides power even after being folded or cut.

Sulfur has been suggested as a material for lithium-ion batteries because of its low cost and potential to hold more energy than lithium-metal oxides and other materials used in traditional ion-based versions. To make Li-S batteries stable at high temperatures, researchers have previously proposed using a carbonate-based electrolyte to separate the two electrodes (an iron sulfide cathode and a lithium metal-containing anode). However, as the sulfide in the cathode dissolves into the electrolyte, it forms an impenetrable precipitate, causing the cell to quickly lose capacity. Liping Wang and colleagues wondered if they could add a layer between the cathode and electrolyte to reduce this corrosion without reducing functionality and rechargeability.

The team coated iron sulfide cathodes in different polymers and found in initial electrochemical performance tests that polyacrylic acid (PAA) performed best, retaining the electrode’s discharge capacity after 300 charge-discharge cycles. Next, the researchers incorporated a PAA-coated iron sulfide cathode into a prototype battery design, which also included a carbonate-based electrolyte, a lithium metal foil as an ion source, and a graphite-based anode. They produced and then tested both pouch cell and coin cell battery prototypes.

After more than 100 charge-discharge cycles, Wang and colleagues observed no substantial capacity decay in the pouch cell. Additional experiments showed that the pouch cell still worked after being folded and cut in half. The coin cell retained 72% of its capacity after 300 charge-discharge cycles. They next applied the polymer coating to cathodes made from other metals, creating lithium-molybdenum and lithium-vanadium batteries. These cells also had stable capacity over 300 charge-discharge cycles. Overall, the results indicate that coated cathodes could produce not only safer Li-S batteries with long lifespans, but also efficient batteries with other metal sulfides, according to Wang’s team.

The authors acknowledge funding from the National Natural Science Foundation of China; the Natural Science Foundation of Sichuan, China; and the Beijing National Laboratory for Condensed Matter Physics.



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