“We know that there are a range of immune responses to COVID-19, and the biological processes underlying those responses are not well understood,” said co-first author Jihoon Lee, a graduate student at Fred Hutchinson Cancer Research Center. “We analyzed thousands of biological markers linked to metabolic pathways that underlie the immune system and found some clues as to what immune-metabolic changes may be pivotal in severe disease. Our hope is that these observations of immune function will help others piece together the body’s response to COVID-19. The deeper understanding gained here may eventually lead to better therapies that can more precisely target the most problematic immune or metabolic changes.”

The researchers collected 374 blood samples — two draws per patient during the first week after being diagnosed with SARS-CoV-2 infection — and analyzed their plasma and single immune cells. The analysis included 1,387 genes involved in metabolic pathways and 1,050 plasma metabolites.

In plasma samples, the team found that increased COVID-19 severity is associated with metabolite alterations, suggesting increased immune-related activity. Furthermore, through single-cell sequencing, researchers found that each major immune cell type has a distinct metabolic signature.

“We have found metabolic reprogramming that is highly specific to individual immune cell classes (e.g. “killer” CD8+ T cells, “helper” CD4+ T cells, antibody-secreting B cells, etc.) and even cell subtypes, and the complex metabolic reprogramming of the immune system is associated with the plasma global metabolome and are predictive of disease severity and even patient death,” said co-first and co-corresponding author Dr. Yapeng Su, a research scientist at Institute for Systems Biology. “Such deep and clinically relevant insights on sophisticated metabolic reprogramming within our heterogeneous immune systems are otherwise impossible to gain without advanced single-cell multi-omic analysis.”

“This work provides significant insights for developing more effective treatments against COVID-19. It also represents a major technological hurdle,” said Dr. Jim Heath, president and professor of ISB and co-corresponding author on the paper. “Many of the data sets that are collected from these patients tend to measure very different aspects of the disease, and are analyzed in isolation. Of course, one would like these different views to contribute to an overall picture of the patient. The approach described here allows for the sum of the different data sets to be much greater than the parts, and provides for a much richer interpretation of the disease.”

The research was conducted by scientists from ISB, Fred Hutchinson Cancer Research Center, Stanford University, Swedish Medical Center St. John’s Cancer Institute at Saint John’s Health Center, the University of Washington, the Howard Hughes Medical Institute.

Funding for this project comes from Merck and the Biomedical Advanced Research and Development Authority (BARDA), the Wilke Family Foundation, the MJ Murdock Charitable Trust, the Swedish Medical Center Foundation, the Parker Institute for Cancer Immunotherapy, Gilead, Amazon Web Services, and the National Institutes of Health.

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“We have found the first observational evidence that white dwarfs can still undergo stable thermonuclear activity,” explained Jianxing Chen of the Alma Mater Studiorum Università di Bologna and the Italian National Institute for Astrophysics, who led this research. “This was quite a surprise, as it is at odds with what is commonly believed.”

White dwarfs are the slowly cooling stars which have cast off their outer layers during the last stages of their lives. They are common objects in the cosmos; roughly 98% of all the stars in the Universe will ultimately end up as white dwarfs, including our own Sun [1]. Studying these cooling stages helps astronomers understand not only white dwarfs, but also their earlier stages as well.

To investigate the physics underpinning white dwarf evolution, astronomers compared cooling white dwarfs in two massive collections of stars: the globular clusters M3 and M13 [2]. These two clusters share many physical properties such as age and metallicity [3] but the populations of stars which will eventually give rise to white dwarfs are different. In particular, the overall colour of stars at an evolutionary stage known as the Horizontal Branch are bluer in M13, indicating a population of hotter stars. This makes M3 and M13 together a perfect natural laboratory in which to test how different populations of white dwarfs cool.

“The superb quality of our Hubble observations provided us with a full view of the stellar populations of the two globular clusters,” continued Chen. “This allowed us to really contrast how stars evolve in M3 and M13.”

Using Hubble’s Wide Field Camera 3 the team observed M3 and M13 at near-ultraviolet wavelengths, allowing them to compare more than 700 white dwarfs in the two clusters. They found that M3 contains standard white dwarfs which are simply cooling stellar cores. M13, on the other hand, contains two populations of white dwarfs: standard white dwarfs and those which have managed to hold on to an outer envelope of hydrogen, allowing them to burn for longer and hence cool more slowly.

Comparing their results with computer simulations of stellar evolution in M13, the researchers were able to show that roughly 70% of the white dwarfs in M13 are burning hydrogen on their surfaces, slowing down the rate at which they are cooling.

This discovery could have consequences for how astronomers measure the ages of stars in the Milky Way. The evolution of white dwarfs has previously been modelled as a predictable cooling process. This relatively straightforward relationship between age and temperature has led astronomers to use the white dwarf cooling rate as a natural clock to determine the ages of star clusters, particularly globular and open clusters. However, white dwarfs burning hydrogen could cause these age estimates to be inaccurate by as much as 1 billion years.

“Our discovery challenges the definition of white dwarfs as we consider a new perspective on the way in which stars get old,” added Francesco Ferraro of the Alma Mater Studiorum Università di Bologna and the Italian National Institute for Astrophysics, who coordinated the study. “We are now investigating other clusters similar to M13 to further constrain the conditions which drive stars to maintain the thin hydrogen envelope which allows them to age slowly”.

Notes

[1] The Sun is only 4.6 billion years through its roughly 10-billion-year lifetime. Once it exhausts hydrogen in its core, the Sun will swell into a red giant, engulfing the inner planets and searing the Earth’s surface. It will then throw off its outer layers, and the exposed core of the Sun will be left as a slowly cooling white dwarf. This stellar ember will be incredibly dense, packing a large fraction of the mass of the Sun into a roughly Earth-sized sphere.

[2] M3 contains roughly half a million stars and lies in the constellation Canes Venatici. M13 — occasionally known as the Great Globular Cluster in Hercules — contains slightly fewer stars, only several hundred thousand. White dwarfs are often used to estimate the ages of globular clusters, and so a significant amount of Hubble time has been dedicated to exploring white dwarfs in old and densely populated globular clusters. Hubble directly observed white dwarfs in globular star clusters for the first time in 2006.

[3] Astronomers use the word “metallicity” to describe the proportion of a star which is composed of elements other than hydrogen and helium. The vast majority of matter in the Universe is either hydrogen or helium — to take the Sun as an example, 74.9% of its mass is hydrogen, 23.8% is helium, and the remaining 1.3% is a mixture of all the other elements, which astronomers refer to as “metals.”

The Hubble Space Telescope is a project of international cooperation between ESA and NASA.

Now an international team of astronomers, co-led by Laura Sales, an astronomer at the University of California, Riverside, reports in Nature Astronomythat it has used sophisticated simulations to detect a few “quenched” UDGs in low-density environments in the universe. A quenched galaxy is one that does not form stars.

“What we have detected is at odds with theories of galaxy formation since quenched dwarfs are required to be in clusters or group environments in order to get their gas removed and stop forming stars,” said Sales, an associate professor of physics and astronomy. “But the quenched UDGs we detected are isolated. We were able to identify a few of these quenched UDGs in the field and trace their evolution backward in time to show they originated in backsplash orbits.”

Here, “in the field” refers to galaxies isolated in quieter environments and not in a group or cluster environment. Sales explained that a backsplash galaxy is an object that looks like an isolated galaxy today but in the past was a satellite of a more massive system — similar to a comet, which visits our sun periodically, but spends the bulk of its journey in isolation, far from most of the solar system.

“Isolated galaxies and satellite galaxies have different properties because the physics of their evolution is quite different,” she said. “These backsplash galaxies are intriguing because they share properties with the population of satellites in the system to which they once belonged, but today they are observed to be isolated from the system.”

Dwarf galaxies are small galaxies that contain anywhere from 100 million to a few billion stars. In contrast, the Milky Way has 200 billion to 400 billion stars. While all UDGs are dwarf galaxies, all dwarf galaxies are not UDGs. For example, at similar luminosity, dwarfs show a very large range of sizes, from compact to diffuse. UDGs are the tail end of most extended objects at a given luminosity. A UDG has the stellar content of a dwarf galaxy, 10-100 times smaller than the Milky Way. But its size is comparable to the Milky Way, giving it the extremely low surface brightness that makes it special.

Sales explained that the dark matter halo of a dwarf galaxy has a mass at least 10 times smaller than the Milky Way, and the size scales similarly. UDGs, however, break this rule and show a radial extension comparable to that of much larger galaxies.

“One of the popular theories to explain this was that UDGs are ‘failed Milky Ways,’ meaning they were destined to be galaxies like our own Milky Way but somehow failed to form stars,” said José A. Benavides, a graduate student at the Institute of Theoretical and Experimental Astronomy in Argentina and the first author of the research paper. “We now know that this scenario cannot explain all UDGs. So theoretical models are arising where more than one formation mechanism may be able to form these ultradiffuse objects.”

According to Sales, the value of the new work is twofold. First, the simulation used by the researchers, called TNG50, successfully predicted UDGs with characteristics similar to observed UDGs. Second, the researchers found a few rare quenched UDGs for which they have no formation mechanism.

“Using TNG50 as a ‘time machine’ to see how the UDGs got to where they are, we found these objects were satellites several billion years before but got expelled into a very elliptical orbit and look isolated today,” she said.

The researchers also report that according to their simulations, quenched UDGs can commonly make up 25% of an ultradiffuse population of galaxies. In observations, however, this percentage is much smaller.

“This means a lot of dwarf galaxies lurking in the dark may have remained undetected to our telescopes,” Sales said. “We hope our results will inspire new strategies for surveying the low-luminosity universe, which would allow for a complete census of this population of dwarf galaxies.”

The study is the first to resolve the myriad of environments — from isolated dwarfs to dwarfs in groups and clusters — necessary to detect UDGs, and with high-enough resolution to study their morphology and structure.

Next, the research team will continue its study of UDGs in TNG50 simulations to better understand why these galaxies are so extended compared to other dwarf galaxies with the same stellar content. The researchers will use the Keck Telescope in Hawaii, one of the most powerful telescopes in the world, to measure the dark matter content of UDGs in the Virgo cluster, the closest galaxy cluster to Earth.

“Future telescopes, such as the Large Synoptic Survey Telescope or the Roman Space Telescope, come online in the next five to 10 years with capabilities of detecting many more of these intriguing UDGs,” Sales said.

The study was partially funded by a National Science Foundation CAREER award and a NASA Astrophysics Theory Program grant to Sales.

Currently in the early stages of development, the actuator will become a key part of research contributing to the future of robotic, bioelectronic and biomedical science.

“Electrochemical devices that transform electrical energy to mechanical energy have potential use in numerous applications, ranging from soft robotics and micropumps to autofocus microlenses and bioelectronics,” said Mohammad Reza Abidian, associate professor of biomedical engineering in the UH Cullen College of Engineering. He’s the corresponding author of the article “Organic Semiconductor Nanotubes for Electrochemical Devices,” published in the journal Advanced Functional Materials, which details the discovery.

Significant movement (which scientists define as actuation and measure as deformation strain) and fast response time have been elusive goals, especially for electrochemical actuator devices that operate in liquid. This is because the drag force of a liquid restricts an actuator’s motion and limits the ion transportation and accumulation in electrode materials and structures. In Abidian’s lab, he and his team refined methods of working around those two stumbling blocks.

“Our organic semiconductor nanotube electrochemical device exhibits high actuation performance with fast ion transport and accumulation and tunable dynamics in liquid and gel-polymer electrolytes. This device demonstrates an excellent performance, including low power consumption/strain, a large deformation, fast response and excellent actuation stability,” Abidian said.

This outstanding performance, he explained, stems from the enormous effective surface area of the nanotubular structure. The larger area facilitates the ion transport and accumulation, which results in high electroactivity and durability.

“The low power consumption/strain values for this OSNT actuator, even when it operates in liquid electrolyte, mark a profound improvement over previously reported electrochemical actuators operating in liquid and air,” Abidian said. “We evaluated long-term stability. This organic semiconductor nanotube actuator exhibited superior long-term stability compared with previously reported conjugated polymer-based actuators operating in liquid electrolyte.”

Joining Abidian on the project were Mohammadjavad Eslamian, Fereshtehsadat Mirab, Vijay Krishna Raghunathan and Sheereen Majd, all from the Department of Biomedical Engineering at the UH Cullen College of Engineering.

The organic semiconductors used, called conjugated polymers, were discovered in the 1970s by three scientists — Alan J. Heeger, Alan MacDiarmid and Hideki Shirakawa — who won a Nobel prize in 2000 for the discovery and development of conjugated polymers.

For a new type of actuator to outshine the status quo, the end product must prove not only to be highly effective (in this case, in both liquid and gel polymer electrolyte), but also that it can last.

“To demonstrate potential applications, we designed and developed a micron-scale movable neural probe that is based on OSNT microactuators. This microprobe potentially can be implanted in the brain, where neural signal recordings that are adversely affected, by either damaged tissue or displacement of neurons, may be enhanced by adjusting the position of the movable microcantilevers,” said Abidian.

The next step is animal testing, which will be undertaken soon at Columbia University. Early results are expected by the end of 2021, with longer term tests to follow.

“Considering the achievements so far, we anticipate these new OSNT-based electrochemical devices will help advance the next generation of soft robotics, artificial muscles, bioelectronics and biomedical devices,” Abidian said.

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Materials provided by University of Houston. Original written by Sally Strong. Note: Content may be edited for style and length.