Dr. Harvey Pollard and colleagues in their recent paper found that cardiac glycoside drugs like ouabain and digitoxin not only inhibit ACE2 binding to SARS-CoV-2 but also can block penetration of SARS-CoV-2 virus into human lungs cells.
For the SARS-CoV-2 virus to infect a target cell, the Receptor Binding Domain (RBD) on the viral Spike protein must bind to the receptor protein ACE2 on the cell surface. However, fully understanding the factors controlling this binding process is only at an early stage.
Now, Dr. Harvey Pollard and colleagues hypothesized that cardiac glycoside drugs such as ouabain, digitoxin, and digoxin might block the binding reaction between human receptor ACE2 and the Spike (S) protein, and thus block viral penetration into human lung cells. They also tested this hypothesis by developing a biochemical assay for ACE2:Spike binding, and tested cardiac glycosides as inhibitors of binding.
They found that, ACE2 binds with positive cooperatively to Receptor Binding Domain (RBD) protiens. They also found that mutations in the RBD, specifically Mink [Y453F] and UK [N501Y], significantly increased ACE2 binding affinity, while the S.Africa [E484K] mutation trended towards reduction in ACE2 binding affinity.
In addition, they also validated a previous finding that the [D614G] mutation, on a part of the spike S1 protein outside of the RBD, also reduced ACE2 binding affinity to the RBD. Thus the effect of a mutation that enhances infectivity need not necessarily increase the affinity of ACE2 for the RBD.
Furthermore, they measured ACE2 binding to the RBD protein in the presence of digitoxin, digoxin and ouabain, in order to test the ability of cardiac glycosides to inhibit ACE2 binding to the RBD protein. They found evidence that ACE2 binding in the presence of these drugs is reduced significantly. They also found that, out of 3 tested drugs, ouabainmost potently block viral penetration into human lung cells, likely at a very early stage of the entry process. It is followed by digitoxin. But, digoxin was unable to block SARS-CoV-2 Spike pseudotyped virus penetration into human lung cells.
Finally, they suggested that, these drugs are widely available, and are clinically safe for those with normal hearts, so these inexpensive drugs could be repurposed for anti-COVID-19 therapy.
Reference: Hung Caohuy, Ofer Eidelman, Tinghua Chen, Qingfeng Yang, Alakesh Bera, Nathan Walton, Harvey B. Pollard, “Common cardiac medications potently inhibit ACE2 binding to the SARS-CoV-2 Spike, and block virus penetration into human lung cells”, bioRxiv 2021.06.02.446343; doi: https://doi.org/10.1101/2021.06.02.446343
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New research from MSU shows that an infant’s gut microbiome could contain clues to help monitor and support healthy neurological development
Why do some babies react to perceived danger more than others? According to new research from Michigan State University and the University of North Carolina, Chapel Hill, part of the answer may be found in a surprising place: an infant’s digestive system.
The human digestive system is home to a vast community of microorganisms known as the gut microbiome. The MSU-UNC research team discovered that the gut microbiome was different in infants with strong fear responses and infants with milder reactions.
These fear responses — how someone reacts to a scary situation — in early life can be indicators of future mental health. And there is growing evidence tying neurological well-being to the microbiome in the gut.
The new findings suggest that the gut microbiome could one day provide researchers and physicians with a new tool to monitor and support healthy neurological development.
“This early developmental period is a time of tremendous opportunity for promoting healthy brain development,” said MSU’s Rebecca Knickmeyer, leader of the new study published June 2 in the journal Nature Communications. “The microbiome is an exciting new target that can be potentially used for that.”
Studies of this connection and its role in fear response in animals led Knickmeyer, an associate professor in the College of Human Medicine’s Department of Pediatrics and Human Development, and her team to look for something similar in humans. And studying how humans, especially young children, handle fear is important because it can help forecast mental health in some cases.
“Fear reactions are a normal part of child development. Children should be aware of threats in their environment and be ready to respond to them” said Knickmeyer, who also works in MSU’s Institute for Quantitative Health Science and Engineering, or IQ. “But if they can’t dampen that response when they’re safe, they may be at heightened risk to develop anxiety and depression later on in life.”
On the other end of the response spectrum, children with exceptionally muted fear responses may go on to develop callous, unemotional traits associated with antisocial behavior, Knickmeyer said.
To determine whether the gut microbiome was connected to fear response in humans, Knickmeyer and her co-workers designed a pilot study with about 30 infants. The researchers selected the cohort carefully to keep as many factors impacting the gut microbiome as consistent as possible. For example, all of the children were breastfed and none was on antibiotics.
The researchers then characterized the children’s microbiome by analyzing stool samples and assessed a child’s fear response using a simple test: observing how a child reacted to someone entering the room while wearing a Halloween mask.
“We really wanted the experience to be enjoyable for both the kids and their parents. The parents were there the whole time and they could jump in whenever they wanted,” Knickmeyer said. “These are really the kinds of experiences infants would have in their everyday lives.”
Compiling all the data, the researchers saw significant associations between specific features of the gut microbiome and the strength of infant fear responses.
For example, children with uneven microbiomes at 1 month of age were more fearful at 1 year of age. Uneven microbiomes are dominated by a small set of bacteria, whereas even microbiomes are more balanced.
The researchers also discovered that the content of the microbial community at 1 year of age related to fear responses. Compared with less fearful children, infants with heightened responses had more of some types of bacteria and less of others.
The team, however, did not observe a connection between the children’s gut microbiome and how the children reacted to strangers who weren’t wearing masks. Knickmeyer said this is likely due to the different parts of the brain involved with processing potentially frightening situations.
“With strangers, there is a social element. So children may have a social wariness, but they don’t see strangers as immediate threats,” Knickmeyer said. “When children see a mask, they don’t see it as social. It goes into that quick-and-dirty assessment part of the brain.”
As part of the study, the team also imaged the children’s brains using MRI technology. They found that the content of the microbial community at 1 year was associated with the size of the amygdala, which is part of the brain involved in making quick decisions about potential threats.
Connecting the dots suggests that the microbiome may influence how the amygdala develops and operates. That’s one of many interesting possibilities uncovered by this new study, which the team is currently working to replicate. Knickmeyer is also preparing to start up new lines of inquiry with new collaborations at IQ, asking new questions that she’s excited to answer.
“We have a great opportunity to support neurological health early on,” she said. “Our long-term goal is that we’ll learn what we can do to foster healthy growth and development.”
Reference: Carlson, A.L., Xia, K., Azcarate-Peril, M.A. et al. Infant gut microbiome composition is associated with non-social fear behavior in a pilot study. Nat Commun 12, 3294 (2021). https://doi.org/10.1038/s41467-021-23281-y
It can be easy to forget that the human skin is an organ. It’s also the largest one and it’s exposed, charged with keeping our inner biology safe from the perils of the outside world.
But Michigan State University’s Sangbum Park is someone who never takes skin or its biological functions for granted. He’s studying skin at the cellular level to better understand it and help us support it when it’s fighting injury, infection or disease.
In the latest installment of that effort, Park, who works in IQ — MSU’s Institute for Quantitative Health Science & Engineering — has helped reveal how the skin’s immune cells organize themselves to ward off would-be intruders. Park and his colleagues published their work in the journal Nature Cell Biology.
“Immune cells are the soldiers of our body. In our skin, that army is maintained according to two factors: density and distribution,” said Park, an assistant professor in the College of Human Medicine’s Department of Medicine and Department of Pharmacology and Toxicology.
“We need enough immune cells to cover the whole area of our skin uniformly for proper protection. Otherwise, our skin would be vulnerable to damage and infection,” Park said. “As sensible as that might sound, it was unclear how, or even if, these immune cells were organized before this study. Many researchers thought the cells’ distribution was random.”
Skin’s immune cells have a history of being misunderstood. Many people don’t realize that our outermost layer of skin, the epidermis, is home to immune cells. And when the German scientist Paul Langerhans first discovered one type of these immune cells in the late 1800s — cells that are now called Langerhans cells — he mistook them for cells from our nervous system (to be fair, they do have a similar morphology).
To bring more clarity to how skin’s immune cells do their jobs, Park and his co-workers used state-of-the-art microscopy tools. The researchers illuminated how live immune cells arranged themselves in the skin of mice, a popular animal model with a skin biology similar to that of humans.
“IQ has so many advantages for a young investigator like me,” said Park, who joined MSU in January 2020. Just two months later, he had to start working from home due to the coronavirus pandemic. But thanks to IQ’s strong microscopy core, Park’s team was able to work almost immediately as restrictions lifted.
“I didn’t have to wait to set up microscopes in my own lab or train my students how to use them,” he said. “At IQ, we already have many different microscopes for a wide range of animal models.”
As a result, Park’s team is revealing the skin’s structure and function like never before. Having validated these new techniques and observing how immune cells are organized in the healthy skin of mice, Park’s team can start probing new questions about how skin heals.
“My lab is interested in how skin regenerates and recovers from injury,” he said. That injury could be a cut, an infection, an allergic reaction or an even more persistent disorder, such as psoriasis. “We can answer so many questions with our intravital imaging technique that you just can’t with conventional methods.”
Reference: Park, S., Matte-Martone, C., Gonzalez, D.G. et al. Skin-resident immune cells actively coordinate their distribution with epidermal cells during homeostasis. Nat Cell Biol 23, 476–484 (2021). https://doi.org/10.1038/s41556-021-00670-5
He said: “Nature’s oldest pharmacy has always been a treasure of potential novel drugs and we questioned if any of these compounds could assist us in battling the Covid-19 pandemic?
“We screened and sorted a library of natural compounds already know to be active against other coronaviruses using an artificial intelligence-aided computer programme.
“Our findings suggested that one of the compounds in green tea could combat the coronavirus behind Covid-19.”
The researchers’ work has now been highlighted by online journal RSC Advances and has been included in its prestigious hot articles collection chosen by editors and reviewers.
Associate Professor Dr Mohankumar emphasised that the research was still in its early days and a long way from any kind of clinical application.
He said: “The compound that our model predicts to be most active is gallocatechin, which is present in green tea and could be readily available, accessible, and affordable. There now needs to be further investigation to show if it can be proven clinically effective and safe for preventing or treating Covid-19.
“This is still a preliminary step, but it could be a potential lead to tackling the devastating Covid-19 pandemic.
Dr Mohankumar has worked in pharmacy education, research and administration around the world for more than 18 years and recently moved to Swansea to join its new MPharm programme.
Head of Pharmacy Professor Andrew Morris said: “This is fascinating research and demonstrates that natural products remain an important source of lead compounds in the fight against infectious diseases. I’m also really pleased to see this international research collaboration continuing now that Dr Mohankumar has joined the Pharmacy team.”
Dr Mohankumar added he is now looking forward to seeing how the work can be developed: “There now needs to be appropriate pre-clinical and clinical studies and we would welcome potential collaborators and partners to help carry this work forward.”
A first encounter with the dengue virus typically causes very mild symptoms; however, a subsequent infection is a different story. For a small proportion of people who are reinfected, the virus can cause severe symptomatic disease, which is often life-threatening.
“The main hypothesis for some time has been that antibodies generated the first time around, instead of providing protection against disease, can actually exacerbate it,” says Stylianos Bournazos, research assistant professor at Rockefeller. “But even in secondary infection, we see a wide range of symptoms—so the presence of antibodies alone cannot explain why only some cases turn deadly.”
Now new findings published in Science by the lab of Jeffrey V. Ravetch in collaboration with the Pasteur Institute in Cambodia suggest that the susceptibility and severity of dengue disease comes down to a particular type of antibody that is missing a specific sugar, fucose, on its stem. This impacts the antibody’s so-called Fc region, which is responsible for binding and passing instructions along to other immune cells.
Previously, researchers in the Ravetch lab found that patients with severe dengue disease have unusually high levels of these fucose-less antibodies. However, it was not clear whether the absence of fucose was the result of severe disease or its cause.
By analyzing samples from a variety of dengue patients early in the onset of their disease, the team found that those who eventually developed the most severe disease also had significantly higher levels of fucose-deficient antibodies at the time of hospital admission. As a result of this change to their structure, the antibodies bind too strongly to white blood cells, increasing inflammation and leading to the destruction of platelets crucial for blood clotting. The result is hemorrhagic fever and shock syndrome often seen in severe dengue disease.
The findings suggest that the fucose status of antibodies represents a robust prognostic tool, says Ravetch, Theresa and Eugene M. Lang Professor and head of the Leonard Wagner Laboratory of Molecular Genetics and Immunology. “It can help us identify patients at risk of severe illness so they can receive appropriate medical care early on.”
Reference: Stylianos Bournazos et al., “Antibody fucosylation predicts disease severity in secondary dengue infection”, Science 04 Jun 2021: Vol. 372, Issue 6546, pp. 1102-1105 DOI: 10.1126/science.abc7303
A recent discovery by a research team that includes Kennedy College of Sciences Prof. Nelson Eby is shedding light on the debris created by an atomic blast, and it could set the stage for advances in materials research, including potential applications in energy, health care and nuclear forensics.
The team, which also included researchers from the University of Florence in Italy, the California Institute of Technology, Los Alamos National Laboratory, Princeton University and the University of Maryland, discovered a new quasicrystal in a trinitite sample it investigated.
“Quasicrystals are strange crystalline forms that do not follow the normal laws of crystal symmetry,” he explains. Quasicrystals were first identified in the early 1980s in an aluminum-manganese alloy. Since then, laboratory experiments have produced a variety of quasicrystal structures.
“Naturally occurring quasicrystals have been found in meteorites and meteorite impact structures,” Eby says. “And most recently, in the debris associated with an atomic detonation, which is the focus of our research.”
A greater understanding of the conditions under which various types of quasicrystals form can be used to design quasicrystals for specific purposes, he says.
“Quasicrystals are not currently used in industrial applications, but some suggested uses include heat insulation, new materials that convert heat to electricity, bone repair and prosthesis applications,” he says.
The team’s findings were presented in a research paper titled, “Accidental Synthesis of a Previously Unknown Quasicrystal in the First Atomic Bomb Test,” which was published in May in the Proceedings of the National Academy of Sciences.
According to Eby, the study of trinitite is important since it serves as a vital tool in nuclear forensic investigations.
“Because of concerns about the proliferation and possible use of atomic weapons by rogue nations and terrorist groups, over the past decade forensic studies of radioactive elements contained in trinitite have been conducted by a number of academic and federal laboratories and institutions, including UMass Lowell,” he says.
“For example, materials recovered from a detonated atomic device would most likely contain remnants of the bomb, and knowing the relationship between glass chemistry and radioactive elements in the materials would be useful in characterizing the device and ultimately identifying the perpetrators.”
Code Name: Trinity
On July 16, 1945, the United States military detonated history’s first atomic bomb, a plutonium device dubbed “Gadget,” at a remote site in southern New Mexico. The mission, which was part of the top-secret Manhattan Project, was to test this prototype of a new breed of weapons that were to be used against Japan to force its surrender in World War II.
The test, code-named “Trinity,” went off as planned, with the device detonating and producing a blast equivalent to 21,000 tons of high explosives (TNT). Heat from the resulting fireball caused the 100-foot steel tower holding Gadget to vaporize instantly. The surrounding desert sand was also melted into a layer of green, glassy material, which was later called trinitite in honor of the test’s name.
Much of the material and debris was sucked into the fireball’s rising mushroom cloud of hot gases. As this material was transported downwind by the gas cloud, molten droplets of glass rained down onto the ground over a wide area.
“Contained within the glass are melted bits of the device and its support structures and various radionuclides formed during the blast,” says Eby.
After three quarters of a century, trinitite is still slightly radioactive but is relatively safe to handle, he notes.
Trinitite-like materials were also found in other U.S. atomic tests that followed after the war.
The majority of trinitite is pale green in color, but the material that the team investigated has a rare, blood-red color due to copper that melted with the desert sand. The copper came from miles of data transmission lines that connected Gadget and the tower to recording instruments.
The material, which was provided by team member William Kolb, is among the samples collected in late 1945 by a meteorite researcher north of the blast site. In it, the scientists discovered a new quasicrystal shaped in an icosahedron (a solid, 3D structure with 20 faces) and composed of silicon, copper, calcium and iron.
This red trinitite quasicrystal represents the oldest such material made by humans that is currently known, and whose origin is well documented from historical records of the Trinity test, according to Italian geologist and professor Luca Bindi, who is the paper’s lead author. Bindi conducted studies on the sample using a scanning electron microscope and electron microprobe, and single-crystal X-ray diffraction techniques.
“The tremendous pressure and temperature generated by an atomic detonation can lead to new forms of quasicrystals, such as the one we identified and described in our paper, that cannot be produced in a laboratory,” says Eby.
The Expanding Field of Nuclear Forensics
“At UMass Lowell, my student researchers and I have been studying the complex chemistry of the trinitite glasses and the distribution of radioactive elements throughout the glasses,” Eby says. “Our research has shown that certain glass chemistries are more likely to contain radioactive material, which could reflect the nature of the atomic blast. And this data is very helpful in nuclear forensics.”
Eby says in any ground-level atomic explosion, glassy materials similar to trinitite will be formed.
“We can therefore use the chemical signatures and radioactivity of these glasses to identify the type of atomic device that was detonated and to estimate its ‘yield,’ or explosive power,” he says. “Also, this knowledge is important for assessing the potential release of radioactive materials into the environment.”
Such a forensic technique is useful, especially in the face of growing terrorist threats from so-called “suitcase bombs.”
“Fortunately, since the end of World War II, an atomic device has not been used against civilian or military targets. However, should this happen – hopefully never – nuclear forensics ultimately could help us identify the bomb and the bomb makers,” says Eby.
Reference: Luca Bindi, William Kolb et al.,”Accidental synthesis of a previously unknown quasicrystal in the first atomic bomb test”, PNAS June 1, 2021 118 (22) e2101350118; https://doi.org/10.1073/pnas.2101350118
Sperm from males must be activated or capacitated on the right time and right place in order to achieve fertilization success. Sperm activation is a process whereby round and still spermatids differentiate into asymmetric and motile spermatozoa without the transcriptional and translational modification. The molecular mechanism underlying this de novo symmetry-breaking process, however, remains largely unknown.
C. elegans sperm contain relatively few organelles, namely a haploid nucleus, mitochondria, and membranous organelles (MOs). In the late stage of sperm activation, the MO membrane fuses with the plasma membrane (PM), leaving a permanent invagination on the cell body surface.
In a study published online in Developmental Cell, Dr. MIAO Long’s team at the Institute of Biophysics of the Chinese Academy of Sciences revealed that during nematode C. elegans sperm activation, Na+/K+-ATPase (also known as Na+/K+ pump), which is initially present on the PM, moves centripetally toward cell body and subsequently enters the fusion pore in the cell body, and the polarization of Na+/K+ pump depends on the transport of cholesterol from the PM to intracellular MOs via membrane contact sites (MCSs).
The researchers found that MOs are apposed at approximately 10 nm to the PM, which indicates that MOs may form MCSs with the PM. There is increasing evidence that MCSs are formed by tether proteins between tightly apposed membranes of diverse organelles, including the PM. The MCSs provide an efficient platform for lipid and ion transfer between distinct organelles in a non-vesicular manner.
Besides, they revealed that in C. elegans sperm, cholesterol is evenly distributed on the PM and is highly enriched in MOs. During sperm activation, Na+/K+ pump and cholesterol transport on the PM is correlated. Both Na+/K+ pump and cholesterol are similarly sorted and transported against their concentration gradients. Cholesterol moves from the PM to MOs against its concentration gradient through the MCSs stably formed between MOs and the PM.
The association between the PI4P phosphatase SAC-1 and MOs implies that the localized PI4P hydrolysis on the PM catalyzed in trans by SAC-1 may provide the energy required for transporting cholesterol from the PM to MOs. A phosphoinositide 5-phosphatase, CIL-1, which preferentially converts PI(4,5)P2 to PI4P, may regulate PI4P biosynthesis, which in turn maintains the driving force to modulate cholesterol trafficking and Na+/K+ pump translocation during sperm activation.
This study implies that lipid transfer at MCSs might facilitate the translocation of ion channels and transporters to modulate cell polarity establishment and cell motility acquisition. Further studies on MOs in C. elegans sperm, for example, investigations on their molecular compositions and formation mechanism, will help to elucidate the functions of lipid homeostasis and lipid transfer proteins in regulating membrane dynamics and organelle interactions in other cell types.
Featured image: Graphical abstract by authors
Reference: Qiushi Wang et al., “Membrane contact site-dependent cholesterol transport regulates Na+/K+-ATPase polarization and spermiogenesis in Caenorhabditis elegans”, Developmental Cell, 2021. DOI: https://doi.org/10.1016/j.devcel.2021.05.002
It is reported that dysfunctional emotional processing found in people with autism spectrum disorder (ASD) may be related to impairment of interoception, which refers to the process of sensing, integrating, and interpreting signals originated inside the body. Studies have shown that people with ASD are impaired in empathy, self-related functions, and around 50% of them also suffer from various degrees of alexithymia (i.e., difficulties in identifying and describing one’s own emotions).
However, since the roles of alexithymia and empathy on interoceptive sensibility and autistic traits have not been clarified, notable limitations of previous studies include that the relationship between autistic features and interoception was examined without accounting for the effects of social-emotional traits such as alexithymia.
In order to address such an issue, Dr. Raymond Chan’s team from the Institute of Psychology has conducted a study utilizing network analysis to clarify the roles of empathy and alexithymia on interoceptive sensibility and autistic traits. Self-report scales were administered to 1,360 healthy volunteers.
In this study, network analysis was used to analyze the relationship between different traits variables. Variables are treated as “nodes”, where interactions between variables are represented by “edges” linking various nodes. An edge represents the relationship between two nodes after controlling for the effect of all other nodes. The nodes and edges together form a network that visually displays the overall structure of the system.
Their findings revealed a network connecting autistic traits to interoceptive sensibility, empathy, alexithymia and self-awareness, with reasonable stability and test-retest consistency. Notably, the node representing alexithymia locates in the central of the network, with the highest centrality and expected influence.
Taken together, the researchers suggest that alexithymia may serve as an important node bridging interoceptive deficits, self-awareness, and empathic performance in individuals with Autistic traits.
They highlighted the importance of co-morbidity of alexithymia in clinical cases with ASD. Future study should take alexithymia into consideration for the study of interoceptive impairments and social deficits in ASD.
This study was supported by the National Science Foundation China and the CAS Key Laboratory of Mental Health of the Institute of Psychology.
Reference: Yang, HX., Hu, HX., Zhang, YJ. et al. A network analysis of interoception, self-awareness, empathy, alexithymia, and autistic traits. Eur Arch Psychiatry Clin Neurosci (2021). https://doi.org/10.1007/s00406-021-01274-8
Heavy water makes biological clocks tick more slowly
Scientists at Leipzig University, in collaboration with colleagues from Germany and England, have succeeded in reversibly slowing down cellular processes. A team of biophysicists led by Professor Josef Alfons Käs and Dr Jörg Schnauß were able to show in experiments that cells can be transferred into slow motion without changing the temperature. From a physical point of view, such possibilities have so far only been available in the context of the theory of relativity. They recently published their findings in the renowned journal “Advanced Materials”.
Cells are not only our biological building blocks, but also highly dynamic, active systems. The research group led by Professor Käs has succeeded in significantly reducing these dynamics with heavy water, without damaging the cells.
“Generally, a lot of people know heavy water for its important technical use in nuclear power plants. We took a different approach here and were able to show that for cells, time – or, more specifically, their dynamics – can be significantly slowed down in the presence of heavy water,” said Käs, who has devoted himself to researching the physical properties of cells and tissue. The research showed on various biological levels that the movement of cells and their dynamics was only taking place in slow motion. “It is very intriguing that cellular dynamics can be slowed down at the same temperature. So far, only the theory of relativity has offered such possibilities in the physical context,” explained Käs. He added that the results form the basis of a method to offer cells and organs longer-lasting protection against degeneration.
The researchers confirmed this effect with a variety of complementary methods and attributed the observations to an increased interaction between the structural proteins. “Heavy water also forms hydrogen bonds, but these are stronger than in normal aqueous environments. As a result, structural proteins such as actin seem to interact more strongly with one another and briefly stick together. What is spectacular here is that the effects are reversible, with cells showing their native properties again as soon as they are transferred into a normal aqueous medium,” said Dr Jörg Schnauß. “What is even more astonishing is that these changes show the fingerprint of a passive material. However, cells are highly active and far from thermodynamic equilibrium. If they behave like a passive material, they are usually dead,” added Käs.
However, as the researchers were able to show, this was not the case in their experiments. They now hope to be able to use the knowledge gained to keep cells or even tissue vital for longer. If this approach is confirmed, heavy water could be used for longer storage times, for example during organ transplants.
Featured image: Fluorescence images showed that cells did not visibly change morphologically. The slowing down of their dynamics was solely due to the presence of heavy water. Photo: Leipzig University / Steffen Grosser, Tom Kunschmann