TheScienceBreaker | Science meets Society

Preventing the perfect crime

2026-03-10 14:41:42

Apoptosis is a form of programmed cell death which appears to be a perfect crime. Killer proteins work together in a huge network to kill the cell and remove evidence resulting in one of our cells dying without us feeling it. Once this network is activated there is no way of stopping this so crime prevention by detective proteins has to occur early on. A dying cell can also protect the body if it became harmful, especially in cancer. This is why cancer cells often produce more detective proteins, finding and arresting any killer proteins. This stops one of the most effective defense mechanisms of the human body: the removal of harmful cells.

This study analyzes the details of an arrest: how a detective protein arrests a killer protein and keeps it locked up. But how to analyze something that small? Most structural methods require big complexes or a lot of material to analyze, which was not possible. Additionally, not only the proteins themselves but also their environment influences the network. The arrest can only take place at membranes limiting methods even more. Here, we introduced labels into both the detective and the killer protein which works similarly to a pinboard where all the evidence and hypotheses are collected. The “evidence” includes distances measured between the pins of the detective and the killer and analysis of their surroundings. Processing the evidence leads to a reconstruction of what the arrest actually looks like.

The detective protein chains itself to one part of the killer protein using a specific lock-mechanism. Even though, the rest of the killer can freely move, it is not able to escape like when a detective handcuffs a criminal to themselves to prevent their escape. Being able to precisely characterize which part of the detective functions as a lock makes it possible to design a lock pick and therefore precisely manipulate the lock in case of a mal function.

However, there are a lot of different killers and detectives in cells. Understanding one lock mechanism is a starting point but further mechanisms need to be analyzed to precisely kill cancer cells with as little side effects as possible.

How obesity can improve the efficacy of cancer treatment: role of the sex hormone estrogens.

2026-03-06 13:27:14

Over the last decades, cancer immunotherapy has brought new hope to patients by significantly improving survival. Contrary to chemotherapy and radiotherapy that target cancer cells, immunotherapy aims to strengthen the immune system to recognize and destroy cancer cells. However, while some patients respond very well to immunotherapy, others do not benefit at all. Understanding why is essential to improving cancer treatment for everyone.

A surprising observation in recent years is that obesity—although a major risk factor for many cancers—appears to improve the effectiveness of immunotherapy in patients with advanced melanoma, a common form of skin cancer. Therefore, we investigated the impact of obesity on the efficacy of cancer immunotherapy.

To investigate this, we used a mouse model to be able to study the interactions between the immune system, fat tissue, and cancer. We first compared the effect of immunotherapy on cancer development between obese and lean mice, and we investigated the mechanisms behind the differences in treatment efficacy. We confirmed our findings with in vitro models using cells from fat tissue, immune cells, and cancer cells. Finally, we assessed the translational impact of our findings in a cohort of patients with melanoma and treated with immunotherapy at the Geneva hospital.

We first observed that obese mice developed larger tumors than non-obese mice, which was expected since obesity is a major risk factor for cancer. However, when treated with immunotherapy, only the obese mice showed a slowing of cancer growth, while lean mice did not respond to the treatment. Interestingly, these results were not observed in female mice; females responded to immunotherapy regardless of whether they were lean or obese. Therefore, we hypothesized that estrogens could play a role in the efficacy of immunotherapy. Indeed, fat tissue can transform testosterone into estrogens, resulting in high levels of circulating estrogens in obese males compared to lean males. To verify our hypothesis, we blocked the production of estrogens in obese males. When we did so, tumors grew faster and immunotherapy no longer worked, suggesting that estrogens were indeed supporting the treatment’s effectiveness. We then investigated how obesity-related estrogens improve the effect of immunotherapy and found that estrogens enhance the activity of dendritic cells. These immune cells act as sentinels: they detect cancer, activate other immune cells, and coordinate the body’s anticancer response. By boosting dendritic cell activation, estrogens help strengthen the immune attack triggered by immunotherapy. To translate these findings to patients, we studied the relationship between obesity, estrogens, and survival of cancer patients treated for melanoma with immunotherapy. Among men, those who responded best to immunotherapy were mostly overweight or obese, whereas few lean men benefited from the treatment. In contrast, women responded equally well regardless of body weight. Next, we measured the levels of estrogens in the blood of these patients, and we observed that higher estrogen levels in men were associated with prolonged survival. This association was not observed in women.

Overall, we showed that not only obesity but also high levels of estrogens were associated with an increased efficacy of cancer immunotherapy, in male mice and men with melanoma. Our work identifies a key role for estrogens in boosting the antitumor immune response by promoting effective dendritic cell activation. However, further investigation is required to elucidate the detailed mechanisms before being able to develop estrogen-based therapies to treat cancer patients. Notably, we need to understand whether the effect of estrogens on dendritic cells is the only mechanism involved, or whether estrogens play other roles in the anticancer immune response. We also need to understand why the effects of obesity and estrogens are restricted to men, and, for now, to melanoma patients. Meanwhile, this work opens the path to identifying the patients who are more likely to respond to immunotherapy, at least in men with melanoma, so more patients can benefit from these cancer treatments.

Rejuvenating the Aged Intestinal System

2026-03-06 13:27:14

Aging disrupts the homeostasis of all tissues in the body, including the intestinal epithelium, known for its robust regenerative capacity, which is crucial for ensuring nutrient absorption and barrier protection. The key players in this regenerative mechanism are intestinal stem cells (ISCs), located at the base of the intestinal crypts, pockets of epithelial cells at the base of the villus. These cells sustain the tissue by undergoing daily divisions and committing to secretory or absorptive lineages. Notably, the proliferative potential of ISCs becomes jeopardized as part of the aging process leading to well-known dysfunctions: nutrient malabsorption, compromised recovery in response to intestinal injuries and acute inflammation, impaired communication between epithelial cells and the intestinal microbiota, as well as severe side effects during chemotherapy treatments. At the cellular level, several molecular processes, some of which are partially understood, lead to an increase of the pool of differentiated cells at the expense of the stem cells compartment in aged epithelium, owing to a reduced proliferation. Furthermore, as ISCs respond to regulatory signals from the surrounding microenvironment, the niche, and, particularly, molecules secreted by neighboring immune cells or by gut microbiota, therefore aging must alter the homeostasis of these compartments as well. Indeed, previous studies have confirmed that aged gut microbiota triggers a chronic systemic inflammatory state, as a part of a process scientists term inflammaging; besides, the disruption of the homeostatic crosstalk between immune cells from lamina propria and the neighboring intestinal epithelium results in the release of stimuli skewing ISCs fate towards differentiation. Here, to unravel how the communication between immune cells and ISCs is impaired during aging, the authors of this study dissected the transcriptional and cellular aspects of their interaction by comparing young and elderly mice.

Total RNA sequencing of intestinal crypts from young and elderly mice showed a significant transcriptional variance upon aging, with a high number of differentially expressed genes. To note, transcriptional changes in inflammation-related pathways, in particular in the Antigen Presenting Pathway (APP), were enriched in both genders as a common signature of aging; this data was supported by the overall increase of cells expressing major histocompatibility complex class II (MHCII) on their surface, a hallmark of ongoing inflammatory process. Strikingly, many of these aging-related transcriptional changes occur at stem cell level, as shown by RNA sequencing on ISCs isolated from young and old mice, which recapitulated what observed in the whole crypts, including APP upregulation, and, additionally, revealed new upregulated pathways, including those related to p53, IGF-1, calcium signaling. Focusing on the balance between stem and differentiated cells within the crypts, single cell level analysis revealed that both male and female old mice experience an exhaustion of stem cells pool concomitantly to an increase of secretory cells. The observed phenotypes, which include cells expressing MHCII and an elevated presence of secretory cells compared to stem cells, suggested that the aged intestine was actually responding to a pro-inflammatory environment. Experiments performed in intestinal organoid cultures displayed that aged intestinal crypts counteract to extrinsic factors released from a perturbated surrounding; indeed, the lamina propria, physically situated close to the epithelium and housing immune cells, experiences a cell-type composition rearrangement during aging, accumulating pro-inflammatory cytotoxic CD4 T and ILC2 cells, which in turn release increased pro-inflammatory signals, particularly, the Interferon gamma (IFN). Consequently, the authors investigated the role of IFN; treating organoids with IFN was able to mimic the in vivo intestinal crypts aging, suggesting that IFN triggers ISC transition to a more proliferating state and to a transcriptionally-primed (towards secretory lineage) state expressing MHCII. Ultimately, it all leads to a depletion of the stem pool. Additionally, aged crypts, by turning into a presenting antigen tissue, trigger an immune response in terms of increase of CD4+ T cells an ILC2 in the lamina propria, as assessed by co-culturing immune cells and IFN pre-treated MHCII+ - to mimic the aged phenotype - young intestinal organoids. Finally, the scientists demonstrated that ISCs functional impairment is due to the activation of a downstream target of IFN, the gene Stat1, which is upregulated during aging, as well as upon IFN administration, and directly binds the promoters of the secretory markers and APP genes.

To delve into the clinical relevance of this discovery, aged mice carrying a profound intestinal damage due to the treatment with the chemotherapeutic drug (5FU) were cured with a molecule capable of blocking IFN. The pre-treatment restored the regenerative capacity of the intestine in these animals to the level of the young ones and rescued the previously observed aging-associated alterations. Remarkably these mice did not lose weight and suffer after the chemotherapeutic-driven intestinal injury. If translated to human these results can advance the current clinical practice, increase the patient well-being and improve the suitability of anti-cancer treatments to a wider pool of people.

Cicada emergence alters forest food webs

2025-01-27 16:46:15

During a periodical cicada emergence, millions upon millions of shrimp-like insects synchronously crawl out of their burrows after 13 or 17 years underground, molt into winged adults, and briefly saturate the local landscape, providing food for a wide range of generalist predators. Despite centuries of scientific research on the bizarre life histories of these eastern North American insects, the ecological impacts of their mass emergences are still poorly understood.

How might this sudden bonanza of palatable, easy-to-catch food alter the functioning of forest food webs? Typically, in what is called a ‘trophic cascade,’ many bird species feed on caterpillars, reducing their numbers and limiting the negative impacts of these herbivores on trees. So, what might happen when the cicadas appear? Would birds temporarily switch over to eating the new arrivals, thereby reducing their consumption of caterpillars, and indirectly resulting in increased damage to trees, or would they mostly ignore this unfamiliar prey?

To find out, our team measured the extent to which birds were feeding on caterpillars before the cicadas showed up. Once a week, throughout the late spring and summer of the year before the emergence, we glued a fresh set of fake caterpillars, made of non-toxic green modeling clay, to understory oak trees at a local field site in central Maryland. The following week we recorded the number of decoys that had been pecked at by birds, which leave tell-tale beak marks in the clay models, providing a simple estimate of the intensity of bird predation on local caterpillars. The next year, during the emergence, we continued to quantify the incidence of bird strikes on our clay caterpillars. We also collected extensive data on which birds were feeding on cicadas, through our own observations and the contributions of community scientists. Additionally, we monitored the densities of caterpillars feeding on the oak trees during the emergence year and for two subsequent years and quantified the extent of herbivore damage to the leaves of those trees for the years before, during, and after the emergence.

Our results were striking! In the year before the emergence, clay caterpillar decoys suffered consistently high rates of attack by birds, which mistook around 30% of them for real caterpillars each week throughout the season. The following year, however, as soon as the cicadas came above ground, the incidence of beak marks on the clay caterpillars dropped dramatically, appearing on less than 10% of the models each week for as long as the cicadas were present, and returning to pre-emergence levels only after the last cicadas disappeared. The year following the emergence, we observed the same high levels of weekly bird strikes that we had seen in the pre-emergence year.

During the emergence, our bird team documented more than 80 species of birds feeding on cicadas, regardless of their regular diet, and ranging in size from tiny gnatcatchers to enormous swans. This avian diet shift dramatically boosted forest caterpillar populations, which experienced a brief summer respite from their normally vigilant predators. Quantitative censuses of oak trees in the spring, before the cicadas emerged, were unchanged from those in subsequent years, whereas the 2021 mid-summer census, conducted near the end of the cicada emergence, saw a doubling of caterpillar densities, as well as an increase in caterpillar size, relative to the next two cicada-free years. Twice as many summer caterpillars, not surprisingly, yielded double the damage to the oak trees, when compared to the flanking non-emergence years.

Why are these results important? Our study reveals interconnections among organisms that are ordinarily hidden from our view. We can see, for example, that in the eastern forests of the US, birds regulate populations of free-living caterpillars, benefitting plants by reducing plant damage, and that the presence of cicadas indirectly benefits caterpillars due to the temporary diet shifts of their shared bird predators. Our results also remind ecologists that when studying an influx of resources into a community, it is important to look not just at how these resources directly impact the organisms consuming them, but it is equally important to measure the ecological consequences stemming from the prey that go uneaten during these feeding frenzies. Finally, as avian populations decline worldwide, a cicada emergence can provide a sneak preview of the reduction in plant productivity that we can expect in a world with fewer birds.

In summary, periodical cicadas not only amaze us with their unique and bizarre life cycle – they also have a lot to teach us about ecology!

Size does not matter: direct estimations of mutation rates in baleen whales

2025-01-27 16:43:02

Mutations drive evolution and thus knowing how often they occur is fundamental to studying biology. Several methods are available to estimate mutation rates, among which phylogenetic estimates are the most common. In essence, this method consists of counting the number of differences in the DNA sequences between two related species. An annual mutation rate is obtained by dividing the number of differences by the years since the two species split. This kind of estimation relies on several assumptions and uncertainties, which makes it difficult to later compare mutation rates among species. In contrast, direct estimations of mutation rates offer an apple-to-apple comparison between different species and rely on fewer assumptions.

Direct estimations of nuclear mutation rates are based on sequencing the entire nuclear genome of “trios”, i.e. a mother, her offspring, and the father. We can subsequently identify mutations in the offspring’s genome that are absent in both parents. Dividing the number of detected mutations by the size of the genome yields an estimate of the mutation rate across one single generation. The main difficulty in this approach is locating the trios. While this is straightforward in captive species with known families, it's an entirely different matter in most wild species.

Baleen whales include the largest and longest-living mammals on Earth. The lower body’s energy use in these gigantic mammals was thought to lead to lower mutation rates relative to smaller mammals, such as humans, which, in turn, might be the reason for the lower incidence of cancer in baleen whales. They travel extensive distances, undertaking some of the longest seasonal migrations among mammals. The large annual ranges and the fact that they do not form family groups make it challenging to sample from complete trios.

We identified trios of whales solely using genetic analyses, used in human forensic and paternity testing. We first compared every female whale against all other individuals to see if the female could be the mother of a second whale. If that was the case, we then searched for a male that could be the father among all the males. Surprisingly, this worked very well and we managed to find many complete trios even though we had never observed the whales together in the field. We then selected a few complete trios and sequenced their genomes to estimate the mutation rate directly.

We also estimated the mutation rate for the mitochondrial DNA, which is a widely used genetic marker. Our mitochondria are inherited from our mother and contain their own genome. Although mitochondrial mutation rates are several hundred times higher than nuclear rates, the mitochondrial genome is 100,000 times smaller. This means that the chances of detecting a mutation between a single mother and her offspring are extremely low.

We used a shortcut by analyzing individuals with two different mitochondrial genomes, called heteroplasmy. The mitochondria contain multiple, usually identical, mitochondrial genomes. When a new mutation occurs in one copy of the genome, the new mutation coexists with the “original” mitochondrial genome. Both versions are transmitted to the female’s offspring until one copy is lost. The frequency of heteroplasmy in a population and how quickly and often this turnover in the mitochondrial genome happens can be used to estimate the mutation rate in the mitochondrial genome.

In our study, we were very fortunate to have access to field observations and genetic data collected during the last four decades from which we could infer a large pedigree of humpback whales in which we found multi-generational maternal lineages, some with mitochondrial heteroplasmies. We used these to estimate the mitochondrial mutation rate.

Our results were quite surprising as both the nuclear and the mitochondrial mutation rates in the gigantic baleen whales were very similar to other smaller-bodied mammals with similar generation times, such as large primates, orcas, and bottlenose dolphins. The similarities did not end there. Most mutations originated from the fathers, with more mutations from older fathers, which has been observed in humans as well.

The estimate of the mitochondrial mutation rate was over ten times higher than the older phylogenetic estimates. This had a large impact on the results in earlier studies; for example, our estimate of the mutation rate suggests that the pre-whaling number of humpback whales in the North Atlantic was overestimated by ~85%.

In summary, this study showed that mutation rates can readily be estimated directly in wild populations with very limited prior knowledge thanks to the sustained long-term ecological research effort by our collaborators. Despite their massive sizes and long lives, we show that baleen whales have mutation rates similar to those of smaller animals. This finding has profound implications from cancer research to conservation, highlighting the need for these studies on wild species.

Discovery of the first radiation belt beyond the Solar System

2025-01-27 16:39:22

Since the late 1950s, we have been aware of the existence of radiation belts around Earth and Jupiter. A radiation belt is a doughnut-shaped region around an object created by its magnetic field. Charged particles (mainly electrons, but not exclusively) are trapped in this region and accelerated so much that astronauts need to take Earth’s radiation belt into consideration when leaving our home planet. Years after this discovery, we found the same structure in the other magnetized planets of the Solar System (Saturn, Uranus and Neptune). Our knowledge of these radiation belts came originally from observations at radio frequencies. However, radio observations of objects beyond the Solar System have not been able to conclude that these magnetic structures also exist there… until now.

On 15 June 2021, our research group carried out radio observations of LSR J1835+3259: an object classified as an “ultracool dwarf” (UCDs) with a surface temperature of 2300 K. It is estimated to be similar in size to Jupiter but 55 times more massive. Only 18.5 light years away from Earth, LSR J1835+3259 represented our best chance of probing the surroundings of UCDs, particularly the region covered by its powerful magnetic field: the magnetosphere.

But to achieve enough “zoom” in our images to discern the magnetosphere, we needed a very special technique: very long baseline interferometry (VLBI). This is the same technique that was employed to obtain the very first images of a black hole back in 2019. In a nutshell, VLBI uses an array of antennas around the globe to create a virtual telescope with the same size as the maximum separation between antennas. For example, in the first black hole image, the maximum separation between antennas was around 10,000 km, which resulted in a virtual telescope so big that one could appreciate, from Earth, the details of a golf ball located on the Moon.

In our observations, we used the European VLBI Network (EVN) for 6 hours. This total observing time is important as it covers two full rotations of the object (yes, LSR J1835+3259 rotates once every 2.8 hours!). We detected two types of radio emission: (i) quiescent emission that remained almost constant during the observations and (ii) bursting radio emission that occurred once per rotation. The bursting emission was approximately 10 times greater than the quiescent emission but only lasted for about 30 minutes. The origin of the bursting emission is usually linked to auroras similar to the ones we have on Earth but much more intense. The origin of the quiescent emission is much less known, with one of the hypotheses being a radiation belt.

To shed some light on the origin of this quiescent emission, we created images of LSR J1835+3259 during each rotation period and were able to resolve its magnetosphere. This object did not look like a point in our images, but showed a very interesting structure. What is even more interesting is that when the bursting emission occurred, we could separate the quiescent contribution, and those images revealed a pattern of emission very similar to a radiation belt. This was the first time resolving the magnetosphere of a UCD and it showed that, at least, part of its emission came from a radiation belt. Our estimations show that, although the energies of the electrons that populate the radiation belt of LSR J1835+3259 are similar to those that populate the Jupiter one, the total size of this newly discovered radiation belt is 10 times larger and millions of times more powerful.

Perhaps the greater significance of this discovery is that this magnetic structure has not been seen on an exoplanet but rather on a much more massive object. This suggests that UCDs exhibit magnetic behaviors more akin to planets than stars, while also opening up exploration for the search for other radiation belts around even more massive objects.

Finally, one may wonder about the origin of the particles of LSR J1835+3259 radiation belt. Although it is still an open question, one possible explanation would be to rely on an exoplanet similar to the one proposed by other authors in 2015 to explain the powerful auroras seen in this UCD (via interaction UCD-exoplanet). This tentative exoplanet could also act as a source of plasma that would populate the radiation belt. This complex yet intriguing scenario awaits further data for validation.

One million (paper) satellites

2025-01-27 16:02:43

Over the past six years, companies and governments have submitted plans to launch over one million satellites. If even a small portion of these satellites launch, it would have serious implications for the environment in space and on Earth. However, many may not launch and the companies could be inflating their numbers, perhaps to get media or investment attention or to sell the plans in future.

Governments must submit information in ‘filings’ to the International Telecommunication Union (ITU), which is a United Nations agency that coordinates radio signals around the world. This information is submitted on behalf of the satellite operator, which may be a company, university or government agency.

The largest filing since 2017 was filed by Rwanda, on behalf of a French startup, for 337,320 satellites. This French company then filed again, this time through France, for 116,640 satellites. Right now, there are only 8,000 working satellites in space, so this would be a big increase. In total, there were over 300 separate projects from all around the world, with more than 90 containing over 1,000 satellites.

If even 100,000 satellites were to launch in the coming years, the rocket launches required would harm the atmosphere by emitting greenhouse gases, and when the satellites and rockets return to Earth after use, they would risk hitting people or aircraft. In Earth orbit, satellites travel fast and if two of these satellites were to collide it would create lots of space debris, which could then hit other satellites.

However, the big filings may be overstating the number of satellites that will launch. Getting lots of satellites into space is hard and expensive, and many projects will fail. Additionally, companies may be asking for more satellites than they will launch, maybe to get media or investment attention. They could also be doing it to secure the radio signal rights in order to sell them later on.

Either way, the sheer number of satellite filings is making it harder for the ITU to coordinate future radio signals. One reason is that it is hard for the ITU to model hundreds of thousands of satellites, all transmitting at the same time. This is to make sure signal limits are not breached, but these filings make that modelling much harder.

Some companies have been filing for satellites through multiple countries. SpaceX, a US company which has launched over 7,000 satellites in recent years, has made filings through Norway, Germany and the United States. OneWeb, another company which has launched over 600 satellites, has made filings through the United Kingdom, France, and Mexico.

Companies may be doing this because different countries have different rules and fees for filings. Shopping around for favourable countries also happens in other industries. In shipping, for example, so-called ‘flag-of-convenience’ countries register ships cheaply and impose only minimal standards – often these ships have poor safety and environmental records. The same thing may be happening with satellite filings.

Either the satellites will launch, and damage the environment, or countries and governments are fiddling the numbers. Either way, the ITU can make changes to its rules to prevent this. The ITU is controlled by its 193 member countries and can change its rules every three to six years at conferences called World Radiocommunication Conferences (WRCs). The most recent one took place from 20November until 15 December 2023.

The ITU could consider introducing fees for larger filings or limiting the number of satellites that can be launched. Making changes at the ITU is slow, and it may be the next conference in 2027 or the one after in 2031 when these changes can be enacted. In the meantime, many satellites will launch, and the problem will only worsen.

The Claws and the Spear: New Evidence of Neanderthal-Cave Lion Interactions

2025-01-27 00:00:00

Felids, ranging from domestic cats to majestic tigers and lions, have wielded a profound influence on human culture throughout history. This impact can be traced back to prehistoric times when European foragers shared their environment with large cats like cave lions (Panthera spelaea), which are now extinct. Our evidence of these early interactions comes from cut marks on predators’ bones, intricately carved ivory figurines, and cave paintings from the Upper Paleolithic: a time period during which our species (Homo sapiens) inhabited Europe, which was in the grip of the Ice Age. However, cave lions inhabited Europe long before the arrival of our species, leaving behind subtle traces of encounters with Neanderthals. How Neanderthals and cave lions engaged with each other is often overlooked.

Until recently, these scattered pieces of evidence were viewed as isolated events, with interactions between Neanderthals and cave lions thought to be primarily in competition with each other for food. Our recent study challenges this perspective.

In 2019, during an excavation at Unicorn Cave in central Germany, three cave lion bones were unearthed, dating back over 190,000 years. Among them were two toe bones and a small sesamoid bone. One toe bone displayed distinctive marks, prompting a 3D microscopy analysis to determine whether they were human-made, animal-induced, or occurred after burial. To better understand these cave lion remains, we decided to compare them with other known samples, including a cave lion skeleton from Siegsdorf in Germany. This skeleton, which dates to approximately 48,000 years ago, was discovered in 1985 and first studied in 1992. The skeleton was known to have cut marks from butchering by Neanderthals. However, despite the extensive examination it underwent, researchers had not yet examined in detail how Neanderthals had interacted with it.

Our comprehensive review revealed new information. We reexamined a puncture mark on the lion's third rib, initially thought to be postmortem carnivore gnawing. Employing 3D microscopy, we measured surface changes, compared features with other carnivore punctures and 'hunting lesions', and conducted linear discriminant analysis. The result indicated the wound matched spear impacts, prompting further analysis through micro-computed tomography scans and digital models to reconstruct the ballistic trajectory. The 3D microscopy analysis of the Unicorn Cave lion's toe bone revealed that the damage on the surface of the bone is most similar to marks created by cutting with a sharp edge. Their shape and other characteristics suggest that the cut marks were produced by a retouched lithic tool, indicating human involvement. This type of tool was also found in the same layer as the bones, reinforcing this interpretation. Because of where these cut marks are, we can see that they resulted from skinning the animal, involving severing the tendons to separate the claw from the rest of the paw. Given the absence of other body parts, it is likely that the lion was skinned elsewhere, and only the pelt with the claws attached was transported into the cave.

Meanwhile, the comparative analysis of the puncture on the lion rib from Siegsdorf showed that it aligns well with injuries caused by spearheads, particularly those with wooden tips, known to be used by Neanderthals. The morphology and placement of the hunting wound allowed for the reconstruction of its ballistic trajectory and the calculation of the kinetic force required for its creation. The results suggest that the puncture resulted from a thrust from a wooden-tipped spear while the lion was lying on its right side. Traces found on different lion bone elements indicate that the lion may have been struck by other projectiles, likely to incapacitate the animal before the fatal blow. Cut marks show that after this fatal wound, the Neanderthals butchered and eviscerated the cave lion. Subsequently, the carcass was abandoned at the site.

These discoveries significantly deepen our understanding of Neanderthal behavior, illuminating a wider range of interactions with large predators that extend beyond mere competition. The lion pelt from the Unicorn Cave not only serves as the oldest evidence of Neanderthals using the skin of a large predator but also hints at a nuanced cultural relationship between this human species and cave lions. Similarly, the hunted lion from Siegsdorf provides the earliest direct proof of a large predator kill, showing Neanderthals' impressive hunting capabilities. These behaviors were previously attributed solely to our species, but our study suggests that Neanderthals were equally adept.

A deep-sea spa: the key to the pearl octopus’ success

2025-01-17 00:00:00

In 2018, scientists exploring the base of an inactive undersea volcano off California were startled to discover a massive breeding ground for deep-sea octopuses. As many as 20,000 pearl octopuses (Muusoctopus robustus) were found at this “Octopus Garden” 3 kilometers underwater, in the largest known octopus nursery. As researchers moved in for a close-up view of nesting mothers, they were surprised again by shimmering waters amongst the nests: an indicator of warm water percolating from the seabed, bathing developing eggs in warmth from unseen hydrothermal springs. This fascinating discovery prompted several questions: Why nest at this site? How do the thermal springs influence the octopuses? My lab group at MBARI and collaborators from the Monterey Bay National Marine Sanctuary set about to shed some light on these mysteries.

Life is tough in the deep sea. High pressure, darkness, little food, and particularly the frigid metabolism: growth, reproduction, and other life processes are sluggish in the cold, challenging species to find ways to survive and reproduce, ensuring the future for the next generation. We know that the time required for brooding by octopuses worldwide is coupled with ocean temperature. Species in warm seas lay smaller eggs that hatch in days to weeks, while octopuses in cold waters have larger eggs and longer, even years-long, brood periods. The longest incubation known for any animal is that for “Octomom”, a deep-water octopus (Graneledone pacifica) that tended her nest in cold (3 ^oC) waters for about 4.5 years before her eggs hatched. The pearl octopus we studied lives in deeper, colder (about 1.6 ^oC) waters where brooding would be expected to take 8 to 10 years or more, a seemingly impossible feat for octopus moms who do not eat while brooding.

The simplest explanation for this breeding aggregation is that pearl octopuses are attracted to the rocky habitat at the Octopus Garden. All octopuses living on the seafloor need clean rock surfaces to attach their eggs. Rocky nesting areas are abundant in this area, unlike most deep-sea environments, where a veneer of mud or sediment covers most of the seabed. However, after checking the temperatures of waters surrounding eggs in dozens of nests, we found that all nests were 1 to 10 ^oC warmer than the surrounding ambient waters. Despite searching, we could not find a single nest in cold waters, making it clear that nesting octopus moms chose locations warmed by thermal springs – but why?

We expected that warmth would speed the metabolism of the mothers and their brood, shortening the time required for hatching and perhaps increasing their reproductive success. However, brooding in thermal springs is also risky; once laid, eggs are immovable, and episodes of hot temperatures, even for seconds, could wipe out the entire brood – there is no guarantee of reproductive success in thermal springs. A higher metabolism also burns energy stored in a mother’s body more rapidly and may influence how long a brooding mom can survive to tend her eggs.

We solved this mystery during several expeditions over 3 years where we repeatedly visited the same group of nesting mothers to measure how quickly eggs were hatching. Nests were indeed warmer, averaging 5.1 ^oC, and the time required for hatching averaged 1.8 years, far shorter than the decade-long period expected for cold waters. How could a shorter brood period increase the reproductive success of pearl octopuses? Ideally, all eggs an octopus mom lays could hatch and survive. But even for a doting mom, some eggs may die before hatching due to injury, infection, or predation. For octopuses in warm seas, eggs hatch quickly, and exposure to deadly risks is brief: thus, most eggs may hatch unscathed. On the other hand, for the very long brood periods required for frigid waters, eggs can be exposed to the risk of injury or death for years – the longer they are at risk, the fewer eggs are expected to survive and hatch. Shortening the brooding period by exploiting warm springs would also shorten the time eggs are exposed to predation risk, presumably increasing the hatching success of the brood. Rocky habitats, ideal for egg-laying, may have initially attracted pearl octopuses to the Octopus Garden; however, the boost in reproductive success that appears linked to warm waters provides embryos with a better chance for hatching and early life, ensuring the continued success of the local pearl octopus populations. How many more fascinating natural wonders await discovery in the vast, yet unexplored areas in the deep ocean?

New, smaller-than-ever devices to help us understand how our brain works from the inside

2024-11-19 16:52:39

The human brain represents arguably the most complex and fascinating organ of our body: hidden inside our head, it controls most of our activities and processes all the information gathered from the outside, pulling it all together to interpret the world around us. Our brain is responsible for our thoughts and our culture; our feelings and our passions; for me writing these words and for you reading them: simply put, the brain is what creates our personality and our consciousness.

It has been almost 700 years since we have started studying the brain. Today, our understanding has come a long way and we now know that the neuron is the functional unity of this organ. The brain contains around 86 billions of these special cells, densely interconnected with each other, exchanging signals and information in the form of electrical pulses. Measuring these signals is not easy; nevertheless, scientists are developing increasingly precise instruments to measure the electrical activity of the brain, which are playing a huge role in revealing its physiological mechanisms.

To do so, today we use the so-called “neuroelectronical interfaces”, that is, tools that establish communication between the brain and external devices, measuring and recording brain activity. Doing this while a task is being performed (such as watching an image, walking, or eating), can give us a useful insight into which areas of the brain are involved in the control of said task. Many instruments of this sort have been developed, and each one of them has a trade-off to face: invasiveness or spatial resolution. Tools that record brain activity from the outside are completely safe and quite bearable for the subject that is asked to wear them, but they can only record the activity of whole areas of the brain. On the other hand, tools that are implanted inside the brain are potentially more dangerous and difficult to tolerate, with the risk of bleeding and infection, but they are precise enough to measure the activity of a single neuron, allowing us to investigate the involvement of individual cells in a process.

A research group led by Anqi Zhang, in a collaboration between the universities of Stanford and Harvard, has recently developed a device that aims to overcome this trade-off: they designed an instrument that could be temporarily inserted into the vasculature of the brain, without the need for permanent implant or any excessively invasive surgery. Why measuring brain activity from inside the blood vessels? The big advantage of this approach is the spatial resolution potential.

The brain needs a lot of energy, which is delivered by a very dense network of capillaries that reach the proximity of virtually every neuron. Therefore, the blood vessels in the brain give access to any area of the brain we might be interested in. However, these blood vessels get smaller the deeper they go into the brain, posing a considerable challenge for the dimensions of these devices.

This is not the first time that brain activity has been recorded from inside its vasculature. However, the tools used so far were relatively large, and they could be inserted only in the largest, most superficial blood vessels, giving access to a limited number of brain areas. Zhang and his team managed instead to build a probe that is so small and flexible that it can be inserted into vessels smaller than 100 micrometers (that is, less than a tenth of a millimeter, similar to the thickness of a single hair!). This tool, called the MEV probe, bears many microscopic metal electrodes, that are pushed to the vessel wall and measure electrical signals coming from the adjacent neurons. Working with rats, they inserted small catheters into the blood vessels of the neck and used them to inject the probe into two different areas of the brain: the cortex and the olfactory bulb. After confirming its correct placement, they managed to record the activity of these areas with great spatial and temporal precision, measuring single electrical pulses from individual neurons. Finally, they evaluated the inflammatory response induced by the probe and found no indication of brain inflammation, neither immediately after implantation nor after 28 days.

These impressive achievements represent a significant technological advancement for the neurosciences. Understanding how the brain works is extremely challenging, and the technological limitations are still a big hurdle to be overcome in this field. However, new instruments such as the MEV probe are a great chance to learn more about our brain, opening the door to a better detection of neurological diseases and more accurate medical intervention.

Volcanic Ash: A Nutrient Boost for Reef-Building Corals

2024-09-17 11:38:37

Volcanic eruptions, although magnificent to observe, put human infrastructure and environmental ecosystems close to them at high risk of danger. Explosive eruptions can eject kilotons of rock fragments, glass, and minerals into the atmosphere. Volcanic ash, composed of fine particles with a diameter below 2 mm, can travel long distances and accumulate in large quantities on land and in the ocean. Ash deposition especially affects sessile organisms that cannot escape the imminent threat. Among these organisms are corals.

Skeleton-secreting corals are engineers of the coral reefs, which represent arguably the largest bioconstructions on Earth. Through the process of biomineralization, reef-building corals precipitate calcium carbonate skeleton that archives the environmental history in which the corals were formed. Corals live in partnership with tiny, photosynthesizing organisms. These organisms help corals get up to 95%¹ of their daily energy from sunlight, which supports their growth and survival.

We initially wanted to see if coral skeletons could record past volcanic eruptions, because tropical corals grow quickly and might capture these events in their structure. To achieve this, we conducted a six-week ash exposure experiment at the Centre Scientifique de Monaco using cultured microcolonies of the branching coral Stylophora pistillata. The corals were reared in tanks with controlled light intensity, temperature, and pH and maintained under two different conditions: a control condition and an experimental condition in which corals were exposed to volcanic ash from the 2021 eruption of the La Soufrière volcano on St. Vincent. A moderate ash concentration was chosen to minimize shading and prevent coral smothering, as this study aimed to develop an understanding of the principles of dilute volcanic ash exposure to corals. Throughout the experimental runtime, physiological parameters (photosynthesis rates, photosynthetic efficiency, skeletal growth rate) were monitored. After the experiment, the coral soft tissue was analyzed for metal concentration, total protein content, chlorophyll content, and symbiont density.

After being exposed to volcanic ash for several days, the corals showed significantly enhanced photosynthetic efficiency, with increased oxygen production and improvements in their ability to capture sunlight for energy, compared to non-exposed corals under similar environmental conditions. Additionally, these corals appeared healthier, with vibrant colors and fuller flesh, thanks to higher levels of chlorophyll in their symbiotic partners. During the experiment, corals exposed to ash experienced accelerated skeletal growth, with microcolonies growing on average twice as fast as those in the control group by the end of the experiment.

Upon examining the metal content, we discovered significantly higher concentrations of certain trace metals such as chromium, manganese, and iron in both the coral host and its symbiotic partners. These metals are essential for various metabolic and enzymatic processes within the coral. Iron and manganese, in particular, play critical roles in photosynthesis and are often limited in ocean environments. The leaching of metals from volcanic ash thus provides corals with important micronutrients, overcoming these limitations, and thereby enhancing certain biological functions and overall coral health. The chosen concentration of ash was found to have a fertilizing effect on the coral microcosm.

Most people don’t think of volcanic eruptions as beneficial for coral reefs. However, our study—the first to look at this interaction in a lab—shows that moderate volcanic ash exposure could enhance coral health. While more research is needed to confirm these results in natural reef environments, our results indicate that the metal supply derived from volcanic ash leaching might bolster coral health and may help mitigate the impacts of external stressors such as climate change-induced disturbances.

Our study sheds light on the complex interactions between geological events and marine ecosystems. Understanding the role of volcanic ash in shaping coral reef dynamics offers new avenues for coral conservation and management strategies in an era of environmental change.

Testing gravity through the distortion of time

2024-09-17 00:00:00

When glancing at the night sky, we admire the arabesques of distant galaxies. It is hard to grasp that these galaxies are moving away from us, pulled by the expansion of the Universe. Even less intuitively, our observations have shown that this expansion is getting faster and faster. Why? This is one of the main open questions of cosmology, the branch of physics that studies the Universe as a whole.

According to the standard cosmological model, this acceleration is due to a mysterious form of repulsive “dark energy”, which constitutes around 70% of the Universe. However, cosmologists are not satisfied with wandering in darkness and are searching for alternative explanations. A well-investigated possibility is that, on very large scales, the laws of gravity could be different from what we observe on Earth, leading to the observed acceleration.

To understand this hypothesis, let us take a stroll in the realm of General Relativity, our current theory of gravity developed by Albert Einstein. General Relativity states that gravity is not a force, but rather a deformation of space and time. We can picture the Universe as a tablecloth that gets distorted by objects with a mass, creating deformations called “gravitational potentials”. The path of any particle traveling across the tablecloth is deviated by these potentials.

The predictions of General Relativity have been verified by observations up to the scale of the Solar System, but what if the theory is insufficient on cosmological scales, beyond the size of individual galaxies? The creativity of researchers has led to several modified models of gravity. The simplest ones introduce a new element, a “scalar field”, which changes the way space and time are distorted by a mass, making the gravitational potentials deeper or shallower. A brilliant physicist named Gregory Horndeski has developed the most general theory of gravity involving a scalar field, which has become a key paradigm.

How can we assess whether the Horndeski theory provides a better description of the Universe than General Relativity? The two theories predict different relations between the mass of an object and the resulting gravitational potential. This will affect the predicted motions of galaxies in their local environments, which in Horndeski gravity are faster or slower than in General Relativity. Current measurements of these motions are not sufficiently precise to discriminate between the two theories, but cosmologists are expecting to achieve this with upcoming galaxy surveys.

However, instead of pausing our stroll while waiting for new data, one more element must be taken into account. The cosmic cocktail described by the standard cosmological model contains another obscure ingredient, dark matter, which does not emit light and accounts for around 80% of the matter in the Universe. Physicists have observed its gravitational impact on galaxies, but its properties remain mysterious. On very large scales, it could be that dark matter falls into the gravitational potentials in a different way from ordinary matter, and this possibility was recently included in an extension of the Horndeski theory.

This extension introduces a complication: in a recent study, we have shown that this allows for compensating effects in the motions of galaxies. For example, we could live in a Horndeski universe where the gravitational potentials are shallower than in General Relativity, leading to slower galactic motions. However, this effect could be compensated by changing the impact of gravity on the dark matter contained in the galaxies, such that their motion would be exactly the same as in General Relativity. This would make the two theories completely indistinguishable.

Luckily, we have identified a new method to settle the dispute. The key ingredient is the fact that time gets distorted in the presence of a gravitational potential, flowing more slowly at the bottom of the potential than outside of it. This effect can be measured from a frequency change in the light emitted by galaxies, which can be compared with the observed galactic motions. The relation between these two measurements is different in the two theories of gravity, providing a clear way to distinguish between them.

The distortion of time is a tiny effect, but is forecasted to be measurable by future missions like the Square Kilometre Array Phase 2 planned for the early 2030s. We have demonstrated that such future measurements might yield evidence in favor of Horndeski gravity or set constraints on the largest allowed deviations from General Relativity. This will be one step forward towards understanding the fundamental properties of gravity, in the quest to shed light on the accelerated cosmic expansion.

Study funded by Prof. Bonvin's ERC consolidator grant - full details: European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No. 863929; project title “Testing the law of gravity with novel large-scale structure observables”).

Stacking molecular chips in multiple dimensions

2024-08-30 00:00:00

Illustration realized in the framework of a collaboration between the Image/Recit option of the HEAD (Haute École d'Art et de Design) - Genève and the Faculty of Sciences of the University of Geneva.

Supramolecular polymers are an alternative to traditional plastics, where monomers or building blocks are held together by weak, reversible interactions. These materials are becoming increasingly relevant due to their valuable properties of recyclability, self-healing or good processability amongst others, and they present numerous promising applications in optoelectronics or biomedicine. The best-known example is DNA, where two strands are held together by hydrogen bonds, forming the classic double helix structure—a feat not possible with conventional plastics.

But how can we control and tune the different factors that lead to an assembly? How can we increase their stability and dictate their final structure? Often this is done by changing the type of interactions between monomers or by applying stimuli such as temperature or light. We, instead, seek to know how the shape of a building block, or more specifically the curvature of a molecule, can affect the outcome of a growing polymer.

Three simplified cases of shaping a molecule are possible: as a disc or flat surface, a bowl, and a saddle. If one thinks of two discs stacked on top of each other, these can rotate and translate off one another. Multiply this a millionfold to the typical length of a classical plastic fiber, this quickly becomes a mess. If we now consider a bowl sitting on top of another bowl, these can still rotate off one another but they cannot translate, giving less freedom to the assembly and thus a better-defined polymer. We have not changed the nature of the interaction between the building blocks, but simply how these systems can come together architecturally. This effect is even more pronounced when we use saddles instead of bowls. We now prevent rotation and translation, just like in a stack of the famous branded potato chips.

With this approach in mind, we have recently introduced a design principle that we named ‘Shape-Assisted Self-Assembly’. We demonstrate that monomers of an appropriate curvature, saddles, are able to form supramolecular polymers without the necessity of incorporating the strong “glue” often used to keep units together. By using a saddle-shaped porphyrinoid derivative that we have termed ‘carpyridine’, we were able to grow two-dimensional supramolecular polymers by following this principle. We found that these molecules aggregate vertically through weak supramolecular interactions, forming loose columns that then associate laterally to form a 2D surface.

In our most recent work, we were able to control the dimensionality of the grown assembly by blocking the lateral association between columns of stacked monomers. As a result, we have been able to form a one-dimensional supramolecular polymer grown from our molecules, just like potato chips packed inside a tube can. We were able to elucidate the mechanism for this process, in which the molecules stack on top of each other, constantly elongating the polymer. These structures, that could be confirmed under the microscope, open the door for studying direct applications such as migration of charge or light inside these columns.

Simply put, we have been able to gain an additional degree of control over the dimensionality of a supramolecular polymer, underlining the power of curvature. Learning how molecules interact and order themselves is key to understanding how large systems like our cells work. We unravel it, one chip at a time.

Feisty fish and birds with attitude: Why does evolution not lead to identical individuals?

2024-08-29 16:24:54

“Survival of the fittest” is synonymous with adaptive evolution. This catchy phrase suggests that all individuals within a population become identical over time by developing “THE fittest” heritable traits. Yet, in nature, we observe many differences between individuals. For example, sticklebacks (tiny fish) in the same lake often have different diets, and many birds show “personality”, or consistent differences in their behaviours.

Small differences between individuals can often be explained by a balance between random mutations and natural selection. Mutation is a random process, so it can have positive or negative impacts on an individual and its ability to reproduce. Biologists quantify this through an individual’s “fitness”. However, selection slowly removes mutations that lead to low fitness from a population. Because selection is not instant, such mutations can remain in a population for some time. Slow selection against harmful mutations can thus maintain small amounts of individual variability.

Our study aimed to identify mechanisms that cause higher levels of individual variability than mutation-selection balance alone. We focussed on a trait that determines how well an individual can compete within its own species for resources. We suggested that differences in the quality of resources lead to differences in how competitive individuals are.

We used an individual-based computer simulation that tracked the evolution of competitiveness in a large population over many generations. We assumed that individuals compete against each other for the best resources and that reproductive success (fitness) depends on both the quality and quantity of resources obtained. Therefore, in each generation, the most competitive individual attained the best available resources, the second most competitive individual attained the second-best available resources, and so on. However, we also assumed that highly competitive individuals had to use more resources to maintain their competitiveness, and therefore could invest less resources into reproduction. A relation like this is called a “trade-off”; here, high competitiveness trades-off with the amount of resources individuals can invest into reproduction. We used this computer simulation to investigate how different distributions of resource quality affect the evolution of competitiveness, and whether this trade-off can explain the maintenance of individual variability.

We discovered that different distributions of resource quality lead to two alternative outcomes. In one scenario, the average competitiveness of individuals remains constant, but each individual can vary widely from the average. The other alternative is a repeated cycle between periods in which all individuals are highly competitive and periods in which all individuals are much less competitive (with very little individual variability at any time). Such cycles represent an arms race. Being just slightly more competitive than others always gives individuals an advantage and causes a gradual increase in average competitiveness of the whole population. Eventually, this leads to states of high competitiveness that are very costly. This allows much weaker competitors, who do not bear the cost of high competitiveness, to replace the strong competitors and restart the arms race.

So, when should populations have constant, high variation in competitiveness, and when should they cycle through arms races? We found that more individual variability occurs when there is little difference in resource quality, or when populations are so small that no bad quality resources need to be used by any individual. We also discovered that individual variability is more likely to occur when resource quality varies and good resources are rare. Given that good resources are usually infrequent in nature, this provides a possible explanation of why we observe so much individual variability in populations.

In summary, large differences between individuals’ competitiveness is a natural consequence of differences in the quality of available resources and the cost for individuals to be competitive. Evolution does not necessarily result in all individuals being similar. Yet, the common phrase of “survival of the fittest” still holds true. Our study shows that when evolution leads to individuals that differ greatly from each other, they still have the same fitness. The cost associated with being more competitive creates subtle balances that allow weaker individuals to have the same fitness as their stronger competitors.

Tobacco smoking and other exposures shut off cancer-fighting genes

2024-08-29 15:49:32

Cancer is a genetic disease caused by mutations in DNA. Most mutations are substitutions of single nucleotides, the basic building blocks of DNA. Mutations occur over time due to natural processes like faulty DNA repair or from external sources like ultraviolet light. Researchers have discovered that these so-called mutational processes tend to mutate DNA in particular ways, preferring some nucleotides over others [1]. These preferences are known as mutational signatures and allow us to study which exposures or defects have altered the DNA in specific cancer samples.

If we think of the genome as an instruction manual for assembling the proteins essential for keeping our cells running like a well-oiled machine, genes would correspond to sentences that outline the sequence of amino acids making up each protein. Similarly to actual manuals, genes end with punctuation marks, known as stop codons, that tell the cell when to stop making a protein from a given sequence of genetic code.

DNA mutations can affect cells in many ways. Some mutations substitute individual letters in protein instructions, causing changes in protein structures. The most damaging type of protein mutations are 'stop-gain' or 'nonsense' mutations. These insert a stop signal in the middle of a gene, causing the cell to stop making the protein too soon. This results in an incomplete protein that the cell usually discards.

In our study [2], we asked whether stop-gain mutations in cancer genomes were preferentially generated by some mutational processes. Using statistics and data science tools, we analysed genomic data from over 12,000 tumour samples from 18 major cancer types. We found that some processes cause stop-gain mutations more often than expected by chance. Tobacco smoking was the most significant cause, especially in lung and liver cancers. Second was the activity of APOBEC proteins in breast cancer, which are a major source of cancer mutations and also act in our natural antiviral defences. Third was reactive oxygen species (ROS) in colorectal cancer. ROS are harmful by-products of cellular metabolism such as free radicals and have been linked to poor diet and excessive alcohol consumption. By examining the genetic code of amino acids along with the mutational signatures, we can explain how these three processes cause stop-gain mutations by targeting certain nucleotide patterns in DNA.

Our findings are supported by molecular and lifestyle associations. We analysed the smoking history of lung cancer patients and found that current smokers and recently-reformed smokers had the highest number of stop-gain mutations while patients who quit smoking over 15 years ago and patients who were always non-smokers had significantly fewer stop-gain mutations. Therefore, smoking habits can directly impact gene function in cells. Similarly, we linked the levels APOBEC enzymes to stop-gain mutations. Breast cancer patients with higher levels of APOBEC enzymes had significantly more stop-gain mutations than those with lower levels of APOBEC enzymes. Lastly, using data from earlier wet-lab experiments [3], we found that experimentally reducing APOBEC activity in cancer cells led to fewer stop-gain mutations, indeed showing that the APOBEC enzymes indeed contribute to the creation of these harmful mutations. APOBEC enzymes are studied intensively due to their many roles in cancer and potential for therapy development.

Some genes, known as tumour suppressor genes, protect us from cancer. When these genes are shut off, cells are allowed to proliferate in an unrestricted manner. We found that stop-gain mutations introduced by tobacco smoking and APOBEC activity frequently occurred in key tumour suppressor genes such as TP53, FAT1 and STK11 in multiple types of cancer. Therefore, these mutational processes can disable our protective mechanisms and contribute to the development and complexity of cancer.

These mutational processes appear to create damaging stop-gain mutations across the genome. Therefore, each individual tumor may have a distinct set of genes disabled by these harmful mutations, increasing the complexity of cancer. Since anti-cancer drugs are often tailored to specific genes, these stop-gain mutations can make tumours more difficult to treat, because drugs that are effective for one person might not be effective for another.

Taken together, our study shows how specific mutational processes can directly disable genes through harmful mutations. Since tobacco smoking and diet are lifestyle choices, these results allow us to better understand preventable causes of cancer with molecular insights. Healthier lifestyle choices can therefore reduce the risks of harmful mutations in cells.

1. Alexandrov, L.B., et al., Signatures of mutational processes in human cancer. Nature, 2013. 500(7463): p. 415-21.

2. Adler, N., et al., Mutational processes of tobacco smoking and APOBEC activity generate protein-truncating mutations in cancer genomes. Sci Adv, 2023. 9(44): p. eadh3083.

3. Petljak, M., et al., Mechanisms of APOBEC3 mutagenesis in human cancer cells. Nature, 2022. 607(7920): p. 799-807.

A hidden clock that times cytoplasmic divisions

2024-08-29 14:53:07

Omnis cellular e cellula – all cells arise from pre-existing cells. This seemingly obvious tenet of cell theory was only formalized when, in 1841, the Polish embryologist Robert Remak boldly described forms of animal cell division when examining chick embryo red blood cell development. Later, in 1882, German biologist Walther Flemming sketched, for the first time, the morphological changes during cell division in salamander embryos as they divide. Deriving from the Greek mitos (“thread”), Flemming coined the term “mitosis”, noting how neatly some “thick” fibers – later recognized as chromosomes – were organized and segregated at the cell’s midplane during its division. More than a century of research has sought to elucidate this elegant process. How do chromosomes arise from the scaffolds of a resting nucleus? How do they segregate evenly to create two daughter cells? And how does a cell know when to kickstart this process?

A major breakthrough came with the discovery of cyclin-dependent kinases (CDKs) and cyclins, molecules that control when cells replicate their DNA and divide. The CDK/cyclin complex was long thought to act as a master clock of the cell cycle. But with all scientific research, knowledge is never set in stone and even some long-standing paradigms can be refuted. A growing body of evidence suggests that a variety of cell cycle processes can cycle independently of CDK/cyclin activity, such as in centriole biogenesis [1-2], ATP/NADH metabolism [3], cellular growth [4], and transcription [5], amongst other sub-cellular events [6]. These recent advances have sparked the emerging concept of ‘autonomous clocks’.

Autonomous clocks are timing mechanisms in organisms that operate at their own frequencies to regulate various cellular phenomena. In dividing cells, these clocks are synchronized by CDKs and cyclins to match the timing of cell divisions. Think of autonomous clocks as the intrinsic motors of metronomes driving their periodic ticking. Only when these metronomes are placed on a common platform balanced on cylinders, do they get “phase-locked” together to click in synchrony. Strikingly, Bakshi et. al. has now discovered yet another cellular process that runs autonomously – cytoplasmic divisions [7].

Usually, during cell division, the nucleus divides first, followed by the cytoplasm. However, Bakshi et al. observed that in fruit fly embryos, this sequence can sometimes go awry. Early in development, cells on the surface of fruit fly embryosundergo synchronized cycles of nuclear divisions and cytoplasmic furrowing before gastrulation, the last step in early fly development. To observe these cycles in living embryos, Bakshi et al. generated embryos that express fluorescently labelled versions of histones and myosin’s regulatory light chain to visualize nuclei and cytoplasmic compartments respectively. The authors noticed that in wild-type fly embryos, 20% of all cytoplasmic compartments formed cytoplasmic furrows before mitotic entry. This observation was contrary to textbook depictions that describe the initiation of cytokinesis as strictly happening after mitosis. Wondering if such divisions occur due to an early local activation of CDK/cyclin complexes, the authors altered CDK activity via genetic means. Remarkably, they found that the timing of such early cytoplasmic divisions cannot be modulated by CDK activity, suggesting that they are uncoupled from nuclear divisions.

Remarkably, the authors also observed for ~3% of blastoderm divisions that the cytoplasm can sustain rounds of divisions completely without nuclei. If they could still divide without nuclei where principal CDK/cyclins normally initiate mitosis, is CDK activity at all required for cytoplasmic divisions? Using a combination of double-stranded RNAs targeting against all mitotic cyclins, Bakshi et. al. could halt CDK activity and its associated nuclear divisions immediately after fertilization. Indeed, they found that cytoplasmic divisions can occur in cycles without the blastoderm nuclei nor detectable oscillations in CDK activity. As CDKs require de novo synthesis of new cyclins at every cell cycle, the authors wished to test if the molecular mechanism for early cytoplasmic divisions also required protein synthesis. Surprisingly, by inhibiting protein translation, they found that cytoplasmic division cycles continued to occur and is likely not required to trigger early divisions.

These findings boldly point towards an autonomous cycle that may regulate the timing of cytokinesis. The next step is clear: what is the molecule(s) acting as a clock for cytoplasmic divisions? It will be exciting to see whether these unexpected findings from the little fly embryo hold true more broadly in cell biology.

References:

1. Aydogan MG, Wainman A, Saurya S, Steinacker TL, Caballe A, Novak ZA, Baumbach J, Muschalik N, Raff JW. A homeostatic clock sets daughter centriole size in flies. J Cell Biol. 2018 Apr 2;217(4):1233-1248. doi: 10.1083/jcb.201801014. Epub 2018 Mar 2. PMID: 29500190; PMCID: PMC5881511.

2. Aydogan MG, Steinacker TL, Mofatteh M, Wilmott ZM, Zhou FY, Gartenmann L, Wainman A, Saurya S, Novak ZA, Wong SS, Goriely A, Boemo MA, Raff JW. An Autonomous Oscillation Times and Executes Centriole Biogenesis. Cell. 2020 Jun 25;181(7):1566-1581.e27. doi: 10.1016/j.cell.2020.05.018. Epub 2020 Jun 11. PMID: 32531200; PMCID: PMC7327525.

3. Özsezen S, Papagiannakis A, Chen H, Niebel B, Milias-Argeitis A, Heinemann M. Inference of the High-Level Interaction Topology between the Metabolic and Cell-Cycle Oscillators from Single-Cell Dynamics. Cell Syst. 2019 Oct 23;9(4):354-365.e6. doi: 10.1016/j.cels.2019.09.003. Epub 2019 Oct 9. PMID: 31606371.

4. Liu X, Oh S, Peshkin L, Kirschner MW. Computationally enhanced quantitative phase microscopy reveals autonomous oscillations in mammalian cell growth. Proc Natl Acad Sci U S A. 2020 Nov 3;117(44):27388-27399. doi: 10.1073/pnas.2002152117. Epub 2020 Oct 21. PMID: 33087574; PMCID: PMC7959529.

5. Cho CY, Kelliher CM, Haase SB. The cell-cycle transcriptional network generates and transmits a pulse of transcription once each cell cycle. Cell Cycle. 2019 Feb;18(4):363-378. doi: 10.1080/15384101.2019.1570655. Epub 2019 Feb 5. PMID: 30668223; PMCID: PMC6422481.

6. Mofatteh M, Echegaray-Iturra F, Alamban A, Dalla Ricca F, Bakshi A, Aydogan MG. Autonomous clocks that regulate organelle biogenesis, cytoskeletal organization, and intracellular dynamics. Elife. 2021 Sep 29;10:e72104. doi: 10.7554/eLife.72104. PMID: 34586070; PMCID: PMC8480978.

7. Bakshi A, Iturra FE, Alamban A, Rosas-Salvans M, Dumont S, Aydogan MG. Cytoplasmic division cycles without the nucleus and mitotic CDK/cyclin complexes. Cell. 2023 Oct 12;186(21):4694-4709.e16. doi: 10.1016/j.cell.2023.09.010. PMID: 37832525; PMCID: PMC10659773.

Ammonia Energy: A Call for Environmental Awareness

2024-08-29 11:13:25

As the world shifts to low-carbon energy, finding alternatives to fossil fuels is essential. Hydrogen (H₂) stands out as a leading candidate because it can be produced in large quantities and used in many ways. Countries representing about 90% of the world's energy supply are already engaged in large-scale hydrogen projects, anticipating robust international trade between renewable-rich regions and demand hubs. However, transporting hydrogen is challenging because it has a low energy density. It needs to be either turned into a liquid at very low temperatures or compressed at high pressures, which is costly and risky due to potential leaks.

A promising solution for transporting hydrogen over long distances is to convert it into ammonia using the Haber-Bosch process. This industrial process is already applied at scale, mostly to produce agricultural fertilizers, making ammonia the second most produced chemical worldwide. As an energy carrier, ammonia would offer advantages like storage at more reasonable conditions, matured transport infrastructure, and the ability to be converted back into hydrogen or burned as a fuel. Overall this strategy holds promise for developing an ammonia-based economy, with ongoing projects exploring its use in vessels and power plants. However, despite the exciting premise, environmental considerations about potential undesired emissions due to improper ammonia management or use need comprehensive exploration.

Ammonia (NH₃) is a toxic gas that can pollute the air and water, harming both ecosystems and human health. The minimization of its leakages will hence be a priority. Additionally, undesired emissions of nitrogen oxides (NO_x) and nitrous oxide (N₂O) could occur during unabated or improper ammonia combustion. NO_x gases contribute to the formation of smog and acid rain and are already a global concern, especially in urban settings. N₂O, the so-called laughing gas, is a greenhouse gas around 300 times more potent than CO₂ -- nothing to laugh about! N₂O is also the leading anthropogenic contributor to stratospheric ozone depletion. In aggregate, these emissions would add another significant perturbation to the nitrogen cycle, a crucial aspect of Earth's ecosystems that has already been disrupted by agricultural activities. At the global level, it is estimated that the safe planetary boundary for nitrogen has already been crossed.

The risk of harmful nitrogen emissions depends on how much ammonia is produced and how much is lost through leaks or unwanted reactions during combustion. For example, if ammonia fuel achieves a market penetration of around 5% of the current global primary energy demand, ammonia production would need to increase by around ten times compared to current levels. If then only a few percent of the nitrogen in ammonia are lost due to leakages or undesired emissions during combustion, the resulting perturbation of the global nitrogen cycle could be comparable to the global impact of fertilizers. Moreover, with a 1% nitrogen conversion of ammonia into N₂O, ammonia combustion would have a greenhouse gas footprint worse than coal. It would hence provide more climate damage than conventional fossil fuels. Minimizing these emissions will hence be a priority for the success of the ammonia economy.

To maximize the benefit of ammonia adoption in the energy sector, it will be necessary to address, before implementation, the environmental challenges through proactive engineering measures. Identifying worst-case scenarios for ammonia systems can highlight areas of concern during development and optimization. Alternative combustion strategies, ammonia cracking, and existing technologies for converting emissions back into nitrogen offer potential solutions. There is an urgent need for early evaluation of combustion systems to mitigate emissions and further work to explore regulatory strategies to ensure optimal outcomes for ammonia fuel. We can learn from the mistakes of the past to guide the transition to an environmentally friend ammonia-based energy system.

When two kinases go for a dance

2024-08-29 10:25:56

Protein phosphorylation is an important cellular regulatory mechanism which acts like a molecular switch in our cells. It is a process where a phosphate group, a small but very consequential chemical tag, is added to a protein. Think of it as turning a light switch on or off: when a protein gets tagged with a phosphate group, it's often turned "on" or activated. Phosphorylation is one of the main strategies cells use to propagate the signals they receive from their environment and control the activity of proteins. This strategy allows a quick adaptation to changes in the environment - a vital reaction for various functions in your body.

Signal propagation through phosphorylation typically happens in ‘cascades’ of cellular events, similar to a relay race where a message is passed from one runner to another. Among the many runners within a cell, protein kinases transmit signals by adding a phosphate group on their target protein, often another kinase, propagating the signal until ultimately triggering a specific response in the cell. The kinases MKK6 and its substrate p38α, both Mitogen-Activated Protein Kinases (MAPK), play a crucial role in transmitting signals related to cell stress and inflammation.

Like in the relay race, the interaction between the kinases needs to be transient to allow the phosphorylation of multiple target proteins sequentially and signal amplification. However, this fast interaction time hinders structural studies that could allow us to see what happens when two kinases come together to phosphorylate one another and give us insights as to how we could interfere with this interaction associated with human diseases.

Therefore, we asked whether we could engineer the complex to stabilise the highly transient p38α -MKK6 dimer in its active form. We introduced the equivalent sequence from the Toxoplasma gondii protein GRA24 at the beginning of the MKK6 in a region called the kinase interaction motif, known to interact with p38α. Thanks to this engineering, we were able to increase the affinity of MKK6 for p38α and stabilise the complex. We also inserted two mutations in the MKK6 activation loop to transform the kinase into an active form that is ready to phosphorylate p38α.

Then, using cryo-electron microscopy (cryo-EM) - a technique used to visualise the three-dimensional structures of biological molecules at high resolution by rapidly freezing them and capturing images of their electron-scattering patterns - we resolved the structure of p38α in complex with MKK6 in a pre-phosphorylation state. The cryo-EM structure showed that the kinases adopt surprisingly a face-to-face conformation with all contacts between the kinases far from the MKK6 active site.

Since this conformation had never been described before, we had to be sure that the observed face-to-face complex corresponds to the ‘real’ complex involved in the physiological phosphorylation mechanism. To ensure that our engineered complex does mimic the endogenous protein in our cells, we compared the behaviour of the mutant and wild-type complexes thanks to a combination of two methods: the Hydrogen/Deuterium exchange coupled with Mass Spectrometry technique monitors protein dynamics and allows the mapping of protein interaction sites, while molecular dynamics simulations, a computer simulation technique, lets us follow the behaviour of the complex over time. Both methods showed that the contacts between the two proteins were the same in the engineered and wild-type complex.

The simulations also revealed that the conformation we see in the cryo-EM facilitates the approach of the activation loop of p38α to the active site of MKK6 without compromising MKK6’s ability to phosphorylate the two known sites on p38α. What is more, we were able to observe the mechanism by which the two kinases approach one another and the different conformations that they adopt to initiate phosphorylation.

Finally, by performing a series of cellular assays using variants of MKK6, we found that the length and structure of the kinase interaction motif linker are essential in making MKK6 specific to p38α.

Characterising the architecture of MKK6 activating its target p38α not only opens exciting new paths to better understand the complex’s inner workings, but also provides crucial information to design new drugs that can modulate the inflammation response regulated by p38α.

Awakening the thymus to cure SARS-CoV-2 infection: a matter of genes

2024-08-27 16:50:59

SarsCov-2, the virus causing COVID-19, became deadly for 1-2% of people infected , causing 7-8 million deaths worldwide. Although in most cases the fatal outcome was associated with old age and/or pre-existing debilitating conditions, it can occur in younger healthy individuals. Indeed, there are certain genes responsible for fighting infections that may markedly impair our chances of survival.

During the first phase of the COVID-19 pandemic, we observed an unexpected feature while studying patients with very severe pulmonary involvement caused by SARS-CoV-2. Many patients showed an unexpected enlargement of their thymus, and this feature was associated with decreased mortality and superior recovery, compared with patients without modification of this organ. The thymus is an organ of the immune system, located in the upper part of the chest behind the sternum, which produces a category of white blood cells essential for fighting pathogens and helping to produce antibodies, known as T-lymphocytes. The thymus is very active during the first part of life, up to early adulthood, and then becomes progressively less and less active. It can nevertheless be reactivated in older individuals, precisely during infections. Thymic activity, which consists of the release of new T-lymphocytes into the blood, can be quantified by laboratory tests. The maturation of T-lymphocytes within the thymus produces by-products known as T-cell receptor excision circles or TRECs, which can be measured by DNA amplification (PCR) from a blood sample. These tests confirmed that, in case of severe COVID-19 pneumonia, a higher production of new T-lymphocytes could contribute to a more favorable prognosis, regardless of the presence of thymus enlargement.

A previous unrelated study, conducted on a general healthy population, had shown that, independently of age and sex, the variation of a single DNA feature (referred to as Single Nucleotide Polymorphism or SNP) in the gene coding for the T-cell receptor (TCR) was associated with different levels of T-lymphocyte production by the thymus. The DNA code is based on 4 nucleotides identified by the A, T, G, and C letters, and every gene is present in two copies (one from the mother and the other from the father). In a specific position of the TCR gene, the presence of two “G” leads to a high level of T-lymphocyte production by the thymus. In case of the presence of two “A”, the production is much lower on average, and the presence of one “G” and one “A” results in an intermediate situation. We made the hypothesis of a potential connection between this finding and the higher production of T-lymphocyte in SARS-CoV-2-infected patients better recovering from severe pneumonia. We therefore investigated whether the SNP, which drives the thymus activity, might also affect the clinical outcome and the immune response in patients with severe COVID-19.

We conducted the study during the second burst of COVID-19 pandemics in Europe on a similar group of patients. We evaluated the SNP in each patient by gene sequencing of a PCR product from white blood cells, which resulted to correlate with both thymic production and the anti-SARS-CoV-2 immune response. Overall, we could validate our hypothesis that GG patients develop a stronger and long-lasting immune response against SARS-CoV-2 than GA and AA patients, independently of age, sex, and confounding factors. Clinically, the pneumonia of individuals harboring the GG genotype was less severe than that of the other patients. GG patients produced more T-lymphocytes (established by higher TREC values), compared to AA and GA individuals. They consequently developed a stronger and more efficient immune response against the virus and produced virus-neutralizing antibodies more often. A subgroup of patients was followed for a longer period and object of repeated tests, which provided interesting additional information. The signal “to produce more lymphocytes” that reaches the thymus during the acute phase of SARS-Cov-2 infection, causes the same increase in T-lymphocyte production in all individuals. However, since the basal level of production is higher in GG individuals, their final amount will reach a sufficient protective threshold after this amplification, a level which cannot be met in AA and GA individuals.

In conclusion, this study demonstrates that an SNP can affect the clinical and immunological responses against a severe viral infection, by determining both the baseline production of T-lymphocytes by the thymus and its infection-induced enhancement. We propose to include the analysis of this SNP among the predictive tests in critically ill COVID-19 patients and in other clinical situations where thymic production is important to fight a disease.

Reversible Anticoagulants: Inspired by Nature, Designed for Safety

2024-06-12 10:23:51

Globally, 1 in 4 adults will experience a stroke, but treatment options are limited.¹ Thrombin an essential enzyme in blood clotting, plays a crucial role in strokes. Thrombin converts fibrinogen, a soluble molecule, into fibrin, an insoluble substance. Fibrin acts like a fishing net, trapping red blood cells to form clots. In certain cases, people are at risk of unprompted blood clotting which can lead to strokes. Patients are commonly treated with anti-thrombin agents to ensure that excessive blood clotting does not occur. One of the therapeutic challenges in addressing blood clotting is that under or over-inhibition is equally dangerous. It has been estimated that anticoagulant-related bleeding is responsible for 15% of all hospital visits for adverse drug events.²Inspired by nature and supramolecular chemistry, our aim within the collaborative project between the University of Geneva and the University of Sydney was to develop an effective anti-coagulant that can be quickly reversed with an antidote.

For many people, blood sucking insects (ticks, leeches, mosquitoes, etc.) are the source of phobia and disgust. For scientists working in the anti-coagulation field, they provide a playground for discovery. Numerous blood sucking insects inject peptide-based anti-coagulants when they bite, in order to enjoy their meal. These natural anticoagulants also keep the meal liquid, which is essential for successful digestion. Hirudin, a protein found in leeches, has inspired approved anti-coagulants. A research group at the University of Sydney, directed by Prof. Richard Payne, previously synthesized these molecules in their lab to study the anti-coagulation activity. These molecules bind to different binding pockets on thrombin and in doing so, they block the transformation of fibrinogen to fibrin.

We transformed insect-derived molecules into two separate, inactive fragments that, when combined, form a powerful anticoagulant. We assembled the two fragments using a dynamic link called Peptide Nucleic Acids (PNA), a type of supramolecular interaction. PNA is similar to DNA, in that the genetic code (nucleobases A, T, C and G) is identical, and the structure is helical, but the backbone is peptide based, resulting in a more stable structure. The two PNA strands come together in the same way as DNA does: like Velcro, but in a very specific manner depending on the PNA sequence. This link has the advantage of being dynamic and reversible. The developed molecules were extensively studied and showed that, individually, the molecules have no effect on blood coagulation but when combined, they strongly decrease thrombin’s activity resulting in decreased blood clotting. They were further tested in vivo (mice-model) and showed comparable effects to an approved anti-coagulant (Argatroban) at lower doses.

As mentioned previously, reversibility is a strongly desired characteristic for the development of novel anti-coagulants, in order to facilitate dosage and to reduce the side-effects and risks. By controlling the link between the two fragments, we can manage the anticoagulant activity. We showed that a fast-acting antidote could unlink the fragments. In practice this is done by adding a third PNA strand which outcompetes for the interaction between these two components. This strand basically ‘unzips’ the drug resulting in two fragments which have little to no effect. This results in switching off the drug and rapidly restoring thrombin’s blood clotting ability. This reversibility was also tested in the in vivo model and showed rapid recovery of blood clotting similar to that when no drug was administered.

This study demonstrated the development of an effective anticoagulant which showed similar effects to a marketed drug. Our new therapeutic could be rapidly reversed by the addition of a simple antidote. We demonstrated this in the case of anticoagulants, but the technology is a general strategy for drug reversibility and could be applied to many fields, such as immunotherapy (where rapid reversal would be desired in the case of infection).

1- Global, Regional, and Country-Specific Lifetime Risks of Stroke, 1990 and 2016. New England Journal of Medicine 2018, 379 (25), 2429-2437. DOI: 10.1056/NEJMoa1804492.

2- Geller, A. I. et al. Emergency Visits for Oral Anticoagulant Bleeding. Journal of General Internal Medicine 2020, 35, 371-373. DOI: 10.1007/s11606-019-05391-y

Distance-preserving moves always keep a point fixed

2024-05-17 16:26:27

They all crucially rely on a fixed-point result. In mathematics, the use of fixed-point theorems is found in many instances, unsurprisingly because it is the way to solve most equations. But what is a fixed point? Intuitively, a fixed point is a point that does not move when we consider a transformation of the space.

For example, take a disc and rotate it around its centre. This transformation moves all the points except the centre of the disc, which remains fixed. A rotation, therefore, has a fixed point.

With this same disc, we can imagine another transformation: we choose a straight line through the centre of the disc and look at the mirror image of each point reflected by this line. With this transformation, all the points on the left of the line are mirrored on the right, and all the points on the right of the line are mirrored to the left. Only the points on the mirror line do not move. As a line or a line segment contains an infinite number of points, we have an infinite number of fixed points.

Some transformations have no fixed point: take an infinite sheet of paper and move it in a given direction by a given distance. All the points of the sheet of paper will have moved and there is no fixed point.

Two of the most celebrated and consequential fixed-point theorems are that of Brouwer from 1911 and the contraction mapping principle as formulated abstractly by Banach in 1920. Nash used the first to define equilibrium in economics, and the second is hidden in Google's search engine.

To better understand the power of the Banach fixed point theorem, let's have a look at the following example: Take two equal-sized sheets of paper and place one on top of the other so that every point on the top sheet can be matched to its corresponding point on the bottom sheet. Now, crumple the top sheet and place it somewhere on top of the flat sheet of paper. The theorem says that a point necessarily exists on the top sheet that lies precisely above its "mapping point" on the bottom sheet.

Anders Karlsson from University of Geneva recently discovered a new isometric fixed-point theorem. There are significant implications for the field of mathematics, and this new theorem offers a fresh perspective on fixed-point theorems.

This fixed-point theorem applies to any isometry, which means a transformation that preserves all distances between points. For example, the three transformations defined above (rotation, symmetry, and translation) are isometries.

For this to be true, we will need to add an element to our space. Mathematicians call this process a “compactification”, making an infinite space into something “compact”. Let’s go back to the translation above which has no fixed point in the plane. The plane is infinite in all directions and has no border. But now, imagine adding a border around it. This boundary lies at infinity and adding it to the plane will make it “compact”. Think that each point on the boundary is representing one direction and the whole boundary all the possible directions. A rotation will move the points within this boundary. But a translation which is defined by moving points in one, and only one direction will keep one point on the boundary unchanged, the point that represents the direction of the translation. After the compactification of our plane, a translation has also a fixed point.

Let's look at another example: imagine a hexagonal lattice and consider the following transformation: choose one hexagon and send each corner to its left-hand neighbour. This operation induces a transformation on the whole lattice, which is, in fact, a rotation. The centre of this rotation is the centre of the hexagon you have chosen. It does not belong to the lattice. So, this transformation has no fixed point in the space formed by the lattice. Mathematicians invented a special compactification, that works for any metric space. For the lattice, it will somehow “fill” it, allowing for our transformation to have a fixed point.

This new result applies to many mathematical fields, such as dynamical systems which study how things change over time like planetary motion or economic models, or operator theory, which provides mathematical tools to understand and predict these changes. Studies are underway to find ways of compactification for various spaces and would lead to further applications.

As mentioned above, the use of fixed-point results is fundamental in theoretical economics, in physics and more generally in science. The nature of mathematics is such that its principles apply simultaneously to a wide range of subjects. As always in fundamental research, the future usage of a theory is impossible to predict but promises exciting new applications.

Keeping the balance: How epigenetics monitors cancer genes

2024-05-13 11:39:54

The human genome contains around 20,000 genes with two copies per gene, one inherited from each parent. Changes in the genome including gene breaks, rearrangements, and extra gene copies are frequent in many diseases, most commonly in cancer. DNA breaks occur often throughout the genome, but are usually repaired with little-to-no long-lasting impact. However, sometimes, very specific regions in our genome can break apart and rearrange incorrectly. Some cells will also contain extra copies of specific genes (three or more copies vs two). Recent studies identified a handful of enzymes that can control the ability of cells to generate extra copies of very specific genes commonly altered in cancer. These enzymes influence genes by adding or removing chemical tags - known as methyl groups (one carbon atom bonded to three hydrogen atoms) - on histone tails (the proteins which our DNA wraps around to help organize DNA). These ‘writer’ (adder) and ‘eraser’ (remover) enzymes control the presence or absence of these methyl chemical marks on histones and act as a counterweight to each other, keeping the stability of the DNA in check, also known as epigenetic regulation.

In infant, adult, and therapy-associated leukemia, the MLL gene is commonly rearranged and often has more than two copies, leading to highly aggressive diseases that are difficult to treat. However, it was unknown exactly how cells rearrange this gene or increase its copies. Another common variation in leukemia is deletion of a specific region of our genome that contains a gene encoding a methyl “eraser” enzyme, KDM3B. With these two points in mind, we hypothesized that deletion or suppression of the KDM3B gene directly stimulates MLL gene copy gain and rearrangement. To look at MLL copy number and rearrangement status within cells, we used an assay that allows us to visualize the gene using fluorescence. Fluorescent labels mark each end of the MLL gene in different colors. If the gene is not rearranged, then they will be directly next to or on top of one another when visualized. If it is rearranged, then the fluorescent labels will be separated. To assess copy number, we counted the number of fluorescent markers per cell, expecting a normal number of two per cell.

To test whether loss of KDM3B directly promotes MLL copy gain or rearrangement, we blocked or inhibited the activity of the KDM3B enzyme. We found that loss or inhibition of KDM3B specifically caused MLL to undergo copy gain and rearrangement. As KDM3Bis an eraser of histone methylation, we wondered if blocking or inhibiting an opposing “writer” enzyme of this methylation, called G9a, would counteract the MLL alterations. When we blocked or inhibited G9a before blocking KDM3B, the MLL copy gains and rearrangements did not occur. This was important because it suggested that the histone methylation status itself is controlling whether MLL gains extra copies or is rearranged. We then wondered what the change in histone methylation could be doing to the gene in order to encourage these changes to occur. A particular protein that binds to the MLL gene called CTCF had previously been suggested to promote MLL alterations, although it was not directly proven. When we blocked or inhibited KDM3B, we found that CTCF was no longer binding to the DNA encoding the MLL gene. Furthermore, we found that if we reduced the amount of CTCF, MLL copy gains and rearrangements occurred. Therefore, reduced CTCF binding on the MLL gene stimulated the MLL alterations.

Doxorubicin (Dox) is a chemotherapy commonly used to treat many cancers, including leukemias. Unfortunately, Dox is also associated with aggressive therapy-associated leukemia that have these MLL alterations. We hypothesized that Dox may be driving therapy-associated leukemia by promoting MLL alterations through reducing KDM3B and CTCF levels. We tested this by treating cells with Dox, and found that CTCF and KDM3B protein levels were reduced, leading to increased MLL copies and rearrangement. The effect of Dox on the MLL gene could be completely rescued by inhibiting the methyl “eraser” enzyme, G9a, which provides the first way to control this process.

In conclusion, direct epigenetic regulation controls MLL gene alterations. Our study suggests that inhibiting G9a before treating patients with Dox could prevent the MLL alterations that associate with therapy-associated leukemia. These findings suggest that additional epigenetic “writer” and/or “eraser” enzymes proteins may be working in concert with one another to control different genes throughout the genome, which are also driving other cancers.

An Emerging Era: Wearable Breast Ultrasonography at Home

2024-05-13 11:22:55

Breast cancer is a long-lasting global health challenge, and its early detection plays an important role in improving survival rates. Ultrasound is one of the most common methods of medical imaging for breast cancer, as it uses high-frequency sound waves to image the body's internal structures. However, current ultrasound methods have limitations, especially when encountering the complex and variable geometries of the breast. We envision a future in which we can detect breast cancer with a simple, user-friendly, at-home use wearable patch, transforming the possibilities for its early detection and increasing the survival rate to up to 98%.

At present, the wide deployment of ultrasound for disease detection and monitoring has been limited by fixed transducer shapes. A transducer is the part of the ultrasound device that is placed on the body, as it emits sound waves and receives the echoes to create an image. This fixed transducer geometry is generally considered a requirement for image reconstruction. However, the curvature of body surfaces is not fixed, which necessitates the application of transducer pressure by an operator during imaging. This compression-based process of imaging requires skill, which increases the variability of results between operators and makes it incompatible with wearable technology. Additionally, it is impractical for existing planar and bulky ultrasound transducers to maintain sufficient contact to image extensively over curved surfaces like the breast. To address these challenges, we have developed a conformable, wearable ultrasound patch that eliminates the need for the operator-applied pressure with a transducer, as it maintains consistent and close contact over large-area, curvilinear soft tissue.

Our new conformable Ultrasound BreastPatch (cUSBr-Patch) makes several novel scientific and engineering contributions. First, it introduces a large-area, conformable transducer design that is flexible to conform to the breast’s shape. The transducer is phased array, meaning that it contains multiple small elements that can be controlled independently to focus the ultrasound waves more precisely on the breast area. By embedding these piezoelectric elements into a soft material, we ensure consistent contact with the skin for clear imaging as the ultrasound patch adapts to the shape of the soft tissue target (in this case, the breast). Moreover, the design of this patch is inspired by the honeycomb structure found in nature. This patch design is composed of a soft fabric bra as an intermediary layer, a honeycomb patch outer layer for scanning guidance, and a tracker attached to the ultrasound array for rotation and handling. This honeycomb design directly guides the user for scanning, resulting in consistent and reliable imaging, in addition to easy use. The design also allows for 360-degree rotation at all points, greatly increasing its range of motion.

We achieved a high contrast resolution of ~3dB by using a novel piezoelectric crystal, which generates an electrical charge when pressure is applied, alongside this nature-inspired honeycomb patch design. Our in vitro experiments revealed that we captured details as small as 0.25 mm from top to bottom (axial) and 1.0 mm from side to side (lateral) at a depth of 30 mm. Using this prototype with a commercial ultrasound imaging system, we successfully detected a small cyst (of about 3 mm) in the breast of a female subject with a history of breast anomalies. This makes the cUSBr-Patch suitable for early breast cancer screening, in which lesion dimensions do not exceed 20 mm. The honeycomb design allows for imaging without a skilled operator, in addition to creating repeatable imaging positions for reliable breast tissue screening in long-term monitoring.

Our cUSBr-Patch will advance the understanding of soft tissue imaging by enabling an ultrasound technology that can be scaled up in size to any human body part. Compared to current diagnostic ultrasound, our patch is operator-independent, allows for standardized and reproducible image acquisition, requires less technician time and effort, and is conformable over the entire breast.

Future development of this system would allow patients to self-screen daily, record historical sonographic data, and send their data profiles to medical practitioners—without needing medical appointments. Integrated AI for imaging analysis could investigate collected images, aid in diagnosis, and predict trends. Complementing mammographic imaging with automated analysis would optimize the use of scarce breast cancer care resources.

In conclusion, our cUSBr-Patch represents a revolutionary step in medical diagnostics, offering a cost-effective, accessible, and user-friendly wearable ultrasound tool. Not only will it save time for doctors and augment standard technical analysis, but it also provides a practical solution to the widespread challenges of accessibility, cost, and infrastructure limitations, particularly in developing nations.

A resonance triggers chemical reactions between the coldest molecules

2024-05-13 00:00:00

Chemical reactions occur in our everyday life. Our basic knowledge of chemistry tells us that temperature, concentration, surface area, and catalysts can speed up or slow down chemical reactions. For example, a carton of milk would spoil much faster if kept out of a refrigerator. In the ultracold regime, typically less than several millionths of a kelvin above the absolute zero (-459 °F or -273 °C), the description of chemical reactions is quite different. Scattering particles are represented as waves, and depending on their quantum states, the reaction rate may not depend on their temperature at all. More surprisingly, chemical reactions in the ultracold regime can be controlled using resonances. You may have seen numerous fallen bridges and demolished buildings by mechanical resonances, showing how powerful such effects can be. Similarly, the effect of collisional resonances can yield dramatic changes in the rate of chemical reactions between ultracold molecules, in degrees much greater than what we would normally expect in our daily lives.

Macroscopically, chemical reactions seem like a magical process in which reactant particles jump into the state of the final product. However, in a microscopic view, there exists an intermediate step where the reactant particles collide and form a collisional complex which can be represented as a single bound state. Feshbach resonance, a type of magnetically tuned collisional resonance, occurs when the energy of the collisional complex is equal to the energy of the two colliding particles. It can immensely change interactions between the reactant particles from weak to strong and/or repulsive to attractive. Since its first observation in sodium atoms (Na) near absolute zero temperature in 1998, Feshbach resonance has become an essential tool in ultracold atomic experiments. As a result of collective efforts to create and manipulate ultracold molecules, Feshbach resonances were recently observed in the two systems of ultracold atom and properly bound molecule mixtures (Na + NaK in 2018 and Na + NaLi in 2021). It has been shown that these atom-molecule collisions with low reactivity can have a much faster chemical reaction through Feshbach resonance. The chemical reaction rate in Na + NaLi has been reported to be enhanced by more than a factor of 10 at a certain magnetic field.

While its effect in atom-molecule reactions is observed, there has been an open question of whether the Feshbach resonance could also be applied to control the rate of molecule-molecule reactions. Many theorists rather predicted negatively, postulating that collisional resonances may not be observed between tightly bound molecules, mainly because of two reasons. First, the collisional resonances may occur at multiple magnetic field values within a small range. Consequently, the resonances are likely to be unresolvable. Second, resonances can be more pronounced when a longer time is spent in an intermediate collisional complex state during a chemical reaction process. However, there exist many mechanisms which can destroy the intermediate collisional complexes. Such mechanisms are likely to broaden the resonant features making it more difficult to identify resonance from the background signal.

Experimentalists always seek empirical evidence of the theory. As such, we searched for Feshbach resonances in collisions between NaLi molecules. With various cooling techniques to prepare ultracold gases of Na and Li atoms and using these atoms as building blocks, we assembled a gas of magnetic NaLi molecules in their ground state at 1.8 micro-Kelvin (0.0000018 K). We searched for collisional resonances by sweeping a large range of magnetic field values and identified a single Feshbach resonance centered at 334.92 Gauss (G). The resonance that we observed can increase the reaction rate by more than a factor of 100 while being extremely narrow (~25 milli-Gauss). The observation of a single Feshbach resonance that is not broadened at all contradicts the current molecular collision theories.

Our observation of the unexpected resonance calls for further studies on the properties of collisional complexes. While the resonance raises many questions, the observation is particularly interesting in two regards. First, the pronounced Feshbach resonance provides strong evidence for a stable, long-lived collision complex, which is unexpected in a molecular system of high reactivity such as NaLi. Is a long-lived state coexisting with unstable states a common feature of molecular systems? Second, the resonance is observed at the magnetic field where another internal quantum state of a NaLi molecule becomes energetically close to the reactant quantum state. It is possible that there are many more resonances existing at other magnetic field values but are only detected by a mechanism that involves another state that has the same energy. Our result suggests a new type of resonance that could be ubiquitous in ultracold molecular physics, offering a powerful new mechanism for controlling ultracold chemical reactions.

Natural products might just be our best weapon against antibiotic resistance

2024-03-27 12:02:23

Plants and their rich biodiversity have been used by humans to treat diseases since the dawn of time. Synthetic chemists still struggle to reproduce the complexity of certain chemical reactions that nature has developed throughout millions of years of evolution, which makes the world of flora a great source of inspiration for new bioactive chemicals to be discovered. Yet one of the challenges in Natural Products research is to disentangle the hundreds of molecules contained within each plant extract to highlight those of biological interest.

Additionally, Natural products have a proven track record in the development of anti-bacterials, while antibiotic resistances are on the rise. This is particularly problematic in the case of the world’s deadliest infectious disease: tuberculosis. This disease is caused by mycobacteria, which are notoriously difficult to treat with only few antibiotics being at hand.

In a collaborative effort with the company Pierre Fabre, our team was able to take advantage of their historical library of 18 000 plant samples that could be used as a source of inspiration, for the search of new anti-mycobacterial molecules. In the frame of our study, we proposed an original approach in which 1600 extracts representing approximately 10% of the entire library of plant extracts were analysed with advanced Mass Spectrometry (MS). This method allowed for the identification/detection of hundreds of chemical constituents in each plant extract.

Among these chemicals, for those that have been previously reported in the literature, we could then associate a possible structure also referred to as an “annotation”.

At the end of this process stood an atlas with over 37 000 predicted structures, that revealed which molecules were likely to be found in which plant. We effectively transformed the collection of extracts into a virtual chemical library of natural compounds.

One way to explore this atlas was to look for natural analogs of commercial molecules previously screened in our advanced biological model. This biological model is in fact an anti-mycobacterial assay carried out using a mycobacterium, hosted in an amoeba, which mimics the behavior of some of our immune cells in the human body when attacking mycobacteria.

In fact, one active molecule from this previous screen (“molecule D”) was targeted using a computational tool called “DataWarrior” that allowed us to search for analog molecules by structural similarity. Within all 37 000 annotations, we found 4 structural analogs of molecule D that were detected in a single plant: Cananga brandisiana. This plant was selected and isolation of said molecules from it was carried out to see if our predicted annotations made from MS data would be correct. Indeed, they were, and these natural analogs were then isolated and subsequently tested against the disease model that was used to identify the previously mentioned template molecule.

Eventually, we managed to isolate a total of 8 analog molecules, of which one in particular (Onychine) showed a promising activity profile when compared to the initial molecule. While in absolute terms its anti-mycobacterial activity was less strong than that of molecule D, it did show a reduced toxicity towards the cells hosting the bacteria in the experiment (amoeba). This information will help us to make links between activity and molecular structure for this type of molecules to improve their bioactivity.

In conclusion, we successfully demonstrated a novel approach for the targeted isolation of bioactive natural products from a diverse collection of plant extracts. Establishing a chemical atlas for our plant library allowed us to avoid cumbersome isolation procedures and instead to efficiently target the molecules of interest. This also provided a large database of over 37 000 predicted molecules that can be explored in different contexts. The combination of computational analysis, mass spectrometry profiling, and biological testing allowed for the isolation of promising molecules with potential for combatting antibiotic resistance in diseases like tuberculosis.

Chemotherapy and heart failure

2024-03-26 15:58:28

One of the chemotherapy treatment options for patients with breast cancer usually includes multiple cycles of therapies based on an intravenous medication of a group called anthracyclines. During the last two decades, the percentage of cure and response rates for cancer patients undergoing this treatment have improved significantly, increasing survivorship and, in turn, the number of patients who have received chemotherapy.

Anthracyclines work by altering cancer cells, genes, causing malfunction. These effects are relevant for cancer treatment; however, one of the potential side effects of anthracyclines is the development of heart failure. In previous studies, anthracycline's toxic effect on the heart has been described as dose-dependent, meaning a higher dose was associated with higher cardiac risks.

We completed a study that focused on evaluating the risk of developing heart failure in cancer patients treated with anthracyclines compared to individuals with similar age and cardiac risk factors from the same region who did not receive this medication (referred to as controls). The study population was located in the midwest of the United States and is part of the Rochester Epidemiology Project (REP) network, which allowed for accurate recollection of information by clinicians and cardiologists.

We assessed 2,196 patients in total, including 812 with breast cancer, Hodgkin and non-Hodgkin lymphoma, and controls. We evaluated the total number of patients who developed heart failure for over 20 years. Interestingly, cancer patients generally had a higher associated risk of heart failure than controls. To address the connection with anthracyclines, we evaluated a subset of patients, comparing anthracycline use to no anthracycline. Those who received an anthracycline-based regimen had an increased risk of developing heart failure. This risk started during the first year of treatment and persisted throughout the 20 years of follow-up, and was present regardless of the dose, even with low to intermediate dosage.

The cumulative incidence evaluates the number of patients at risk that developed heart failure during a specific time. This cumulative incidence showed that patients with anthracycline use had more than double risk of developing heart failure after 20 years, compared to cancer patients with no anthracycline use.

In our study, we evaluated what other conditions might be associated with increasing the risk of developing heart failure in this patient population. We identified the age of diagnosis as an important consideration. Other risk factors, such as high cholesterol, diabetes mellitus, hypertension, or the concomitant use of radiotherapy regimens, were not significantly associated with a higher risk of heart failure.

Patients with breast cancer or lymphoma (Hodgkin or non-Hodgkin) have a significantly greater risk of developing heart failure (10.75% vs 4.98% for controls) up to 20 years after the diagnosis of their malignancy, and this is associated with the use of anthracycline chemotherapy.

To summarize, this study contributes to expanding the current literature, supporting, and creating guidelines for patients undergoing a chemotherapy regimen based on anthracyclines. Our goal is the close monitoring and time-efficient identification of signs and symptoms of cardiotoxicity, to prevent further damage. Patients should be frequently screened for symptoms such as shortness of breath, fatigue, and lower extremity edema. Additionally, imaging such as echocardiography (cardiac ultrasound), cardiac MRI, or stress tests should be implemented periodically to identify early deterioration of cardiac function.

Monoclonal antibodies that are effective against all COVID-19 -related viruses

2024-01-31 16:17:22

In late 2019, a novel coronavirus approximately 80% similar to the virus that caused the Severe Acute Respiratory Syndrome (SARS) in 2003 was first reported in China. This virus designated as SARS-2 (the COVID-19 virus) later swept through the globe, causing millions of infections and deaths, greatly disrupted lives and economies as countries strive to protect their citizens by limiting the spread of infection and rapidly developed diagnostics, therapeutics and vaccines. Despite these global efforts, SARS-2 continues to circulate widely in the population more than three years after the pandemic was first announced. The virus started to mutate rapidly when vaccines and therapeutics (i.e. small molecules and monoclonal antibodies) were rolled out to manage the pandemic, and the viral mutants that had higher transmissibility and were able to evade population immunity conferred by vaccination and infection became new circulating strains. All the monoclonal antibodies that are licensed to treat severe COVID-19 disease thus became ineffective after some time due to the constant renewal of resistant circulating variants in the population.

Antibodies are one of our body’s key defences to external insults (e.g. infection by bacteria and viruses). People who have been infected by the SARS-2 virus during the early pandemic period were recruited by researchers to learn more about this novel virus and these participants would have naturally made antibodies that helped them to recover from the COVID-19 disease. Antibodies made by the body are a mixture of strong and weak clones (polyclonal), and by isolating these antibodies into their single clones, strong monoclonal antibodies against SARS-2 can be identified.

In this study, we recognized the high similarity of the SARS-1 virus that caused a small outbreak in a few countries in 2003, and the SARS-2 virus that caused the pandemic in 2019. Thus we asked the question: “Could we find monoclonal antibodies that have potent activity against both SARS-1 and SARS-2, that potentially also cross react to the broader SARS-related virus family called sarbecoviruses found in animal hosts that may have the possibility to jump hosts to humans in the future?” If such antibodies can be discovered, then we can be ahead of the SARS-2 virus as these antibodies are likely to be effective on new mutants. More importantly, we can also be prepared for the next outbreak caused by sarbecoviruses by readying these antibodies for treatment of infected people, or for pre-emptively treating people who have had close contact with infected people, to break the infection cycle.

To achieve our goal of finding highly potent monoclonal antibodies that work against all sarbecoviruses, we started from a special cohort of participants who recovered from SARS-1 in 2003 and received vaccinations against SARS-2 in 2021. Our hypothesis is that people who have experienced two or more strains of fairly different sarbecoviruses will make antibodies that react against common patches of the viruses. As the common patches of the viruses are important for virus viability, they are shared amongst many family members. On the other hand, different patches between the different family members give each virus their uniqueness and we wanted to avoid that as much as possible, otherwise we might experience the same issues of existing monoclonal antibodies, whereby it worked well against the current strain of SARS-2 but lost activity against new viral evolutions. Our findings support our hypothesis. We were able to identify a lot of monoclonal antibodies that cross react to both SARS-1 and SARS-2 viruses. In addition, our best antibody E7 also neutralizes multiple animal sarbecoviruses (i.e. RaTG13, GX-P5L and WIV-1) and newly emerged SARS-2 variants (currently tested until Omicron EG.5.1 subvariant). E7 reacts to two distinct patches on the SARS-2 virus, prevents binding of SARS-2 virus to its target cell receptor and subsequent entry of the virus into the cell. As E7 is able to neutralize so many members of the sarbecovirus family, it may be safe to extrapolate that the virus patches E7 bind to are highly conserved between many members of the sarbecovirus family so E7 will continue to work against new viral emergents.

Our strategy to target shared important patches of the sarbecovirus family has additional implications beyond the identification of pan-sarbecovirus neutralizing monoclonal antibodies. With the majority of the world’s population vaccinated against SARS-2, we should consider the development of SARS-1 and/or animal sarbecoviruses vaccines as booster vaccines, rather than waiting for the next variant-of-concern before updating our SARS-2 vaccines. By doing so, we could broaden our immunity against sarbecoviruses and reduce our susceptibility to constant waves of SARS-2 infection in the future.

Stressing the gut-brain axis

2024-01-31 15:58:12

Inflammatory bowel disease (IBD) is a group of chronic intestinal disorders that mainly manifests in two forms: Crohn’s disease and ulcerative colitis. These diseases involve persistent inflammation of the gastrointestinal tract and can cause severe symptoms including abdominal pain, diarrhea, and intestinal obstruction. If left unmanaged, IBD often leads to serious complications such as colorectal cancer or sepsis. The exact cause of IBD remains elusive, though it is thought to emerge from a complex interplay of genetic predisposition, lifestyle, and environmental factors. Studies linking stressful life events with IBD flare-ups suggest that psychological stress is a pivotal contributor to IBD development. However, until recently, the underlying mechanisms responsible for this connection have remained enigmatic.

To investigate the effects of psychological stress on IBD, we used a mouse model with chemically induced bowel inflammation. We simulated stress in the mice by physically restraining them or exposing them to more aggressive mice. Interestingly, the stressed mice developed more severe colitis, mirroring the situation in humans.

When our bodies (or those of mice) get stressed, two pathways are activated: the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis which causes the release of a hormone called corticosterone. As expected, we saw that when the mice were stressed, both pathways became more active. However, when we tested blocking each pathway in turn, blocking of adrenal-gland derived corticosterone signaling, but not sympathetic signaling, provided protection against the effects of psychological stress on gut inflammation. This suggests that during stress, the release of corticosterone is the important link that connects our stressed nervous systems to the increased gut inflammation and diseases like colitis.

Next, we sought to understand mechanistically how elevated corticosterone levels contribute to inflammation of the gut. Using different experimental strategies including studying gene activity in single cells, we identified that a type of white blood cell, known as a monocyte, is a key driver of stress-induced gut inflammation. Upon psychological stress, these monocytes accumulate in the gut and produce a protein called tumor necrosis factor (TNF) which worsens colitis. However, we found that elevated corticosterone levels do not act directly on monocytes. Even when we specifically removed the corticosterone receptor in monocytes, it did not protect against colitis worsening.

These results indicated the existence of a signaling hub mediating the effects of stress-induced corticosterone on monocytes and ultimately on bowel inflammation. Thus, we focused on the gut-residing enteric nervous system, which controls many essential gut functions and is known to respond to corticosterone.

By studying gene expression in individual cell nuclei, we found that psychological stress leads to profound changes in gene activity in gut cells called enteric glial cells. We found that this stress also triggers the emergence of a new type of enteric glial cell, which we named enteric glial cells associated with psychological stress (eGAPS). These eGAPS produce a protein called CSF-1 which is known to attract monocytes, and we found this to be a driving force of the harmful effect of psychological stress on colitis via TNF production. Additionally, stress leads to distinct gene activity in enteric neurons which is influenced by a protein called TGFβ2. These changes make the neurons less mature, which causes constipation and issues with gut movement which further worsen inflammation.

Do these experimental findings mirror the situation in humans? Yes, they do. We studied data from various databases: the UK Biobank study, the myIBDcoach real-world prospective cohort study, and a colonoscopy study we conducted at Penn Medicine. We found that elevated levels of perceived stress strongly correlated with higher incidence and increased colitis severity. Furthermore, stress levels strongly correlated with the expression of distinct genes indicating monocyte recruitment, TNF production, general inflammation and elevated TGFB2 in colon biopsies from IBD patients. This provides mechanistic evidence for our findings in humans.

In summary, we unveiled a multi-step signaling link between psychological stress and the development and worsening of inflammatory bowel disease. By clarifying the intricate mechanisms by which stress impacts the gut, these findings open new avenues for understanding and treating IBD. Furthermore, they underscore the importance of addressing psychological well-being as an integral component of IBD care, offering hope for more effective and holistic treatment strategies in the future.

Taurine: a supplement for extending life-span and health

2024-01-31 15:44:28

Aging is a complex biological process that has always captivated scientists, drawing them into often long research journeys to unravel the mysteries of this natural process. In our quest to understand the mechanisms that underlie the aging process, we serendipitously stumbled upon taurine in a screen performed in aged humans. Taurine is not a new molecule, it was identified in 1827 in ox bile by Tiedmann and Gmelin. Taurine’s functions or actions remained poorly understood for almost 150 years. Due to the increase in affluence in societies in the 1950s, there was an increased demand for packed pet foods. This introduction of pet foods led to increased incidence of diseases in the pets, such as cardiac failure and diabetes. One of the most striking aspects of this episode was an increased incidence of blindness in cats. According to the study published in 1975, researchers identified that retinal degeneration or blindness in these cats is caused by deficiency of a single molecule in their diet, taurine. Since then, taurine has been shown to be associated with several parameters in animals and humans. However, it was not known whether changes in taurine abundance affects aging.

Our results show that taurine abundance declines with age in several species. We thus sought to determine whether the decline in taurine concentration was merely a consequence of aging or whether it played a role in driving the aging process. To address this question, we began supplementing mice, worms, and yeast with taurine. Our investigations showed that mice supplemented with taurine lived longer. When we analysed organ health in taurine-supplemented mice, we saw an improved functioning of several organ systems such as bone, muscle, brain, pancreas, and the immune system. These results show that taurine supplementation helps mice live longer and healthier. Taurine supplementation also made worms live longer and healthier, and improved several organ functions in monkeys. At the cellular level taurine regulated several processes classified as hallmarks of aging in mice; Taurine suppressed cellular DNA damage, cell-replication arrest, inflammation and it enhanced protein regulation and energy generation by mitochondria in the cells. Taurine appeared to have influence on all major hallmarks of aging.

We further performed an association analysis of taurine and metabolites with health-related parameters in approximately 12,000 aged humans. This analysis showed that lower abundance of circulating taurine and its metabolites is associated with higher incidence of diseases, such as obesity, type 2 diabetes, hypertension, and inflammation. Conversely, exercise that is known to promote health in humans and is considered anti-aging, increased circulating levels of taurine and its metabolites. Although these studies in humans are just associations, they are consistent with the idea that taurine deficiency could be a driver of aging in humans, too.

In summary, our studies suggest that taurine supplementation is a potential anti-aging intervention. Taurine increases lifespan in worms and mice, improves healthspan in worms, mice and monkeys, and changes in its abundance associates with several health parameters in humans. These studies contribute to the increasing importance of dietary molecules as regulators of health. In future, a randomized placebo controlled clinical trial is needed to find out whether taurine supplementation increases healthspan in humans as it does in lower species.

Take Them Outside: Cold Air Helps Croup Symptoms in Kids

2023-12-22 14:53:48

Croup is a common infection that mainly affects babies and young children from six months to three years old. Croup symptoms include a characteristic barking cough that predominantly occurs during the night, a hoarse voice and a squeaky, high-pitched noise when breathing in. Although most cases are mild, croup is a significant health care burden that causes 3 to 5% of visits to paediatric emergency departments and 72-hour readmissions for children under the age of two.

The recommended treatment for croup is a single oral dose of dexamethasone, a steroid that takes about 30 minutes to take effect. However, paediatricians and parents alike have long reported that cold fresh air helps soothe the symptoms of croup. Many parents even noticed improvements in their child’s symptoms in the fresh air on the way to the hospital. Until now, this cold air treatment remained predominantly anecdotal, with no documented scientific evidence to support it.
This motivated a group of paediatricians at Geneva University Hospitals (HUG) and The University of Geneva to carry out the first randomized study asking whether cold air genuinely reduces the severity of croup symptoms in children.

On cold days (below 10°C) between November 2016 and May 2021, Dr. Siebert and his colleagues conducted the clinical study on 118 children brought to the hospital with croup. Children between three months and ten years who had a croup severity of 2 or above on the Westley Croup Score were included in the trial. The Westley Croup Score, or WCS for short, is a scale ranging from 0 to 17 that clinicians use to categorize how severe a patient’s croup symptoms are.

In the hospital’s emergency department, after triage and a standard dexamethasone steroid treatment, children were randomly assigned to wait for 30 minutes either outside in the cold air with a blanket, or inside at 25°C. After the half-hour wait, patients in the outdoor group returned inside the emergency department and all the children were re-examined. The clinicians assessed whether the child’s symptoms had decreased by 2 WCS points compared to before the 30 minutes.

The results were striking. The team found that almost half (49%) of children from the outdoor group had decreased symptoms compared to only 23.7% of the indoor group. The benefit of the cold air intervention was most apparent in children with moderate croup (who arrived with a WCS score of 3-5) for which 63% of the outdoor group had at least a 2-point drop on the WCS scale compared to only 17% of the indoor group. This shows that exposure to cold fresh air helps improve croup symptoms within the first 30 minutes.

The oral dexamethasone steroid treatment is known to have a 30-minute delay before effect. When the clinicians reassessed the children again 60 minutes after the steroid treatment, they no longer found a significant difference between the outdoor and indoor groups. This may be because the steroid partially alleviated symptoms by 60 minutes. Alternatively, it could be that the cold air benefits stopped at 30 minutes when the children came back inside into the warm. It’s also possible that the cold air helped to speed up the relief of symptoms that would have improved eventually but at a slower pace.

When they returned home, parents were asked to assess their child’s symptoms for one week after the hospital visit. They again did this using a point-based system based on their child’s symptoms, including whether they made noise when breathing in and if they had a barking cough. The overall total score showed no significant difference between the indoor versus outdoor treatment groups. However, slightly more children in the outdoor group had no persisting symptoms at the end of the week compared to the indoor group.

Overall, this study supports the common belief that exposing children with croup to fresh cold air improves their symptoms. Although the effect is short term, taking children outside until the therapeutic benefits of steroids take effect could be a useful and easy initial measure for parents and clinicians to take. This research not only validates a long-held belief but also offers a practical intervention for relieving croup at early stages.

Likely increase in coral thermal tolerance at a Pacific archipelago

2023-12-22 14:36:12

Coral reefs are remarkable ecosystems estimated to harbour over a quarter of all marine biodiversity. They create habitat for seafood species that in turn provide protein for millions of people, support coastal tourism and fisheries and protect coastal communities from storms and flooding. Yet, reef-building corals are highly sensitive to increases in temperature of even 1°C above normal warm-season levels.

Corals live in symbiosis with microscopic algae. Similar to us and our gut microbiome, corals cannot survive without their symbionts. These algae give corals their beautiful colours and nourish them through photosynthesis. However, the symbiosis breaks down under heat stress: without microalgae coral become stark white, or bleached, which usually leads to death. Extreme temperatures can even kill corals outright.

In Palau, an island nation in the western Pacific ocean, coral reefs experienced intense marine heatwaves in 1998, 2010, and 2017. Curiously, bleaching impacts were fewer in each successive event. Similar trends had also been observed in Australia’s Great Barrier Reef, French Polynesia, and Southeast Asia.

We set out to test whether thermal tolerance of Palauan corals had increased over the past three decades. Our team designed a simulation study, using 35 years of sea surface temperature data and historic bleaching survey records. We found that the thermal tolerance of Palauan coral communities likely increased at 0.1 °C/decade, indicating an innate level of climate resilience.

Various mechanisms could explain such trends. (1) Through species-turnover, severe heatwaves could weed out the sensitive species leaving the tougher ones behind, coming at a cost to important ecological functions like reef growth. (2) Genetic adaptation through natural selection could lead to increased prevalence of genes associated with thermal tolerance in populations. (3) Acclimatisation of coral individuals to low-level thermal stress within their lifetime could improve their later survival under high-level thermal stress. These processes can also occur in the microalgae communities living within each coral, so an upcoming challenge will be to disentangle the role of these mechanisms in shifting thermal tolerance in Palau and elsewhere.

We then tackled the question of whether the emergent rise in tolerance for Palau is sufficient to keep pace with ocean warming. Using high-resolution future temperature projections from 17 global climate models, our analysis reaffirms the scientific consensus; the future of coral reefs ultimately depends on collective global action on rapidly reducing carbon emissions. However, bleaching impacts could be avoided on some reefs, or at least delayed, if coral thermal tolerance can continue to rise at the historic rate.

While this provides a glimmer of hope and may mean there is some additional time to implement adaptive management solutions, this all hinges on rapid climate action. The number of reefs that escape bleaching conditions drops rapidly under the hotter climate futures.

Novel ideas are currently being investigated to help corals persist into the future. These include conventional conservation measures, like marine protected areas; restoration and rehabilitation efforts such as planting or reseeding reefs with corals or larvae; as well as more experimental interventions to boost their thermal tolerance artificially, for example, through selective breeding. Restorative interventions offer promise at small spatial scales, but much more research is needed to fully harness their potential.

Coral reefs clearly have some level of innate climate resilience which could reduce projected bleaching impacts over the coming decades. However, we still don’t know whether such reefs will continue providing the goods and services that society needs. Ultimately, concerted global action on reducing carbon emissions is the only sure way of securing a future for coral reefs.

Is evolution predictable?

2023-12-22 14:15:56

RNA molecules are one of the key biomolecules of life as they appear in organisms as catalysts, building blocks, and information carriers. RNA is made up of sequences of chemical `letters’ called nucleotides, similar to the chemicals that make up DNA sequences. RNA sequences can fold up into different shapes, depending on which `letters’ appear in the sequence. Billions of possible RNA shapes can exist given the appropriate sequences, yet in nature we only find a relatively small number of shapes. Why only a small number and why these?

The Darwinian perspective puts forward natural selection as the answer, arguing that of the billions of possible shapes only a few are biologically useful and improve an organism’s fitness. Therefore, only these few are preserved. Additionally, paleontologist Stephen Gould argued that random historically contingent events, like meteor strikes, have culled most organisms, leaving only a small fraction of `lucky’ creatures (and shapes) with us today. Hence, if we were to rerun the tape of life, a very different biological world would likely prevail.

Our team decided to investigate these questions from a different angle: the way RNA sequences are associated to RNA shapes is strongly biased, in the sense that most shapes have very few associated sequences, while a few shapes have many associated sequences. This is called phenotype bias. This bias means that upon a random genetic mutation, certain shapes are much more likely to appear than others. It also means that if a random sequence of `letters’ is chosen, the outcome is highly non-random, with certain shapes much more likely than others. Phenotype bias is analogous to a loaded dice, in which some outcomes are more likely. We expect that gambling or playing a board game with a loaded dice will make a large difference to the outcome, but could the loaded dice of phenotype bias also affect evolutionary outcomes?

To begin, we used computational methods to generate random RNA sequences, find their corresponding shapes, and thereby estimate how abundant each shape is. Next, we turned to a large database to study naturally occurring RNA found in living organisms. Using these data we found the abundances of the different RNA shapes in nature. Interestingly, we found that the shapes in nature were those that the phenotype bias caused to be most likely. More surprisingly, the actual abundances of natural shapes are predictable: if bias implied that some shape occurred with a given frequency, we found that the shape appeared with roughly the same frequency in nature. To get a sense of the strength of the bias, consider for example we calculated that there are approximately a trillion possible shapes with length 126 nucleotides, but only 68 shapes are found in nature, and these are among the 98 most likely to appear. In other words, the bias limits the RNA to one in ten billionth of the space of possible shapes.

A key notion in biochemistry is that the shape of a molecule helps to determine its function, and hence we might expect the natural shapes to be highly structured and tuned via selection. Remarkably, it appears as if the shapes in nature are just the ones offered by bias. Perhaps the most famous example of a functional RNA shape is transfer-RNA (tRNA) with its cloverleaf form. This form is important for its function in communicating information from DNA to proteins. Interestingly, we found that the cloverleaf shape is one of the most likely shapes to appear from a mere random sequence due to phenotype bias.

Natural selection no doubt plays an important role in determining which RNA shapes appear in organisms and for which function, but we find a surprisingly strong influence of phenotype bias as well. Moreover, the fact that both the shapes and their relative abundances are predictable from phenotype bias suggests only a small role for historical contingency. Recently, in our follow-on study looking at bias in larger RNA, we found similar results to our earlier study. More broadly, phenotype bias has been observed in many biological models, including protein molecules, gene networks, and teeth shapes. Further, arguments based on the information content of shapes predict it to be a common property. Could phenotype bias have influenced the biological forms we observe around us today? We hope that our work will stimulate many more studies to test this hypothesis.

Earth’s large lakes are shrinking

2023-12-22 00:00:00

Lakes are a crucial source of Earth's freshwater, providing various ecosystem and socioeconomic services. They offer water and food supply, habitats for waterbirds, nutrient cycling, recreational activities, navigation, and hydropower generation. The usesof lakes are heavily influenced by their water volumes, which can be affected by changes in precipitation, river inflow, and evaporation. There have been significant shifts in lake levels, as seen in the Aral Sea and Lake Mead, indicating the growing threats from climate change and human activities.

One important question is: “are drying lakes limited to specific regions or is this a global trend?”. However, it is challenging to obtain data on the variation of a lake’s water level over time, especially on a global scale. In-situ measurements are mainly concentrated in certain areas, and satellite altimeters have limited spatial and temporal coverage, hindering consistent analysis of global-scale trends.

To address this issue, we developed a new method to generate near-monthly water storage data for all large water bodies worldwide over the past three decades. We combined short-term level measurements from recent altimeters with longer-term water areas mapped from historical satellite images. This allowed us to reconstruct water levels over the course of several decades on a global scale. By applying this novel approach to nearly 250,000 satellite images and water level measurements from altimeters, we were able to provide a comprehensive view of lake water storage trends in the 1,972 largest lakes on Earth.

To understand the reasons behind water losses or gains in lakes, we identified three key factors. First, we analyzed ‘natural’ changes by examining precipitation and river flow, which are primarily influenced by natural climate variability. Secondly, we investigated the impacts of climate change by studying temperature and evaporative demand, i.e., measuring how ‘thirsty’ the atmosphere is. Lastly, we considered human water consumption by incorporating data from models. Using statistical techniques, we modeled the response of lake volume variability to changes in these climate and human variables.

Our findings indicate that 53% of Earth’s large water bodies experienced drying between 1992 and 2020. What is surprising is that this phenomenon occurred not only in arid regions but also in humid regions. Previous climate studies indicate a “dry-get-drier and wet-get-wetter” pattern in a warming climate. This is widely recognized in observations and models. Our study confirms a “dry-get-drier” pattern in lake water storage. However, we also observed widespread lake water losses in the humid tropics and high latitude regions over the last three decades, suggesting that drying lakes worldwide are more extensive than previously thought, certainly concerning lake water storage.

More than half of the total water loss in natural lakes can be attributed to both warming and increased human water consumption. Therefore, the widespread global declines in lake water storage may signify global aridification under warming and increasing human water use. Additionally, our study reveals that sedimentation dominated the total water loss in existing reservoirs filled before 1992. Sedimentation is an ongoing, slow process that gradually reduces the capacity of reservoirs to store water, thereby becoming less reliable for freshwater and hydroelectric energy supply. Reservoir sedimentation rates can accelerate under climate change due to increasing extreme precipitation, as well as land disturbances such as wildfires, landslides, and deforestation.

By providing new insights into the extent of changes occurring in global lakes, our study aims to raise awareness about this issue. It is important to note that approximately a quarter of the global population lives in a basin with a large, drying lake. The potential impacts of drying lakes, such as freshwater shortages, environmental degradation, and hydropower energy reduction, can be significant. Therefore, it is crucial to manage lakes effectively to maintain healthy levels in order to mitigate the impacts, ensuring long-term sustainability.

How the immune response to a common virus may target the brain in multiple sclerosis

2023-12-21 10:07:13

Over 2.8 million individuals are living with multiple sclerosis (MS) which occurs when the brain and spinal cord become damaged due to inflammation. Persons with MS (pwMS) experience various symptoms such as vision disturbance, cognitive dysfunction and problems with balance and mobility. Around 85% of pwMS experience unpredicted relapses of severe symptoms followed by remission for months to years and a small proportion have gradually worsening symptoms over time. Unfortunately, both forms eventually lead to permanent disability. We don’t know the exact causes for MS, but several genetic and lifestyle factors have been identified such as smoking, obesity, vitamin D levels, socioeconomic factors and also viruses.

Autoimmune diseases occur when the body’s own immune system damages tissues leading to inflammation and, in the case of MS, the central nervous system is affected which causes neurological symptoms. In some autoimmune diseases, an initial infection may trigger the immune response that causes the damage and strong evidence supports a role for Epstein-Barr virus (EBV) in the development of MS.

EBV is the common cause of infectious mononucleosis – also called glandular fever or the “kissing disease” – and is the strongest known environmental risk factor linked to MS. Around 90% of adults become infected with EBV throughout their life yet only a small proportion develop the disease, and one particular study in 2022 showed that almost all pwMS acquire the virus at least 1 year before the disease onset. However, despite this link, we still do not know exactly how the virus may contribute to MS development and there are currently several theories. Due to the delay between EBV infection and MS onset, it is unlikely that the disease develops from uncontrolled infection (although this remains a possibility). Instead, we think that the immune response to EBV – which would normally fight EBV infection – may be damaging the brain in MS, and pwMS have altered immune responses to parts of the virus compared to healthy people. There is evidence that both T cells and antibodies are involved in disease, and we investigated how this might occur by studying patients from Sweden.

In a recent study published in Science Advances, we investigated how the immune response to EBV may be different in pwMS by looking at the blood of 700 pwMS and 700 control subjects. We specifically looked at how two components of the immune system – called antibodies and T cells – response to EBV may differ. Antibodies are proteins produced by B cells of the immune system in response to infections, and similarly T cells act as soldiers of the immune system to remove infected cells from the body.

We first confirmed previous findings that pwMS have higher antibody responses in their blood to a part of EBV called EBNA1 and went on to show that these EBNA1 antibodies could cross-react with a protein in the body called alpha-crystallin B (CRYAB). This means that EBNA1 antibodies can also attack CRYAB and may contribute to inflammation in pwMS. Up to 27% of pwMS had increased levels of CRYAB antibodies compared to only 16.9% of controls, and individuals in the study who had antibody responses to both EBNA1 and CRYAB were up to 9 times more likely to have MS than control subjects.

It was also found that T cell responses to EBNA1 and CRYAB were increased in the blood of pwMS treated with the drug natalizumab. Natalizumab therapy works by blocking immune cells from entering the brain of MS patients, preventing damage and leading to their accumulation in the blood. Further investigation of these T cells suggested that they likely cross-react in a similar way to antibodies. CRYAB has a role in dampening down inflammation and therefore, if immune responses against EBNA1 are also mistakenly targeting CRYAB, they may contribute to tissue damage in MS.

These results build upon previous findings of similar cross-reactivity between EBNA1 immune responses, and two other proteins expressed in the brain called Anoctamin-2 and GlialCAM and suggests that other proteins can be targeted by EBV immune responses in MS. Whilst current therapies are effective at reducing relapse rates, many have severe side effects and none ultimately prevent disease progression. Further understanding of how immune responses to EBV may lead to MS will help us to develop future personalised treatments with fewer side effects and the potential to cure MS.

Heading underground with cold atoms

2023-12-01 15:35:28

Delving deep into Earth to extract information is crucial for various industries. Whether it is for oil and gas prospecting, mineral exploration, or monitoring carbon capture and storage, boreholes constitute gateways to underground secrets. To navigate these intricate labyrinths, we need advanced sensing technologies. During the construction and operating lifetime of a borehole, different sensors will be lowered to obtain information about the borehole and the surrounding geology.

Among these are gravity sensors, which can map the density of the surrounding geology. Unlike methods such as ground penetrating radar or nuclear logging, gravity sensors offer an edge: gravity is not weakened by intervening materials, such as the borehole's casing. This allows them to detect features at greater distances. Moreover, gravity sensing avoids the use of radioactive isotopes, eliminating related health and security concerns.

Despite the advantages of borehole gravity sensing, a significant limitation is the need for extended time periods to perform measurements, compared to other remote sensing techniques. This prolonged duration stems from the need to average out vibrations, which, according to the laws of physics, are indistinguishable from gravity. Such vibrations can be due to natural seismic activities or human actions such as road traffic and construction. The only workaround is to measure over longer periods and average the results. This limitation of traditional borehole gravity sensors might be overcome with the advent of quantum sensors based on cold atoms.

These quantum sensors are called atom interferometers. They employ lasers as precise rulers and falling atoms as perfect test masses. Millimetre-sized clouds of millions of atoms are trapped and cooled to a fraction of a degree above absolute zero. The atoms are dropped, and precisely-timed laser pulses place them into quantum superposition states travelling separate paths before causing the atoms to interfere. The resulting interference pattern offers precise information about gravity.

With two atom interferometers, vertically separated by some distance, it is possible to measure the gravity gradient - the variation of gravity with depth. By simultaneously measuring with both atom interferometers using the same lasers, the effects of vibrations are cancelled out. This means atom interferometry-based gravity gradiometers can operate more efficiently in vibrationally noisy areas where classical gravity sensors struggle.

Yet, the very nature of boreholes brings forth a unique challenge: their depth, narrowness, and harsh environmental conditions entail a far cry from the typical environments where quantum sensors have so far demonstrated their potential. To be lowered down these deep, narrow holes, they need to be both compact and robust against the physical conditions they encounter.

Researchers from the University of Birmingham and Fraunhofer UK have teamed up to address these challenges, creating the first compact cold atoms source capable of operating in a borehole. This source of atoms, a magneto-optical trap or MOT, uses a combination of lasers and magnetic fields to cool and trap the atom clouds that would be required in atom interferometry. The package was deployed in a 50 m deep borehole of diameter 14 cm, full with water to near the ground level. The system proved to be robust during the trial deployment, producing atom clouds of about 3 million rubidium atoms.

This marks the first significant step towards deploying quantum technology in boreholes for gravity sensing. As with every pioneering technology, there are further steps ahead. To transition this from a prototype to a full-fledged, borehole-ready quantum sensor, certain refinements and enhancements are required. Once realised, quantum gravity sensors could one day become the gold standard for borehole surveying, revealing the Earth's hidden depths with unparalleled precision.

Rudimentary form of syntax present in chimpanzees

2023-12-01 00:00:00

Our language-based complex communication system is one of the defining features that makes us unique among all species. Syntax -combining words together into phrases- makes language-based communication limitless in terms of the amount and type of information we can communicate about. This is due to the compositional nature our syntax mostly holds, where the meaning of the phrases we pronounce is directly related to the meaning of the words within the phrase (e.g. duck and cover). However, recent evidence demonstrated the presence of compositional syntax in other species such as monkeys and birds. These accumulated observations challenge the notion that compositionality is unique to humans and question the evolutionary origins of such capacity.

Therefore, we decided to retrace the evolutionary history of compositionality to understand where language came from, and when it emerged exactly: is it truly unique to humans or is it evolutionary more ancient? To begin with, we investigated the combinatorial capacities of chimpanzees. Chimpanzees are our closest living relatives. We share 99% of our DNAs and our last common ancestor was extinct less than 7 million years ago.

To investigate the compositional properties of chimpanzee communication, we observed chimpanzees in their natural habitat for more than two years, in the Budongo forest, Uganda. Previous work established that chimpanzees produce a call named “alarm-huu” when individuals are surprised or afraid (e.g. during an earthquake, or when seeing a dead monkey, or a snake…) and another call named “waa-bark” when recruiting other group members (e.g. during a hunt). Following our observations, we noticed chimpanzees combined the two calls in a larger sequence specifically when encountering a snake, and that the individuals in the vicinity that heard this “alarm-huu+waa-bark” combination immediately joined the chimpanzee calling. The call combination appeared to function as a recruitment call in the presence of a snake specifically, making it a very promising case for compositionality in chimpanzees.

To verify the meaning of this structure, we presented chimpanzees in the Budongo forest with a dead python that we animated using a fishing line. In this specific context, chimpanzees produced this combination, and we further demonstrated that the production of the combination systematically led to the approach of individuals in the vicinity. We concluded the “alarm-huu+waa-bark” combination did indeed function as a recruitment signal in a dangerous situation specifically.

To confirm the meaning of this structure is derived from the meaning of the calls composing it, we conducted playback experiments. We broadcasted the different calls to chimpanzees in Uganda and compared their reaction to the “alarm-huu” alone, the “waa-bark” alone, or the combination of the two vocalisations. We observed the strongest response to the playback of the combination. We also observed specific behaviours after playing the combination, such as displaying toward or approaching the loudspeaker, or climbing up on nearby trees. These are typical behaviours exhibited by chimpanzees in the presence of snake, suggesting that hearing a call combination (but not the “alarm-huu” nor the “waa-bark” produced alone) was sufficient for chimpanzees to understand a snake was around, and that they should approach to locate the source of the threat and/or potentially scare it away.

These results indicate chimpanzees are able to combine two calls together into a larger sequence, and that the meaning of this sequence is related to the meaning of the calls composing it. This suggests rudimentary forms of compositional syntax are present in our closest living relatives, and that this capacity we considered unique to our species might be evolutionary more ancient and inherited form our last common ancestor with chimpanzees, almost 7 million years ago.

An incredibly massive ancient whale skeleton reveals a new way to become a giant

2023-11-27 17:42:33

Which animal is the largest? The fastest? The most ferocious? These are some of the first topics in natural sciences to be discussed between children. These should not be considered as trivial, as they often lead to relevant questions about how, when, and why such extreme living beings evolved. With a total body weight occasionally reaching 190 tons, the blue whale has long been recognized as the heaviest animal that ever lived on Earth, far above the largest sauropod dinosaurs. Up to now, the fossil record of cetaceans (whales, dolphins and their extinct relatives) revealed that the emergence of giants is a relatively recent phenomenon (considering an origin of the group from a terrestrial ancestor dated to more than 50 million years ago). It was thought to have occurred among fully oceanic, filter-feeding baleen whales about 5 million years ago. But paleontological research is constantly yielding new, fascinating discoveries that make us revise our views of the history of life.

Thirteen years ago, the first fossil remains of a mysterious giant marine animal were discovered by the paleontologist Mario Urbina in a desert along the southern coast of Peru. It took several years and multiple fieldtrips to eventually realize that the enormous bones, now dated from the middle Eocene (about 39 million years old), belong to an extinct whale with extreme dimensions. In total, 13 vertebrae, four ribs and one hip bone were collected by our Peruvian colleagues. The huge vertebrae, each weighing more than 100 kgs, and the large ribs, up to 1.4 m-long, point to a giant marine mammal, but the tiny hip bone proved crucial for the identification of this skeleton. Indeed, its shape indicates the presence of tiny hind limbs, as described in the extinct cetacean family Basilosauridae. This group includes the first fully aquatic cetaceans (without adequately sized hind limbs, it is not possible to move on land anymore), and it is thought to have given rise to the two modern cetacean suborders, Mysticeti (baleen whales) and Odontoceti (echolocating toothed whales).

Apart from its large size (total length estimated at 20 m), the new basilosaurid is unique in the extremely high volume and compactness of all the recovered bones, a condition named pachyosteosclerosis. Surface scanning allowed for the calculation of bone volumes, while drillings revealed bone inner structure. Together, these parameters helped us in calculating the original weight of each bone. Then, completing the missing parts with other basilosaurid skeletons, we could provide a range of estimates for the total weight of the skeleton. Between 5 and 7.5 tons, which is two to three times heavier than a blue whale's skeleton! And that's not all, based on a database of skeletal and total body weights for many mammals, we calculated an interval of body weight estimate for this extinct whale between 85 and 340 tons. This is in the range of the blue whale (weighing up to 190 tons), or even higher.

These astonishing numbers made our international team propose the name Perucetus colossus (the colossal whale from Peru) for this new species, but also led to a series of questions. What were the advantages of having such a heavy skeleton? In which environment did this whale live? Which prey types did it target? And how did it acquire its food?

Similarly, massive bones are generally observed in slow-swimming aquatic animals, feeding along the seafloor in coastal waters. The best modern example is sirenians (manatees and dugong), and we do not take too many risks in proposing that Perucetus was a slow animal living in shallow waters, where its weigh may have helped it keeping the right position along the bottom, even while undergoing strong waves. However, all sirenians are herbivorous, feeding on algae and seagrasses, whereas all cetaceans, including other basilosaurids, prey(ed) upon other animals. Though a shift of Perucetus to an herbivorous diet cannot be completely ruled out, this sounds rather unlikely. Another hypothesis is that it fed on slow-moving or even immobile invertebrates, like modern walruses targeting clams. Discovering the skull and teeth of Perucetus would be essential to test these different hypotheses. Also, finding new fossils of this unique animal could provide clues about its extinction. All basilosaurids disappeared before 33 million years ago, and this event has been tentatively correlated to a cooling phase and associated changes in the biodiversity of coastal environments. Some of their descendants, the first mysticetes and odontocetes, invaded more oceanic regions and became the successful groups that we know today, including some of the heaviest (but maybe not the heaviest...) animals ever.

What keeps trees grounded?

2023-11-23 16:26:30

When asked to sketch a tree, you'll likely draw branches reaching towards the sky and roots delving into the earth. Sounds alright, but have you ever wondered how trees know where the earth is?

If you were to tip over a potted plant, its roots wouldn't grow along the surface but instead curve downwards, following the pull of gravity. Now, imagine if some plants had genetic modifications that disrupted their gravity-sensing ability, causing their roots to grow erratically. This intriguing possibility led scientists to explore which genes help plants detect gravity.

Wait, what are genes? - They're like the instruction manuals for the tiny factories inside all living organisms called cells. These factories keep everything in our bodies running smoothly. Genes usually contain instructions for building proteins, the engines of these factories. The shape and place of proteins in cells are super important for how they work. Scientists often remove a gene to understand how it affects the protein it makes and its function in the cell. It's a bit like taking a piece out of a machine to see what goes wrong.

By studying different genetic changes that made plants unresponsive to gravity, scientists previously discovered a few layers of column-like cells at the root tip that detect gravity. These unique cells are called 'columella' cells because of their shape. Inside these columella cells, there are starch deposits in small packets. These packets always sink to the cell's bottom due to their weight. However, if it is their weight that the cell senses or their position that defines the 'bottom' of these cells remained a question.

While exploring this question, a team of scientists from the National Institute for Basic Biology in Japan found a group of genes known as 'LAZY’ genes, that produce the ‘LAZY’ proteins. When plants lacked these genes, they grew in random directions, earning them the name 'LAZY'. We find these LAZY proteins inside starch-filled packets and also in the cell's outer layer, called the plasma membrane. Interestingly, these LAZY proteins are always near the 'bottom' of the columella cells. When plants changed their orientation, so their roots didn't align with gravity, these proteins moved to the 'new lower' side of the cells' plasma membrane. This showed they played a role in sensing gravity. But what exactly was their role?

To answer this question, another one needed an answer first: why do these proteins stick to the plasma membrane?. Often, proteins have built-in signals that guide them to specific spots. In the case of LAZY proteins, they had two positively charged patches on their surface that helped them stick to the negatively charged plasma membrane. When Nishimura and colleagues replaced these patches with uncharged versions through genetic changes, the LAZY proteins no longer stuck to the plasma membrane. This confirmed that these positively charged patches were crucial for the proteins to attach to the membrane and determine their direction. It also confirmed that LAZY proteins could naturally stick to the membrane due to their structure.

Now, the question was how these proteins identified the 'lower' side of columella cells. Remember, LAZY proteins are also in starch-filled packets. To explore the connection between starch-filled packets and LAZY proteins, the Japanese scientists studied LAZY protein localization in plants without starch. These starchless plants lacked genes for starch production, making the supposed starch-filled packets lighter and preventing them from settling at the bottom of the columella cells. In these starchless plants, LAZY proteins localized to the supposed starch-carrying packets and the plasma membrane, but they couldn't find the 'lower' side of the cell and instead were found all over the cell. So, the presence of starch-filled packets was crucial for LAZY proteins to locate the bottom of columella cells.

Additionally, to understand the timing of events in gravity sensing, the scientists closely observed the movements of LAZY proteins, starch-filled packets, and the influx of auxin - a growth hormone - before and after reorienting the root under a microscope. It took 3, 15, and 30 minutes for the starch packets, LAZY proteins, and auxin influx, respectively, to adjust to the 'new lower' side after root reorientation.

From the knowledge gained so far, it seemed logical to think that LAZY proteins followed the starch-filled packets in columella cells. But how could we confirm this idea? Imagine if one could move the starch-filled packets without changing the root's direction! Well, Nishimura and colleagues achieved this using a strong laser beam to push the starch-filled packets inside plant cells. With these 'optical tweezers', they moved the starch-filled packets against gravity and watched how LAZY proteins reacted. Voila! LAZY proteins followed the starch-filled packets and gathered near them on the plasma membrane, in the opposite direction of gravity.

In other words, the LAZY proteins set up polarity in the columella cells by sensing where the starch-filled packets are (and, not the force they exert on the cells). This further triggers signals that draw growth hormones toward the roots, helping them grow towards gravity. And, this is how trees stay grounded!

Gas in distant galaxies: mixed or matched?

2023-11-23 16:20:44

Illustration realized in the framework of a collaboration between the Image/Recit option of the HEAD (Haute École d'Art et de Design) - Genève and the Faculty of Sciences of the University of Geneva.

What is a galaxy? The common conception of a galaxy, in which it is an island of stars in the vastness of space, is not the entire picture. A very important ingredient of galaxies is their gas because stars are born from this fuel. The gas – called interstellar medium - is present all through the galaxy.

Hydrogen and helium, the most abundant elements in the Universe, make up most of the interstellar medium. There are, however, small amounts of heavier elements, which astronomers refer to as metals – for example carbon, oxygen, magnesium and sulphur. Stars produce those metals when they die and explode as supernovae, subsequently being pushed out into the galaxy and enriching the gas in the interstellar medium.

Why is it important to study the gas in galaxies? Probing the gas gives us key insight into the ways galaxies form and evolve over time. Simulations of the Universe tell us that gas moves in and out of galaxies on scales larger than the galaxy itself, thereby interacting with their environment. The movement of gas around galaxies are known as galactic gas flows. Tracing gas properties and how it moves is a challenge we face because we can’t observe the gas in the same ways that we see stars.

We might think that because the galaxy rotates, the metals become evenly distributed throughout it. But what if there is a contribution from a metal-poor gas from outside the galaxy that dilutes the interstellar medium? In such case, an interstellar medium would not contain the same amount of metals in all locations and indicate that a galaxy interacts with its environment.

As an analogy, consider a galaxy as a cup of coffee. Before adding milk, the coffee is uniform in the cup, isolated from outside influences. But if milk is slowly added without the cup being stirred fast enough, we would expect that there would not be the same amount of milk and coffee in all locations. So how well are the Milky Way and other galaxies stirred?

Uncovering this would allow us to indirectly study these galactic gas flows. In addition, an interstellar medium that does not have a uniform chemical composition can affect what is formed out of this gas, which is the formation of stars and planets.

In this work we used absorption-line spectroscopy, a method which has three important components: a very bright background object (in this case, the core of a distant galaxy, emitting bright light due to its black hole), the galaxy that we are studying, and our telescopes. For the method to work, the three components have to line up in exactly that order in space. The light from the bright background object travels through the gas in the galaxy and eventually reaches us on Earth. However, metals eat up some of this light as it travels through the gas. This means that part of the light in the spectrum is missing by the time it reaches us. Elements have unique, signature bite marks in the spectrum, and so the missing part of the spectrum tells us which elements are present in the gas, and their abundance.

Absorption-line spectroscopy is a powerful method for several reasons. On one hand we get a lot of information about the metal content of the gas, and on the other hand this method allows us to see the small and faint galaxies, which are the most numerous in the Universe and difficult to observe otherwise. In our work, we used absorption-line spectroscopy to probe the gas in 64 small, distant galaxies. We investigated whether their interstellar media is well-mixed, and whether we can see evidence for the interaction of the galaxies with the gas around them.

We found that the gas in our sample of galaxies does not contain the same mix of elements in all locations. This means that the gas is not well-mixed (like your coffee should be), which could be evidence for gas moving in, out and around the galaxy. These results contribute significantly to uncovering and understanding the complexities of the interstellar medium, and how they impact the formation and evolution of galaxies.

The astonishing jet of an extreme gamma-ray burst

2023-11-23 16:09:27

Gamma-ray bursts (GRBs) are short duration transient phenomena lasting from a few seconds to hundreds of seconds. These bursts are localized on the sky using gamma-ray detectors onboard satellites orbiting Earth. The satellites pinpoint the direction of the burst, allowing astronomers to rapidly point their telescopes and observe the emission across the light spectrum.

GRBs were first discovered serendipitously in 1967 by the Vela Satellites, which were actually monitoring for nuclear weapons tests on Earth. It wasn’t until 1973 that these phenomena were introduced to the rest of the world, as their earlier discovery was highly classified. The multiple Vela satellites were able to triangulate that the signal was coming from somewhere other than Earth, leading to their origin remaining a mystery. It took decades for their cosmological nature to be agreed upon, and more than a hundred models had been put forth to explain their emission in that time period.

Fortunately, astronomers have now identified thousands of GRBs, leading to the Golden Age of studying the GRB mystery. Thanks to the Compton Gamma-ray Observatory, Fermi Gamma-ray Space Telescope, and the Neil Gehrels Swift Observatory, astronomers were able to understand that these explosions are created by the collapse of massive stars. The stellar collapse is thought to form a black hole, which rapidly accretes matter and launches it outwards as a narrow beam of material (a jet) moving at nearly the speed of light. The jet of material produces both the gamma-ray radiation that signals the GRB as well as broadband emission all the way from radio waves to gamma-rays. The broadband emission component is referred to as the ‘afterglow’ and is produced as the jet collides with the environment surrounding the exploding star.

The afterglow allows us to determine the total energy of the jet as well as its collimation (how wide or how narrow it is). Astronomers have identified that GRBs are highly collimated (narrow) outflows, with a typical opening angle of a few degrees. This narrow angle means that we only observe GRBs that are pointed directly at us, like waiting for a lighthouse to point in your direction.

On October 9th, 2022, gamma-ray satellites detected an extremely bright GRB lasting for almost 10 minutes. The GRB was so bright (~70 times brighter than the previous record holder) that astronomers initially determined that it must be coming from within our own Galaxy at close proximity. As further observations were obtained, it became clear that this explosion was a GRB at a distance of more than 2 billion light-years away. Quickly, it was determined that GRB 221009A is the most energetic GRB we had ever seen, and the rate of similar events occurring at this proximity to Earth was once in a millennium or more. Based on these calculations, we were extremely fortunate to have observed this explosion in our lifetime, and even more fortunate that it was directed towards Earth.

While at first the GRB seemed typical, despite the extreme brightness and rarity, when modeling the overall emission out to ~100 days after the explosion, we discovered that it had some distinctive properties. We found that the GRB jet was characterized by a peculiar decrease in energy with increasing angle away from the core of the jet. This energy profile allowed us to explain the decrease in brightness of the emission over time, and the fact that we never observed the ‘edge’ of the jet.

In typical GRBs, we measure the width of their jet by identifying the time when the emission begins to decrease in brightness more rapidly. At this time, there is no other matter emitting light in our direction, leading to the rapid drop in brightness, known as a ‘jet-break’. However, GRB 221009A never displayed this sharp drop-off, requiring instead a very wide jet (>15-20 degrees), compared to other GRBs (~5-10 degrees). We have still not observed a ‘jet-break’ in GRB 221009A out to more than 200 days after the explosion.

There is still a lot of work left to be done to understand the consequences of these jet properties. There is evidence that the most extreme and energetic GRBs may share similarly wide jets, which could imply they are formed by similar explosions. The most pressing issue though, is how to produce such a wide and structured jet in numerical simulations of exploding stars. This will help us to understand the type of star that exploded and the degree of mixing of material as the jet drills through the layers of the star.

HIV pushes the nuclear envelope to start an infection

2023-11-14 17:46:44

Viruses need to be better understood. After all, the common cold deals misery to hundreds of millions of people every year, and the world stood still for almost a year waiting for a vaccine against SARS-CoV-2. Viruses are difficult to treat because they are simple, consisting of genetic material (RNA or DNA) and a protein coat called a capsid. They can reproduce only if they enter host cells and take over the manufacturing systems inside.

Research on viral infection of host cells has largely focused on cell entry, resulting in anti-viral drugs that interfere with viral entry into the cell. This makes sense for most RNA viruses, which enter the cell and reproduce outside the nucleus. However, those with DNA and some with RNA, like human immunodeficiency virus-1 (HIV-1), must be in the nucleus of the cell to establish an infection, so there is an additional place to block entry as they pass through the nuclear membranes, also known as nuclear envelope. Up to this point, it hasn’t been well understood how a virus that is inside the cell gets into the nucleus. The nuclear envelope has some holes, called nuclear pores, but viruses are generally much too large to passively make their way through.

We used human cells cultured in the lab, infected with a modified HIV-1 virus that could be handled more safely than the original. Some experiments were done using T cells, a type of immune cell which is the main target of HIV-1 in patients, so we could be sure our findings were relevant to human infections. Certain proteins were fluorescently labeled so we could track the infection process using a super-resolution microscope. In previous studies, we had identified proteins that were involved in transporting non-virus cargo across the nuclear envelope. We hypothesized that the process used to transport non-virus cargo was also being used by viruses to sneak into the nucleus.

We found that HIV-1 gains access to the cell nucleus through the interaction of three proteins, which form the VOR complex. First, the virus enters the cell by endocytosis, which refers to entering a cell by being engulfed by the cell membrane to form a membrane-covered package called an early endosome. As it traverses the cell, it matures into a late endosome. Late endosomes have the first member of the VOR complex, a protein called Rab7, embedded in the membrane which covers them. The second member of the VOR complex is another membrane-embedded protein called VAP-A, which is embedded in the nuclear envelope. The third protein, called ORP3, interacts with Rab7 and VAP-A to form the VOR complex.

We observed HIV-1 entering cells by endocytosis. The virus-containing endosomes matured to late endosomes and interacted with the nuclear envelope using the VOR complex to create invaginations. The virus-containing endosomes moved into the space within the invaginations, and the contents were transferred through the nuclear envelope. To understand how the VOR complex might be involved in the process, we interfered with VAP-A or ORP3 in a genetically targeted way, and we also used a molecule called PRR851, which inhibits formation of the VOR complex and has potential as a new drug. Whenever we interfered with formation of the VOR complex, the number of nuclear envelope invaginations was severely reduced, and there was no evidence that HIV-1 could enter the nucleus and start replicating.

This is a new pathway, so there are many unanswered questions. For example, we do not know how many other proteins are involved in the process, why the endosomes with virus inside are not degraded by the cell, how the virus may come apart and pass through the nuclear envelope, and how many other viruses use this pathway. Armed with new information about how viruses can enter the cell nucleus, we hope this discovery leads to new approaches for addressing viral diseases.

An interesting side note is that the first paper about this pathway came from a few members of our author team who are cancer researchers, not virologists. They found that tumor cells talk to other non-tumor cells in the body by sending signals that enter by endocytosis. The tumor signal endosomes access the nucleus using the same pathway that HIV-1 used in the current study. Cells that received such signals changed in ways that would allow metastasis (spread of cancer to other parts of the body) to occur. There is still much to learn, but it appears this pathway and its inhibitors may be relevant to more than just HIV-1.

Holographic sound fields shape 3D matter without a touch

2023-11-14 17:26:01

3D printing is about to revolutionize the way we fabricate products. Building up objects point-by-point (also called additive manufacturing) enables the fabrication of single parts of arbitrary shape and composition without slow and complicated machining steps. The realm of 3D printing is still young and evolving, with new technologies constantly being introduced and even more important the pool of printable materials expanded. Over the last few years, a new technology called bioprinting emerged, where cells are shaped in a gel matrix to further grow and develop. Building functional and realistic tissues in the lab could be a turning point for medicine, for example to find and test new drugs. However, a major issue encountered in 3D printing is its speed. The way current methods deposit material is inherently slow and hard to scale up. This is certainly true if living cells are included in the materials, where some types are very sensitive to mechanical shear forces and temperature variations.

We therefore asked ourselves if there could be an alternative to 3D printing, where a whole 3D object is formed at once, assembled from a soup of particles? This would require a 3D force field, which pushes the particles in place. To approach this problem, we explored the known effects stemming from light, magnetism or sound, which have all been used in the past to move or trap microparticles. After all, the 2018 Nobel prize in physics was awarded to Arthur Ashkin for his work on optical trapping. In our case, it was sound waves in the form of ultrasound (far beyond the highest frequencies humans can hear) that looked the most promising. This is because ultrasound can propagate through different materials much better and further than light.

Similar to optical waves, sound waves can be used for a process called acoustic trapping. When a sound wave hits a particle in a liquid, it pushes that particle along. A second sound wave travelling in the opposite direction counters that force and it is then possible to trap or tweeze the particle at one location. By precisely steering the sound waves we can define the location of the trap and the simplest way to do this is by using lenses. To put it simply, the same way a magnifying glass works to focus light in one spot, an acoustic lens will focus sound in one spot.

In the first experiment, we attempted to trap microscopic glass particles that were suspended in water. As we just learned, sonicating from one side is not enough as this would push the particles away in the direction of the sound beam. By using two sound sources, each equipped with a lens, it was possible to trap the particles in a single spot. Surprisingly, the sources did not need to directly face each other. Even a 90 degrees angle between the sound beams already provided enough tweezing force to keep the particles in place. A more advanced method to shape a sound field would be an acoustic hologram. It operates like a lens, but instead of a lens’ smooth curved surface, a hologram has a rather complicated looking profile. We can compute this profile so that the sound waves focus not on one but many spots in parallel, effectively forming an image of sound. By optimizing our computation algorithms further, we were finally able to connect the dots and trap particles along lines, ultimately leading to a helix and a figure 8 curve in the experiment.

The particles would be trapped for as long as we left the ultrasound sources on. When turned off, the forces would disappear and the particles would sediment under gravity - the assembly collapses. To prevent this from happening and preserve the assembled object we chose to solidify the surrounding medium, which was limited to a small sample container. We added polymeric precursors to the water, which crosslinked over time and fixed the particles in place. Then the sound sources could be turned off and the product removed.

Note that our approach is not limited to glass particles. Up to now, we were able to demonstrate acoustic assembly with many other materials, including hydrogel capsules and mammalian cells (for example cancer cells or muscle cells). At the frequencies and power levels that we use for assembly, ultrasound propagates well through suspensions and biological tissue, while cell viability remains high. We therefore see acoustic assembly as a promising alternative to conventional bioprinting and tissue engineering to be explored in the coming years.

Vikings and Migrants: Unravelling Scandinavia's Genetic Mosaic in the Viking Era

2023-11-14 16:51:30

We recently published a study in Cell that reveals that the Viking period, spanning from the late 8^th to mid-11^th century, saw a massive influx of people into Scandinavia. Interestingly, later Scandinavians don't have as much ancestry from other places from outside Scandinavia as their Viking ancestors did.

In our study, we retrieve and analyse the genomes (i.e., the complete set of DNA found in human cells) of 297 individuals buried in Scandinavia. These remains were co-analysed together with nearly 17,000 Scandinavian individuals. This vast dataset covered a period of 2,000 years and allowed us to delve into the region's population dynamics. Many of the new DNA samples originated from prominent Swedish archaeological sites, such as Sandby Borg, Vendel, and Kronan, with a unique historical significance.

Building on two previous studies, this research offers new insights into the genetic makeup of Scandinavia during the Viking Age. Specifically, we followed how the proportion of non-local genetic ancestry has changed in different parts of Scandinavia over time. We then employed contemporary genetic data from various European regions to pinpoint the source of the shifts in genetic diversity within Scandinavia. The large amount of both ancient and modern Scandinavian samples allowed for a resolution seldom reached in ancient DNA studies.

Our results indicate an increase of British-Irish, Baltic, and south-European ancestries during the Viking period and onwards. The British-Irish gene-flow had an impact in all Scandinavian regions, whereas the south-European mainly affected south Scandinavia, and the Baltic influence is especially marked in Gotland and central Sweden and had less impact on Norway.

The study's 2,000-year timeline revealed an increase in migration during the Viking era, followed by a decline after the medieval period. The non-local ancestry introduced during this time appears to diminish in later periods. There are at least two non-exclusive explanations for this phenomenon: i) Newcomers to Scandinavia during the Viking and medieval times could have had fewer children than the main local population. For instance, migrants could have belonged to groups forbidden from having families or children, such as slaves or priests. They could also have been diplomates or merchants who died before they made it back home. ii) Bias in the archaeological record during the Viking Age. The archaeological record might have more individuals with a specific ancestry compared to the actual population. This could result from differences in burial customs associated with different ancestries. Note that cremation was the most common burial practice during the Iron Age including the early Viking Age in Scandinavia. However, we also analysed late Viking age burials that were Christian, and thus from a time when inhumation was practiced.

We also examined other influences on Scandinavian DNA. For instance, modern Scandinavians exhibit a genetic "cline" (a gradient) from north to south, resulting from the migration of Uralic-speaking groups with a likely Siberian origin. Although this influence is more noticeable after the Viking and medieval periods, we found traces of this north–south genetic cline already during the late Viking Age.

Other fascinating stories emerged from this study, such as the discovery of a woman with a fully British/Irish genomic composition buried in a Viking-period boat burial. This type of burial is usually seen as prestigious, but the grave goods indicated that the woman was of upper middle class. While her societal role remains a mystery, she was likely neither a slave nor a priest.

Our research unveils the complex historical events that shaped Scandinavia's population over time. The Viking Age reflects the curiosity of Scandinavians about the world beyond their shores, as much as the curiosity of outsiders about the Vikings, inspiring them to travel to Scandinavia.

Mutations in the germline: How the mother repairs the father’s damaged genome

2023-10-27 15:25:40

The genome is passed on from generation to generation. Germ cells, which are sperm and egg cells and any precursory cells they developed from, are tasked with maintaining the genomes. These cells are fundamental for maintaining the genomes across generations. The DNA, however, can be exposed to a myriad of damage and damaged DNA can lead to mutations and thus alter the genetic information.

Mutations that occur in the germline can have long-lasting effects. Genome evolution is driven by germline mutations, but also genetic diseases are caused by inheritable mutations. 80% of new mutations including single nucleotide variants (SNVs), i.e. mutations affecting the change of a single building block of DNA, and the more severe structural variants (SVs), i.e. more severe changes in the structure of the DNA, are generated in the paternal genome that is passed on by the father.

The vulnerability of the paternal genome has been the source of long debates about the consequences of exposure to radiation or other sources of DNA damage on the children. Such debates were held in the context of the nuclear bombings in Hiroshima and Nagasaki, the nuclear accident in Chernobyl, or radiation exposure of nuclear power plant workers. A major limitation in those debates, however, has been the lack of mechanistic understanding of the consequences of DNA damage in the genomes of the paternal germ cells.

Using the simple nematode worm, Caenorhabditis elegans, as a model, we recently showed that specific irradiation of mature sperm resulted in transgenerational lethality that only showed in the next generation. Just like in humans, the DNA in the worm’s mature sperm is densely packed and thus cannot repair the damage inflicted by radiations. Only once the sperm fertilizes an egg (forming a “zygote”), the damage is repaired by the mother’s DNA repair machinery.

However, the zygote uses a highly error-prone repair mechanism, the so-called “theta-mediated endjoining”, short TMEJ. TMEJ is a special DNA repair mechanism that joins the ends rather randomly resulting in structural variants (SVs), within the paternal genome. These SVs give rise to ongoing breaks in the genome, while the zygote develops into an embryo, which then grows into an adult animal. These adult animals that were fathered with damaged sperm DNA then produce a high degree of dead progeny.

On the molecular level, we realized that these animals had a high degree of densely packed DNA structures. Such structures are generated by high levels of so-called linker histones, which are proteins that wrap up the DNA. When we alleviated the density of those histone structures, an error-free repair mechanism could gain access to repair the damage and restore viability.

Strikingly, we found the very same SVs in human genomes and here also, they were almost exclusively generated in the fathers’ germ cells. Our data thus opens the possibility to specify when the father’s genomes are vulnerable and suggest potential interventions to enhance the stability of inheritable genomes and prevent the occurrence of inheritable diseases in humans.

Edible Microparticles: A Revolutionary Solution to Global Vitamin A Deficiency

2023-10-26 17:24:46

Vitamin A is crucial for our ability to see, fight off diseases, and for babies to grow healthily. Vitamin A is currently the second most deficient micronutrient among the malnutrition population globally, just after iron. Vitamin A deficiency (VAD) causes blindness in children and increases the risk of death due to infectious diseases. The World Health Organization (WHO) estimated that about one-third of the global population of preschool-aged children suffers from VAD.

WHO implemented the global vitamin A supplementation program in 1990, distributing high-dose vitamin A capsules to children every 4 to 6 months. Despite these efforts, millions of children and pregnant women still suffer from VAD, highlighting the urgent need for more effective solutions.

Consuming a small amount of vitamin A everyday ensures a good uptake and has been proven to be a more efficient way to increase the vitamin A content in the body. Therefore, adding vitamin A to staple food is, potentially, a more impactful strategy for defeating VAD worldwide.

Yet, the fortification of vitamin A is not easy. Firstly, vitamin A is oil-like, hindering its direct amalgamation with dry foods. Secondly, Vitamin A breaks down easily when exposed to air, light, or heat, making it difficult to add to foods without losing its benefits. The high temperature and high humidity during cooking and storage can further accelerate the breakdown of vitamin A, destroying the vitamin A in food before it is consumed.

We developed an edible microparticle that can be easily combined with dry food, protects vitamin A from degradation during storage and cooking, and can be readily absorbed after ingestion in humans. The study was recently published in the Proceedings of the National Academy of Sciences. This new technology could revolutionize the way we address vitamin A deficiency, making it easier to get this vital nutrient to those who need it most.

In 2019, we identified a material called BMC from fifty polymers to encapsulate a wide range of nutrients. BMC is an FDA-approved polymer and has a specific pH-controlled solubility. In water, BMC is not soluble, but in acidic water, such as stomach fluids, BMC quickly dissolves and releases the essential micronutrients.

The microparticles, composed of vitamin A and BMC, were created using the spinning disc process and were then coated with starch to ensure protection from light. The stability of vitamin A in microparticles during cooking (100 ^oC in boiling water) for up to five hours was largely improved compared to free vitamin A and VitA 250, which is the vitamin A microparticle currently used in food fortification. We also simulated cooking with copper ions, an oxidative species abundant in seafood and meat. Our vitamin A microparticles retained their great stability, while that of VitA 250 dramatically decreased.

Half-life, or the time for half of the compound to degrade, is used to indicate the stability of vitamin A microparticles after it is mixed in a bouillon cube. In tropical climate (40^oC and 75 percent humidity), the half-life of our vitamin A microparticle is 333 days, while that of VitA 250 is about 81 days.

After determining its outstanding heat stability, the absorption of vitamin A from microparticles was validated through in vitro, in vivo, and human studies. When rats consumed our BMC vitamin A microparticles, cooked or uncooked, the absorption level remained similar to the uncooked vitamin A, while the absorption levels were much higher compared to cooked unencapsulated vitamin A. These results indicate our vitamin A microparticles are highly stable and can be easily absorbed after ingestion in animals.

The strongest evidence for the absorption of encapsulated vitamin A comes from the clinical trial carried out in the United States by MIT and Biofortis. The bread made of vitamin A-fortified flour was given to 32 women, and the vitamin A level in their blood was monitored over a 24-hour period. The encapsulated vitamin A resulted in a comparable absorption level to free vitamin A, and it was not influenced by the codelivery of encapsulated iron and free folic acid. These results exemplified that our microparticles can effectively deliver vitamin A, even when combined with other nutrients, revealing new possibilities for treating nutrient deficiencies worldwide.

Ideally, we envision our microparticles as rainbow sprinkles that are easily added to different types of food, magically ensuring the food contains all the necessary nutrients. This could revolutionize the way we address nutrient deficiencies, potentially improving the health of millions of people around the world.

How to make a kilonova: Finding a path for cosmic alchemy

2023-10-25 11:58:09

In 2017, a cosmic event occurred that changed our understanding of the universe when the Laser Interferometer Gravitational-Wave Observatory (LIGO) detected a merger event from two neutron stars caught in a tight orbit in an event dubbed GW 170817. Neutron stars are stars so dense that a teaspoonful would weigh a billion tons on Earth. Astronomers worked to quickly find a visible counterpart in the galaxy NGC 4993. The merger event triggered a fast production of heavy elements such as gold and platinum in vast abundance. This analysis also showed that such events could provide most of these elements in the Universe.

But, there is at least one lingering question from GW 170817 - how does the binary neutron star system form? Neutron stars form when a massive star dies in a spectacular explosion called a supernova, a massive explosion that occurs when a star dies. This explosion often gives a kick to the binary in some way – either sending the stars in opposite directions and breaking apart the binary or by making the system’s orbit elliptical rather than circular.

The answer to this formation conundrum may be to study systems that have a neutron star and another massive star, these systems are called high-mass X-ray binaries. These systems are pairs of massive stars that emit powerful X-rays when material falls onto a neutron star or black hole. These systems have a massive star with the neutron star orbiting, usually in an elliptical orbit. One recently characterized system seems unique amongst these systems: CPD -29 2176. This binary has an orbit that takes about two months to complete and unlike many other high-mass binaries, the orbit is very circular.

This binary was measured to be circular using spectroscopy taken with a NOIR Lab telescope in Chile that has a 1.5-m diameter mirror. Spectroscopy is a technique that allows scientists to determine the composition and motion of stars by analyzing their light. These spectra showed that the B-type star in the binary has a hydrogen and helium disk surrounding it, typical of a type of star called a B‘e’ star.

The disk around a B‘e’ star is sometimes called a decretion disk – meaning it acts opposite of the normal accretion disks mentioned in astronomy. Accretion disks are rings of dust and/or gas that circle around stars, eventually falling onto their surface. In the case of CPD -29 2176, the star is rotating at a near critical rate which causes the material around its equator to be ejected into a disk. Then the major question becomes how the system got into this configuration, which was a topic in the recent paper by Richardson et al.

In the paper, the system’s history was modeled using a code called BPASS. This code is able to look at binary configurations and compare them to a large grid of models with binary interactions determined. The results are shown in the infographic here. The system, as depicted in (1) started with a primary star weighing 12 suns and a second star weighing about 9 suns. As the main star ran out of hydrogen in its core, it began to change and was near the biggest size it could be in a binary based on tidal forces, a limit called a Roche limit (2). At this time, it began sending material onto the second star (3).

The material overflowed onto the secondary star twice before the initial primary star exploded as a supernova (4). However, the interactions at this point had stripped almost all the outer material off of the original star, leaving very little material left to eject during a supernova explosion. As a result, the system couldn’t become elliptical like many systems with a supernova.

Today the system exists as a B‘e’ star with a neutron star orbiting it in a circular orbit (5). Eventually, this star will evolve and then explode as a supernova (6). But before this, the B‘e’ star will fill its Roche limit and send material towards the neutron star. This interaction will strip the B‘e’ star of most of its hydrogen and helium outer layers, and then we will have very little material for during its explosion so that the neutron stars remain bound in an orbit (7).

With two compact objects like neutron stars (or black holes) in an orbit, they will slowly spiral in towards each other as a result of Einstein’s General Theory of Relativity, the best theory that describes how gravity works. This will make the binary get closer and closer (8), until they eventually merge in a kilonova explosion like GW 170817 (9).

With these new observations and models, astronomers have now found a way with which to explain the production of very heavy elements like gold. Such systems tell us the details of how these systems evolve and eventually merge, even if astronomers only expect 10 such systems in the same phase of evolution in the Milky Way Galaxy. This groundbreaking discovery not only helps us understand how gold is created in the cosmos, but also gives us a glimpse into the life and death of stars as they live their lives and death throes in double systems.

Surfing the Waves of Quantum Matter in Warm Classical Seas

2023-10-20 17:12:21

Understanding a physical system is the art of distillation. Within an infinitely entangled reality, one must look at the proper scale and focus on the relevant phenomena to unlock the underlying simplicity. For example, to understand the motion of the sea, it would be futile to think about how each water molecule bounces around. Thinking about waves is much more effective.

This principle is particularly true in condensed matter. Here, atoms are close to each other and, therefore, strongly interact. This “many-body” physics is impossible to understand based on the dynamics of single particles. However, a brilliant solution to this problem was introduced by Lev Landau in 1941: Don’t look at strongly-interacting particles, like the water molecules in the sea. Instead, think about the excitations of the system, much like we do when we think about sea waves. Then, we can consider the excitations as “effective particles” or quasiparticles. Landau’s idea has been immensely fruitful in quantum matter. Famous examples include superconductivity and superfluidity and, recently, the motion of electrons in 2D honeycomb crystals made of carbon - a material called graphene.

As we mentioned, all known examples of quasiparticles occur in quantum systems, which is not accidental. In classical materials, excitations collide too frequently, so any potential quasiparticles would die out too quickly to be observed. In the following, we describe how one can break this paradigm that quasiparticles exist only in quantum mechanics. The surprising counter-example we will discuss is the discovery of quasiparticles in a classical system: a 2D lattice made of particles in viscous flow. As in quantum matter, the classical quasiparticles clearly explained a collective feature of the flowing crystal: the melting transition of a hydrodynamic crystal.

In our example, the quasiparticles are simply pairs of micron-size particles. These pairs emerge thanks to a peculiar symmetry of the viscous flow. When the particles are pushed through a channel filled with water, their motion perturbs the streamlines of water around them. In this manner, the particles “feel” and affect the motion of other particles around them. These are hydrodynamic forces similar to those we feel in a swimming pool when another swimmer passes nearby. The peculiar symmetry of these interactions induced by the flow is that the forces between two particles are equal in magnitude but are also in the same direction. In contrast, forces between particles are opposite in their direction. For example, when we push a wall with a specific force, the wall exerts an opposite force equal in magnitude on us. The critical result of this “same-direction” symmetry is that pairs of particles emerge and remain stable because the two particles apply on each other equal forces, so they keep moving together at equal velocities.

These particle pairs (or duos) are classical quasiparticles, which one may call “duons”. These are the fundamental excitations of the flowing system, just like excitations of electrons are the basis of superconductivity. Our idea was confirmed by analyzing how large 2D hydrodynamic crystals vibrate when they flow in a viscous fluid. Looking at the spectrum of the vibrations, we found a noticeable conical shape. In graphene electronics, these shapes got the name “Dirac cones” because the electronic quasiparticles obey an equation proposed by the physicist Paul Dirac. We were surprised to find that the flowing pairs (“duons”) are actually Dirac quasiparticles, but in an utterly classical system.

When the duons collide further and further, the crystal eventually melts, and we see a random collection of particles. To understand how the melting occurs, we followed a flowing crystal and saw how the vibrations developed. This examination showed the emergence of strong vibrations precisely at the Dirac cones - a clear indication that duons were generated. When the newly generated duons become dense, they violently collide, bringing about melting the crystal. Another way to see this is to start from a perfect crystal with an isolated duon (see figure). Much like a supersonic jet plane leaving behind a trail, our duon quasiparticle moves quickly, causing a ripple effect that creates more and more pairs. These two observations reveal the excitation of duons quasiparticles is what drives the melting transition.

But quasiparticles are not the whole story. We found a qualitatively different pathway to disorder by melting in hexagonal crystals. This is a special case because the three-fold symmetry of the crystal matches the symmetry of flow-induced forces. The result is the formation of an exotic structure called a “flat band” – a region in the spectrum dense with ultra-slow vibrations. Electronic flat bands were recently discovered in graphene, and they are of great interest because these “flat” excitations strongly interact. In the hexagonal crystal, we observed a second type of melting transition driven by these flat band waves.

Our results suggest that emergent collective phenomena – like quasiparticles and flat bands – are not at all limited to quantum systems. They may be observed in classical settings such as chemical systems and even living matter. Thus, they may be more abundant them we previously realized. We expect that many more quantum-like phenomena will be observed in other classical systems and will help explain their emergent modes.

Unravelling the Secrets of Pine Roots: A Tale of Nutrition and Adaptation

2023-10-19 17:54:17

In 1970, Francis Crick proposed “the central dogma of molecular biology”. This theory explained how genes (DNA) are used to produce proteins in all living organisms. Essentially, the information contained in genes flows in only one direction, from DNA to mRNA (the process of transcription) and from this to protein (the process of translation).

However, it is known that transcription and translation processes are not always directly linked since there are several biological processes involved in their regulations. In recent years, an increasing research interest has focused on assessing the biological role of RNA chemical modifications and its relationship to cellular regulation processes, forming what is commonly known as the epitranscriptome. Thus, the epitranscriptome comprises the study of the set of chemical modifications present in the different RNA types. To date, about 170 different modifications have been identified in RNAs of all living organisms. Regarding eukaryotic cells, N⁶-methyladenosine (m⁶A) has been identified as the most prevalent RNA modification in mRNAs (transcripts), which are the intermediary RNAs used during translation to synthesize proteins. In plants, the epitranscriptome regulates different cellular and physiological processes, although knowledge of its role in many of these processes is limited. This is the case of the epitranscriptomic response in relation to nitrogen nutrition.

Nitrogen is one of the main limiting factors for crop growth and yield. In fact, it is well known that there is a direct relationship between crop yields and the amount of nitrogen available in the soil. Therefore, the use of nitrogen fertilizers in today's agriculture is essential to meet the nutritional needs of humankind in the current scenario of world population growth. Furthermore, the availability of nitrogen influences many aspects of plant development. For example, the greenness of leaves depends on nitrogen, as it is essential for the synthesis of chlorophyll, the pigment that gives plants their green color and enables photosynthesis. Being this a parameter commonly used in agriculture to know when to fertilize crops.

This relationship is so strong that each type of nitrogen molecules in the soil can elicit distinct plant growth and development responses involving the activation/suppression of different cellular pathways. Thus, the main inorganic nitrogen molecules in the soil, nitrate, and ammonium, promote changes in root architecture that may be different depending on the plant species and its environmental adaptations. In this context, the proper development of plant roots is very important as they have the potential to prevent soil erosion, help mitigate climate change and ultimately guarantee food supply. Therefore, the study of this plant organ becomes an essential aspect at multiple levels.

In our work, we used maritime pine (Pinus pinaster) a western Mediterranean conifer tree. This pine is of great environmental importance in the region as it forms extensive forests in France, Spain, and Portugal where it is also a major source of raw materials such as wood and resin. Interestingly, maritime pine seedlings fed with ammonium can generate a greater number of lateral roots and biomass than those fed with nitrate, in contrast to many crop plants in which ammonium decreases root development. In other words, its study is very interesting since many crops do not tolerate ammonium well and its use as a fertilizer is preferred to that of nitrate because of the environmental problems nitrate can cause.

We have analyzed the effects of ammonium nutrition over the root epitranscriptome of maritime pine seedlings at short-term. This has been made using a method that allows us to read the mRNA directly including its chemical modifications. Our results showed that ammoniumtriggers a root systemic response that mainly involved changes in key pathways such as primary metabolism, hormone signaling pathway, translation, and root growth. However, the main novelty are the correlations of the epitranscriptome, with transcript and protein abundances regarding ammonium nutrition. Thus, a higher abundance of a specific chemical modification (m⁶A) in transcripts is related to a lower abundance of these transcripts and a higher abundance of their proteins. Although it may initially seem contradictory, it is not, and it makes a lot of sense if it is considered the role of m⁶A in granting an increase in the stability (half-life) of these modified transcripts. In this way, although the abundance of these transcripts is lower, as they probably have a longer half-life, it may ensure that their translation into proteins is sufficient to provide the adequate cellular response. In terms of energy, this could mean a necessary energy saving step for gene transcription, since a large amount of resources are being derived to promote plant growth.

Therefore, our results suggest that quick changes in gene activity can be controlled through intermediate steps, such as epitranscriptomic regulation, to generate a balanced and effective cellular reaction in order to provide a proper response to environmental stimuli. This knowledge of the molecular mechanisms involved in root development will allow for the future development of new crop lines better adapted to the use of ammonium fertilizers.

Fish identify themselves in mirrors and portraits

2023-10-19 09:52:09

“Intelligent animals” like chimpanzees and dolphins, possess an ability to recognize themselves in a mirror. Mirror self-recognition (MSR) via mental image of the self provides a background of the animal’s private self-awareness or “mind”. However, implications remain controversial since an alternative process, such as checking the synchronicity of the mirror-image has not been ruled out. To show animals’ mental self-image is used in MSR, no studies, so far, have taken place.

Previous studies revealed that the small cleaner fish (Labroides dimidiatus) have MSR-capacity. What mental image of self do they have? They have individually different facial color patterns and use them to recognize familiar individuals. Similarly, we recognize ourselves by the mental image of our own or known people's faces in the mirror. Therefore, we assumed the fish would also recognize mirror-image as self via mental image of self-face. We tested this hypothesis using a self-photograph as the self motionless.

A total of ten cleaner fish were exposed to a mirror for a week; a mark-test confirmed that all fish had MSR-capacity. Before exposure, these fish frequently attacked photo models of themselves and unknown strangers. After passing the mark-test, they still strongly attacked unknown fish photographs, but not their own. Results indicate that cleaner fish may recognize self-photographs as themselves.

They were shown two types of composite photographs of their own face/stranger body and stranger face/own body. The formers were not attacked like the self-photograph. In contrast, the latter were attacked as frequently as the photograph of stranger fish. This strongly suggests that cleaner fish with MSR-capacity recognize their own facial characteristics in photographs. Since the recognition of motionless photographs does not involve a kinesthetic-visual matching process, we provide evidence that the MSR mechanism of cleaner fish is likely based on a mental image of their own face. That is, cleaner fish have internal mental images like humans.

However, fish may consider the self-photograph to be a “super-familiar” fish, and they should not attack it. To reject this possibility, we tested whether cleaner fish identified self-photographs as themselves using the “self-photograph mark-test.” We prepared eight new cleaner fish with MSR-capacity. Focal fish were shown their self-photograph with a parasite-like mark on the throat. Since these fish would have mental images of self, we predicted that they would scrape their own throat to remove the mark (no mark was on their throat) when they saw the photograph.

As predicted, six out of eight fish scraped their own throats on the bottom substrates when they saw the photographs, but no fish did so when they saw the unmarked self- or familiar-neighbor photographs with marks. So, we concluded that cleaner fish recognize the self-photographs as themselves; neither self-face nor mark itself triggered throat scraping, and they had no opportunity for associative learning.

Thus, cleaner fish likely consider the mark an ectoparasite, which will induce their motivation to remove it. Indeed, after scraping their throat, they immediately looked at their reflection in the mirror or at the photographs to see if they successfully removed the mark. This recognition might be an example of meta self-awareness. Meta self-awareness is the next level of awareness in which one is aware of awareness. We are further exploring this hypothesis in ongoing studies. Cleaner fish have a mental image of their self-face, probably together with motivations, aims, and intentions. Thus, they may have private self-awareness, or “mind.”

In social groups, animals need to readily recall previous interactions with other individuals, and having mental images of conspecific faces would facilitate the rapid identification of recently encountered individuals. We show that fish can distinguish between the faces of self, familiar, and unknown fish. The ability to recognize faces and to adjust behaviors accordingly (e.g., friendly or aggressive) suggests that cleaner fish can distinguish the self and others without any language.

Our study implies that intelligence and self-awareness may not be directly relevant either to brain size or phylogenetic proximity to humans. We believe that our study will be a milestone in animal cognitive studies and challenge the anthropocentrism that has persisted since Descartes.

On how to use earthquakes to study a volcano

2023-10-13 15:47:31

The occurrence of earthquakes preceding or during volcanic eruptions has been known since ancient times. The first-time earthquakes associated with a volcano eruption in scientific literature were in the description of the Vesuvius eruption in 79 AD by Pliny the Younger. At that time, neither the origin of earthquakes, nor why they occurred in volcanic environments were known. Nowadays, we know that most earthquakes associated with volcanoes are related to the movement of magma and fluids under the surface. Before eruptions, the magma and fluids that have been accumulated in reservoirs at depth start to ascend to the surface forcing their way up through shallow underground fractures and passageways. As they advance opening this magmatic plumbing system, they will cause the surrounding wall-rocks to break creating earthquakes. This fact mostly occurs on long-dormant volcanoes which typically exhibit more pronounced seismicity changes prior to eruptions. Once the eruption has started, the withdrawal of magma accumulated in the different reservoirs and the possible ascent of new magma from depth can also trigger earthquakes in the surrounding rock.

For many centuries, the number of earthquakes felt by the population was the only information that scientists had about the seismicity associated with historical eruptions. Thanks to the great advances in technology and instrumentation, it is now possible to use accurate sensors to detect smaller earthquakes. With an appropriate seismic network in the vicinity of a volcano, it is possible to obtain the location of these earthquakes beneath the volcanic building and infer their "focal mechanism", which provides information on the geometry of the activated fractures. In favourable circumstances, estimation, if the earthquake rupture was accompanied by an increase or decrease in volume, is possible, for example in response to opening and closing of cracks.

Therefore, the analyses of seismic waveforms allow us to track magma and volcanic fluids during a volcanic reactivation indirectly. Monitoring the evolution of volcanic unrest using seismological data only, however, faces important challenges. First, seismicity does not occur uniformly within the volcano, and it is not unusual to find some "aseismic” zones, where pressure, temperature and structural properties inhibit the occurrence of earthquakes. Second, the interpretation of seismicity may be difficult, potentially being explained by different scenarios. For these reasons, it is important to combine the analysis of seismicity with other observations, such as ground deformation, gas emission or gravity variations. A joint interpretation of different data helps the correct interpretation of the processes happening beneath a volcano and the development of conceptual models that can be used to improve early warning and volcano monitoring.

Our research focuses on the reactivation of La Palma, Canary Islands (Spain) and the volcanic eruption that began on September 19, 2021. This eruption had a great media impact due to its consequences for the local population, with more than 1,600 buildings destroyed by lava flows and more than 7,000 people evacuated. Abundant seismicity, moderate in magnitude but widely felt, started a week before the eruption onset and continued throughout the eruption keeping the population on edge. 13 earthquakes reached a maximum intensity of IV-V (European Macroseismic Scale-98) and a few of them were also felt at neighbouring islands.

This eruption was the first fully monitored on the island and little was known about this volcano’s feeding system before the eruption began. We analysed seismic data over nearly 5 years, from the first signs of reactivation in 2017 until the end of the eruption in December 2021. We relocated the whole series (8488 earthquakes) and obtained the focal mechanisms of the largest 156 earthquakes. Seismicity locations revealed the presence of magma accumulation at two different depth levels, in the lower crust and the upper mantle respectively, forming a complex magma storage system. The focal mechanism results provide the key to understand its behaviour during the eruption. In particular, the peculiar observation of rotated focal mechanisms for earthquakes located at very close distance provided evidence for the progressive depletion of the two reservoirs during the eruption, which is also supported for the shallowest one by deformation data. Based on our findings, we have developed a new conceptual model of the magma feeding and reservoir system beneath the island.

In our work, we took advantage of the unprecedented dataset to improve our understanding of both the long-term precursor activity, with the progressive destabilisation of the plumbing system and the short-term instability of the magmatic plumbing system.