Cellular switch casts light on why humans are active in the day

 Early mammalian ancestors were nocturnal, sleeping during the day while the dinosaurs dominated the land. However, some mammalian lineages, including human ancestors, independently transitioned to diurnality (active during the day). Scientists have now discovered why humans are not nocturnal. A new study published in Science reveals that the answer is in the genes.

How the transition happened has been a long-standing puzzle because the brain's master circadian clock works similarly in both nocturnal and diurnal species.

Cells, signals and daily rhythms

The new research shows that the crucial difference lies not in the brain's wiring but in how individual cells respond to signals in their microenvironment. Over each 24-hour cycle, small shifts in the body's internal conditions like temperature or fluid balance subtly influence the chemical reactions inside cells.

These physical cues adjust basic cell processes, such as how proteins are made and modified, core processes that help determine when a cell "expects" day or night.

The team, led by Andrew Beale and John O'Neill at the Medical Research Council (MRC) Laboratory of Molecular Biology, studied cells from both diurnal mammals (including humans) and nocturnal mammals (such as mice). When exposed to daily temperature cycles, diurnal mammal cells and nocturnal mammal cells shifted their internal circadian clocks in opposite directions.

Key pathways and evolutionary changes

These opposite responses echo the animals' natural activity patterns. The researchers found that these contrasting reactions involve two major cellular signaling pathways:

• mechanistic target of rapamycin (mTOR)
• with-no-lysine (WNK)

These pathways help cells detect nutrients and regulate fundamental biochemical reactions.

Temperature changes caused human and mouse cells to alter protein synthesis and activities in different, and sometimes opposite, ways. This points to differences in how sensitive their mTOR and WNK pathways are.

Aided by Matthew Christmas, based at the Science for Life Laboratory at Uppsala University, Sweden, the group looked to contextualize this finding against the backdrop of mammalian evolution.

After analyzing genetic data across several species, Christmas found that genes within the mTOR and WNK networks have evolved unusually quickly in diurnal mammals. This suggests that the shift from nighttime to daytime activity required evolutionary tuning of basic cellular function at the genetic level.

Switching mice and broader implications

This discovery suggested that modification of their activity could enable nocturnal mammals to switch to more diurnal activity.

To explore this, the group gently altered mTOR activity in nocturnal mice using diet-based treatments. Once mTOR function was reduced, the mice began behaving more like diurnal animals, shifting their active hours into the daytime.

This underlined that changes in cellular pathways can influence when an animal is active, functioning like a day or night switch.

O'Neill explained, "Understanding why humans are diurnal while many other mammals are not shines new light on our circadian rhythm, part of our biology that is important for long-term health. Our research leverages an evolutionary approach to reveal the fine details of how fundamental cellular pathways sense and respond to daily environmental rhythms. These differ between species in ways we simply hadn't appreciated before."

The findings also highlight how climate change could impact mammal behavior as they adapt to transforming conditions.

Beale added, "As the atmosphere warms up, the current relationship between the external environment and food availability is rapidly changing. As a result, many mammals may shift the time of day they are active. This could have wide-ranging and detrimental effects on whole ecosystems."

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Fossil amber reveals the secret lives of Cretaceous ants

Tiny insects trapped in amber could tell us a great deal about their roles in past ecosystems: pollinators, parasites, predators, and prey. But how many of the insects preserved alongside each other reflect interactions during life, and how many are just unlucky coincidences?

Scientists in Spain scrutinized six key samples which preserve now-extinct insects unusually well, to try to learn more about the ants that lived at the same time as the dinosaurs.

"Amber inclusions are representative of possible interactions between different organisms shaping the environment," explained Dr. Jose de la Fuente of the Institute for Game and Wildlife Research, Spain, lead author of the article in Frontiers in Ecology and Evolution.

"The identification and morphological characterization of fossil ants in amber with other inclusions of insects provides a snapshot of life on Earth millions of years ago."

Snapshots of the past

The scientists looked at six different pieces of amber which include multiple different organisms of different species, a rare phenomenon called syninclusion. They chose these pieces of amber because they include ants, which are considered particularly important to ecosystems.

The earliest ants, which were first found in the Upper Cretaceous, are known as Stem ants and didn't leave modern descendants; all ants alive today evolved from Crown ants. Both species are found in the six pieces of amber studied by the scientists, as well as Hell ants, which evolved from Stem ants.

The study sample included four pieces of Cretaceous amber (around 99 million years old), one piece of Eocene amber (from approximately 56–34 million years ago), and one piece of Oligocene amber (from approximately 34–23 million years ago). The scientists used powerful microscopes to examine the amber, identify the different species found inside, and measure the distance between ants and other species.

In three of the six pieces of amber, the scientists found ants in close proximity to mites. In the first piece of amber, Case 1, the scientists found a Crown ant, wasp, and two mites so close to the ant that they may have been traveling on it. Similarly, Case 4 contained a Stem ant and a mite, about four millimeters apart. Case 5 also contained three different species of ant close to a mite and some termites, as well as poorly-preserved mosquitoes and a winged insect.

In Case 6 the scientists found a Stem ant alongside a probable parasitic wasp and a spider. The ant seems to have been feeding on something. It is resting against another insect inclusion, which could be a worm or a larva, but as there's no indication that the two were interacting, the scientists think this was a coincidence.

Finally, Case 2 contained a Stem ant and a spider, while Case 3 contained a Hell ant, a snail, a millipede, and some unidentifiable insects.

"The closest ant syninclusions are more likely to reflect behavior and interactions between these organisms," said de la Fuente. "The proposed ant-mite interactions in Case 4 may reflect two possible scenarios. First, a commensal specialized temporal relationship where mites attach to ants for free ride dispersal to new habitats. Second, a parasitism when mites feed on the ant host during transport."

Although pieces of amber that contain ants are rare, and pieces of amber that contain multiple species are rarer, there is some published evidence that points to interactions between mites and ants, sometimes mutually beneficial.

Future research could help clarify this by using micro-CT scanning to look for attachment structures on mites which would have allowed them to clamber onboard ants for travel purposes. Similarly, the spider in Case 6 is a species which could camouflage itself as an ant and might have benefited from proximity to real ants.

The scientists say that smaller distances between insects in amber are more likely to reflect interactions during life, such as those between ants and mites. But they call for caution around inferred interactions: insects that aren't in contact could just be insects that got stuck in the same resin.

"To improve the analysis of interactions between different organisms in fossil amber inclusions, future research should use advanced imaging techniques," said de la Fuente. "Nevertheless, these results provide evidence of insect behavior and ecological habits."

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Tackling the global tuberculosis crisis: An emerging class of antibiotics offers hope

Researchers from the University of Sydney and the Centenary Institute have discovered how a promising class of experimental antibiotics disrupts the bacterium that causes tuberculosis (TB), paving the way for urgently needed new treatments.

Globally, TB remains a major health crisis, claiming around 1.2 million lives each year and ranking among the world's deadliest infectious diseases. The rise of drug-resistant strains, including in the Asia-Pacific region, has made the search for new treatment strategies increasingly urgent.

Investigating three experimental compounds

In a study published in Nature Communications, the team investigated how three naturally occurring antibiotic compounds—ecumicin, ilamycin and cyclomarin—act on a vital protein degradation machine inside Mycobacterium tuberculosis, the bacterium that causes TB.

The molecular machine, known as the ClpC1–ClpP1P2 complex, allows the bacterium to break down damaged or unneeded proteins, helping it to survive stress and maintain essential functions. Without it, the TB bacterium can't survive, making it an attractive drug target.

How the compounds disrupt TB bacteria

Co-senior author Professor Warwick Britton, Laboratory Head in the Centenary Institute's Center for Infection & Immunity, said the study uncovers surprising complexity in how the three antibiotic compounds affect this system.

"TB bacteria depend on this recycling system to stay alive, particularly under stressful conditions inside the human body," Professor Britton said.

"Our findings show these compounds don't simply shut the system down. Instead, each one interferes with it in a different way, triggering widespread imbalances across the whole bacterium. This disruption weakens its ability to function and survive."

Mapping protein-level changes inside bacteria

First author Isabel Barter, Ph.D. candidate at the University of Sydney, who also conducted part of the study at the Centenary Institute, said they had measured changes across over 3,000 proteins in Mycobacterium tuberculosis.

"By tracking changes across most of the bacterium's protein network, we were able to see how disrupting a single essential complex can reshape the bacterium's entire internal protein landscape," she said.

"This deeper understanding gives us valuable insight into how we might refine these compounds and design more precise and effective anti-TB treatments."

Implications for next-generation TB drugs

Co-senior author Professor Richard Payne from the University of Sydney said the ClpC1–ClpP1P2 complex represents a promising but still relatively underexplored drug target.

"Our study highlights the potential of directly targeting this protein degradation system," Professor Payne said. "By understanding how different compounds interact with it and disrupt its normal function, we can more strategically design the next-generation of anti-TB drugs."

The team believes the study marks an important step towards expanding the pipeline of potential new treatment options for TB, including drug-resistant forms.

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Bacterial pathogens build antibiotic-resistant 'bunkers' using filament scaffolds

Researchers have discovered and characterized at the atomic level a mechanism that enables bacterial pathogens—including hospital bacteria Acinetobacter baumannii and Pseudomonas aeruginosa—to assemble antibiotic-resistant three-dimensional (3D) biofilms. These findings open a new avenue for developing therapies against multidrug-resistant bacterial infections by targeting the biofilm assembly. The work is published in the journal Nature Communications.

Many pathogenic bacteria form 3D biofilms to protect themselves from the immune system, antibiotic treatments, and drying on environmental surfaces. Some of the most problematic hospital bacteria, such as multidrug-resistant A. baumannii and P. aeruginosa, use specialized hair-like filaments called adhesive pili to attach to tissues or abiotic surfaces. After attaching, the bacteria then grow into thick 3D biofilms consisting of multiple layers of bacteria. This process is also mediated by adhesive pili, but until now it has been unclear how they prevent the growing 3D biofilm from falling apart.

Using a combination of advanced electron microscopy methods, the researchers at the MediCity Research Laboratory of the University of Turku in Finland, led by S. Jusélius Senior Researcher Anton Zavialov, discovered that adhesive Csu pili from neighboring A. baumannii bacteria attach to each other in an antiparallel manner. These pili rapidly assemble into flat sheets that link bacteria together and shield them from hostile environments.

"Impressively, Csu pili can self-assemble into huge, complex networks connecting hundreds of bacterial cells," says Dr. Zavialov.

The team demonstrated that Csu pili can form at least two types of flat structures and resolved them at a near-atomic resolution.

"Cryo-electron microscopy methods are developing very rapidly. To obtain the first model, I initially developed a manual approach, and only later did we apply computational tools to solve these exceptionally large assemblies in 3D," explains first author Doctoral Researcher Henri Malmi.

The researchers also found that the pilus network becomes embedded in a less defined matrix composed of polysaccharides and DNA secreted by the bacteria.

"This final structure somewhat resembles reinforced concrete: the pili act like steel bars, while polysaccharides and DNA form the concrete. In this way, the bacteria effectively hide in a bunker," adds Dr. Zavialov.

The team is now focused on developing inhibitors that target the connections between pili. Such inhibitors could be used in combination therapies to prevent 3D biofilm assembly and help antibiotics eliminate the pathogens more effectively.

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Why do microbes team up? A new model explains nutrient sharing in fluctuating environments

 Depending on others for something you need may feel like a risky proposition—and perhaps a human one. It is actually a survival strategy found in the microbial world, and far more frequently than one might expect. Discovering why is key to understanding how microbes form stable communities across medical, industrial, and ecological settings.

A new study by bioengineering professor Sergei Maslov (CAIM co-leader), computational scientist Ashish George, and biology professor Tong Wang explores why interdependence can be such a winning move for microbial communities. Their work, published in Cell Systems, demonstrated that a mathematical model of how bacteria produce and share resources accurately predicted the outcome of experiments with living E. coli strains.

The researchers' collaboration began during their time as colleagues at the Carl R. Woese Institute for Genomic Biology at the University of Illinois Urbana-Champaign. George continued the collaboration in his position at the Broad Institute; Wang, in his appointment at Purdue University. Maslov, who led the study, remains at Illinois and is an affiliate member of the National Institute for Theory and Mathematics in Biology.

"Microbes rarely live in isolation. They actually live in communities just like humans," Wang said to explain their inspiration for embarking on the study. "We wanted to establish a mathematical model to try to capture how they trade essential nutrients, and eventually what kind of community they will be able to assemble due to their cooperative interactions."

Maslov and Wang focused in particular on auxotrophs—microbes that are missing the capability to make one or several essential nutrients, often amino acids, which they must instead absorb from their environment. Auxotrophy seems—at first glance—like a weakness. The cell's survival is dependent upon its surroundings, and most often its neighbors. Yet auxotrophs are not a rare occurrence; they are commonly found in microbial communities.

"Previous studies seem to show that when a community has more auxotrophic species, it seems to be more stable, and these communities are actually pretty prevalent," Wang said. "So another reason why we want to establish this type of model is to answer: Why are there so many auxotrophic species, and what's their connection with ecological stability?"

Other research groups have explored—through laboratory experiments and a mathematical model only based on pairwise species–species interactions—how auxotrophs can remain a functioning part of communities by focusing on how two types of auxotrophs might pair up, each one supplying a resource the other needs. The experimental dynamic is intriguing, but the model can't fully portray microbial cooperation accurately, failing to predict how interdependencies develop across a whole community of 14 members with many different nutrients to share or consume.

The research team wanted a mathematical model that could describe in numbers how the interplay across a whole community of multiple types of microbes might develop. Based on the established model, they derived two key ecological principles.

"One principle is that we have to balance all the fluxes. Let's make sure that everything that is being generated, all the amino acids being generated by the community, is consumed by somebody in the community, so nothing is left," Maslov said. "The second one is, let's make sure that for every species, there is actually something that limits its growth, because if nothing is limiting your growth, you will be growing exponentially and eventually you will take over ... so we explored in this model how we can simultaneously balance fluxes, and make sure that all the species have their unique limiting resource and they can all coexist because they are fighting for different things."

Their model's results showed how the presence of auxotrophs can make a community more stable in the face of environmental fluctuations, because collectively, their network of interdependent production and consumption is more self-sufficient. In addition, once a group has formed, it is difficult for other microbes to "invade" unless their own nutrient requirements fit into the established group dynamic.

To test their model, the researchers applied their model to predict the outcome of a past study from another group that combined 14 lab-created auxotroph strains of E. coli. In that study, four strains survived to form a stable community. The present model was able to correctly predict the identities of three of the four strains, a marked improvement over past modeling efforts.

From here, Tong and Maslov plan to apply the new modeling approach to a variety of real-world conditions, such as understanding the communities of bacteria and other microbes that live in and on our bodies and impact our health.

"We would like to study community assembly and try to explain some of the patterns of the human gut microbiome, why some species tend to sort of coexist together," Tong said. "Maybe they are complementary to each other regarding the generation of different amino acids, or even include other essential resources like vitamins. That's actually one of the applications we can imagine."

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Electrochemical signals can reshape bacterial protein patterns, boosting electron transfer

 Sometimes, transporting electrons from one cell to another is a team effort. In electroactive bacteria, that team is a group of proteins that shepherds electrons forward, passing them along like a relay baton, so they can penetrate the thick cell envelope comprising multiple layers of membranes that otherwise are not electroconductive. But how these proteins collaborate to achieve this has not been clear.

Cornell researchers have discovered this electron transfer is mediated by CymA proteins' ability to synchronize and form a biomolecular condensate in the inner membrane—something that had not been previously observed in electroactive bacteria. The researchers then demonstrated for the first time that by applying an electrochemical signal to the bacteria, they could manipulate the spatial pattern of the proteins and spur the extracellular process.

The technique could eventually find applications in biotechnologies such as microbial energy conversion, in which electrons need to be shuttled to other cells or electrodes. The findings were published in Nature Communications. The lead author is former postdoctoral researcher Youngchan Park, now an assistant professor at Indiana University.

The project was led by Peng Chen, the Peter J.W. Debye Professor of Chemistry in the College of Arts and Sciences. It grew out of a collaboration with co-author Buz Barstow, Ph.D. '09, assistant professor of biological and environmental engineering in the College of Agriculture and Life Sciences, that explored how electroactive bacteria interact with semiconducting materials.

That research inspired Chen to delve further into extracellular electron transport in bacteria—specifically Shewanella oneidensis, the most well-known and extensively studied microbe used for electron transport. As a so-called Gram-negative bacteria, S. oneidensis has inner and outer membranes, connected by a kind of buffer zone of periplasm. Those stacked layers are a structural advantage, protecting the bacteria in unfriendly environments—for example, ones rife with heavy metals or antibiotics. However, the membranes, which mostly consist of insulating fatty lipids, aren't electroconductive.

"Electrons have to go through the cell envelope: the inner membrane, outer membrane and the periplasmic space," Chen said. "Now, electron transfer in biology, of course, doesn't just go through solutions. Electrons do not swim through water. Otherwise, they would get short-circuited."

But both membranes and the periplasm contain a secret asset: proteins. Using photoelectrochemistry-fluorescence microscopy, the researchers determined that during extracellular electron transfer, CymA proteins in the inner membrane reorganize in a confined region and drive their electron-transfer partners to do the same in the periplasm.

This type of condensate is a well-documented phenomenon in bacteria and many other types of cells, playing a role in metabolic enzymatic reactions and gene regulation, but it was not known to be important for electron transfer and hadn't been observed in electroactive bacteria, Chen said. The researchers were able to induce the formation of CymA condensate by applying electrochemical signals, which allowed them to quantify the spatiotemporal dynamics of protein reorganization at the single-cell level.

"Many people have applied electrical signals to bacteria, but we discovered that by applying an electrochemical signal to the cell, it can change the spatial pattern of the protein," Chen said. "The pattern initially is homogeneous, and then you condense it. The electrical signal—basically, the electron transfer—will drive the change of a spatial pattern. That's a new thing."

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Nuclear speckles play a key role in the progression of viral infection, research reveals

 Herpes simplex virus type 1 (HSV-1) infection dramatically remodels the host cell's nuclear structures. Infection leads to the formation of viral replication compartments and to chromatin marginalization to the nuclear periphery. Joint research by the Universities of Jyväskylä (Finland) and Bar-Ilan (Israel) reveals that viral infection also alters the structure of nuclear speckles, which are essential for messenger RNA processing.

The study was published in the Proceedings of the National Academy of Sciences.

"Nuclear speckles are dynamic, membraneless nuclear bodies that primarily function as sites for the storage, assembly, and modification of factors involved in gene expression. Both cellular and viral messenger RNAs are processed in nuclear speckles. The disassembly of nuclear speckles severely limits the export of viral messenger RNAs from the nucleus," explains Research Director Maija Vihinen-Ranta from the University of Jyväskylä.

The research indicates that nuclear speckles function as intermediate hubs for the modification of viral messenger RNAs, thereby highlighting their essential role in viral messenger RNA processing and nuclear export pathways. Without them, viruses cannot function normally, and infection cannot progress.

"A better understanding of how viruses interact with host cells and exploit their cellular machinery can help us develop new ways to treat and prevent viral diseases," says Vihinen-Ranta.

The study was conducted in cooperation with Professor Shav-Tal's research group, Bar-Ilan University (Israel).

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