Marco Archetti

Eukaryotic cells secrete growth factors that facilitate the proliferation and survival of neighboring cells in a coordinated manner essential for tissue development, repair, and homeostasis. However, mutant cells that fail to produce these factors may exploit the benefits provided by neighboring producers, thereby gaining a proliferative advantage that could lead to the extinction of the producer clone. Evolutionary theory predicts that preventing this “tragedy of the commons” requires a fixed spatial structure or other mechanisms that enable cells to interact preferentially with copies of themselves. Contrary to this expectation, we found that, in competition experiments, cells producing the diffusible growth factor interleukin-3 (IL3) resist invasion by non-producing mutant cells even in well-mixed populations, and that non-producers are driven to extinction instead. Using evolutionary game theory, we show that this outcome arises when the cost-to-benefit ratio of growth factor production falls below a critical threshold. We derive this tipping point analytically across the full parameter space of benefit function shape and group size and confirm that IL3 production in our experimental system satisfies this condition — with a production cost less than 0.1% of the benefit conferred. These results demonstrate that efficient public good production alone can resolve the tragedy of the commons in populations of cells, and potentially in other biological systems.

Insulin‐like growth factor 2 (IGF2) is implicated in osteosarcoma, but direct functional evidence of its role is lacking. Here, we used CRISPR‐Cas9 to knock out IGF2 in Saos2 osteosarcoma cells. Knockout cells showed reduced proliferation in vitro which was fully restored by exogenous IGF2. In vivo , knockout xenografts reached only ~25% of wild‐type tumor volume. Furthermore, transcriptomic analysis revealed depletion of angiogenesis‐related genes but no major changes in IGF2 pathway components. Finally, while integration with receptor dependency data suggested alternative signaling pathways, IGF2 loss remained functionally limiting. These findings demonstrate that IGF2 promotes osteosarcoma proliferation and tumor growth but is not strictly essential for survival.

Coronavirus genome encapsidation depends on cis-acting RNA elements that interact with viral structural proteins. While such packaging signals have been characterized in several coronaviruses, their definition in SARS-CoV-2 remains incomplete. Using synthetic defective SARS-CoV-2 genomes, we identify a 667-nucleotide region within the nsp15 coding sequence that preferentially binds SARS-CoV-2 nucleoprotein and enhances the accumulation of defective viral genomes both in vitro and in vivo. Sequential and targeted deletion analyses further delineate candidate RNA secondary structures within this region that contribute to this enrichment. These structures show similarity to elements within the putative packaging signal of SARS-CoV but are not conserved across other coronaviruses. Together, these findings support the presence of a structured RNA element within nsp15 that contributes to SARS-CoV-2 genome encapsidation and provide a framework for further structural and functional dissection of coronavirus packaging signals.

Hyperbranched poly(beta-amino ester) (hPBAE) nanoparticles represent a promising platform for nucleic acid delivery, particularly to the lungs. In this study, we evaluate the potential of hPBAE nanoparticles to deliver defective interfering RNA (diRNA) antivirals targeting betacoronaviruses under a range of formulations and storage conditions. hPBAE-diRNA nanoparticles demonstrated efficient cellular uptake of functional diRNA across diverse cell types, conferred protection against nuclease-mediated degradation, and exhibited low in vitro cytotoxicity. In vivo, these nanoparticles enabled effective delivery of functional diRNA to the lungs of golden hamsters without inducing adverse physiological effects. Collectively, these findings support hPBAE nanoparticles as a safe and effective platform for diRNA delivery for the treatment of respiratory viral infections.

Defective viral genomes (DVGs) affect viral dynamics, pathogenicity and evolution, have been found in many in vivo viral infections, and in theory can be detected from sequencing data. We explored the utility of the currently available bioinformatic programs ViReMa, DI-tector, DVGfinder, DG-Seq and VODKA2 for identifying junction points in plant virus high-throughput sequencing data, looking at whether the outputs from these bioinformatic tools generally agree and exploring the possibility of using these tools to help us understand whether DVGs are consistently generated and maintained in a specific virus-host combination. We conducted a meta-analysis of eight previously published RNA sequencing datasets utilizing all five programs and compared the degree of output overlap, the most common junctions present in each output and whether these junctions match previously reported junctions for that virus. Our results demonstrate a low degree of agreement regarding identified junctions between programs, including the most frequently identified one, although the most frequently identified junctions typically corresponded to large, disruptive deletions. We found preliminary support for our prevalence hypothesis, although we ultimately conclude that a more robust dataset generated expressly for testing this hypothesis will be required for a convincing answer. Finally, we suggest that when using bioinformatic programs to search for DVGs, it is best to run the same dataset through multiple programs and look at the overlap to inform decisions on downstream characterization.

Background: The ability to respond plastically to environmental variation is a key determinant of fitness. Females may use cues to strategically place their eggs, for example adjusting the number or location of eggs according to whether other females are present and driving the dynamics of local competition or cooperation. The expression of plasticity in egg-laying patterns within individual patches (i.e. in contact clusters or not) represents an additional, under-researched, and potentially important opportunity for fitness gains. Clustered eggs might benefit from increased protection or defence, and clustering could facilitate cooperative feeding. However, increased clustering is also expected to increase the risk of overexploitation through direct competition. These potential benefits and costs likely covary with the number of individuals present; hence, egg-clustering behaviour within resource patches should be socially responsive. We investigate this new topic using the fruit fly Drosophila melanogaster. Results: Our mathematical model, parameterised by data, verified that females cluster their eggs non-randomly and increase clustering as group size increases. We also showed that as the density of adult females increased, females laid more eggs, laid them faster, and laid more eggs in clusters. Females also preferred to place eggs within existing clusters. Most egg clusters were of mixed maternity. Conclusions: Collectively, the results reveal that females express plasticity in egg clustering according to social environment cues and prefer to lay in clusters of mixed maternity, despite the potential for increased competition. These findings are consistent with egg-clustering plasticity being selected due to cooperative benefits.

In ovipositing animals, egg placement decisions can be key determinants of offspring survival. One oviposition strategy reported across taxa is laying eggs in clusters. In some species, mothers provision eggs with diffusible defence compounds, such as antimicrobials, raising the possibility of public good benefits arising from egg clustering. Here we report that Drosophila melanogaster females frequently lay eggs in mixed-maternity clusters. We tested two hypotheses for potential drivers of this oviposition behaviour: (i) the microbial environment affects fecundity and egg placement in groups of females; (ii) eggs exhibit antimicrobial activity. The results partially supported the first hypothesis. Females reduced egg laying but did not alter egg clustering, on non-sterile substrates that had been naturally colonized with microbes from the environment. However, oviposition remained unaffected when the substrate community consisted of commensal (fly-associated) microbes. The second hypothesis was not supported. There was no evidence of antimicrobial activity, either in whole eggs or in soluble egg-surface material. In conclusion, while we found no behavioural or physiological evidence that egg clustering decisions are shaped by the opportunity to share antimicrobials, females are sensitive to their microbial environment and can adjust egg-laying rates accordingly.

Altruism, an act of benefiting others at a cost to the self, challenges our understanding of evolution. This Perspective delves into the importance of altruism in cancer cells and its implications for therapy. Against the backdrop of existing knowledge on various social organisms found in nature, we explore the mechanisms underlying the manifestation of altruism within breast tumors, revealing a complex interplay of seemingly counteracting cancer signaling pathways and processes that orchestrate the delicate balance between cost and benefit underlying altruistic cooperation. We also discuss how evolutionary game theory, coupled with contemporary molecular tools, may shed light on understudied mechanisms governing the dynamics of altruistic cooperation in cancer cells. Finally, we discuss how molecular insights gleaned from these mechanistic dissections may fuel advancements in our comprehension of altruism among cancer cells, with implications across multiple disciplines, offering innovative prospects for therapeutic strategies, molecular discoveries, and evolutionary investigations.

Background: The ability to respond plastically to environmental variation is a key determinant of fitness. Females may use cues to strategically place their eggs, for example adjusting the number or location of eggs according to whether other females are present, driving the dynamics of local competition or cooperation. The expression of plasticity in egg laying patterns within individual patches, i.e., in contact clusters or not, represents an additional, under-researched and potentially important opportunity for fitness gains. Clustered eggs might benefit from increased protection or defence, and clustering could facilitate cooperative feeding. However, increased clustering is also expected to increase the risk of over-exploitation through direct competition. These potential benefits and costs likely covary with the number of individuals present, hence egg clustering behaviour within resource patches should be socially responsive. We investigate this new topic using the fruit fly Drosophila melanogaster . Results: Our mathematical model, parameterised by data, verified that females cluster their eggs non-randomly, and increase clustering as group size increases. We also showed that, as the density of adult females increased, females laid more eggs, laid them faster, and laid more eggs in clusters. Females also preferred to place eggs within existing clusters. Most egg clusters were of mixed maternity. Conclusions: Collectively, the results reveal that females actively express plasticity in egg clustering according to social environment cues and prefer to lay in clusters of mixed maternity, despite the potential for increased competition. These findings are consistent with egg clustering plasticity being selected due to public goods-related benefits.

In ovipositing animals, egg placement decisions can be key determinants of offspring survival. One oviposition strategy reported across taxa is egg clustering, whereby a female lays multiple eggs next to one another or next to the eggs of other females. The fitness benefits of egg clustering, especially in mixed maternity clusters, are unknown. In some species, mothers provision eggs with diffusible defence compounds, such as antimicrobials, raising the possibility of public good benefits arising from egg clustering. Here we report that Drosophila melanogaster females frequently lay eggs in mixed maternity clusters. We tested two hypotheses for potential drivers of this oviposition behaviour: (i) the microbial environment affects fecundity and egg placement in groups of D. melanogaster females; (ii) D. melanogaster eggs exhibit antimicrobial activity. The results partially supported the first hypothesis. Females exposed to environmental microbes that naturally colonised the oviposition substrates in the absence of antimicrobial preservatives reduced their levels of fecundity but did not significantly alter egg clustering. In contrast, the presence of commensal (fly-associated) microbes did not affect oviposition. The second hypothesis was not supported. There was no evidence of antimicrobial activity, either in whole eggs or in soluble surface material extracted from them. In conclusion, while there was no evidence that oviposition decisions are shaped by the opportunity to share antimicrobials, there is evidence that the microbial environment provides cues that females use to make sophisticated decisions on fecundity and egg placement.