@article{19453, abstract = {A key feature of biological and artificial neural networks is the progressive refinement of their neural representations with experience. In neuroscience, this fact has inspired several recent studies in sensory and motor systems. However, less is known about how higher associational cortical areas, such as the hippocampus, modify representations throughout the learning of complex tasks. Here, we focus on associative learning, a process that requires forming a connection between the representations of different variables for appropriate behavioral response. We trained rats in a space-context associative task and monitored hippocampal neural activity throughout the entire learning period, over several days. This allowed us to assess changes in the representations of context, movement direction, and position, as well as their relationship to behavior. We identified a hierarchical representational structure in the encoding of these three task variables that was preserved throughout learning. Nevertheless, we also observed changes at the lower levels of the hierarchy where context was encoded. These changes were local in neural activity space and restricted to physical positions where context identification was necessary for correct decision-making, supporting better context decoding and contextual code compression. Our results demonstrate that the hippocampal code not only accommodates hierarchical relationships between different variables but also enables efficient learning through minimal changes in neural activity space. Beyond the hippocampus, our work reveals a representation learning mechanism that might be implemented in other biological and artificial networks performing similar tasks.}, author = {Chiossi, Heloisa and Nardin, Michele and Tkačik, Gašper and Csicsvari, Jozsef L}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences}, number = {11}, publisher = {National Academy of Sciences}, title = {{Learning reshapes the hippocampal representation hierarchy}}, doi = {10.1073/pnas.2417025122}, volume = {122}, year = {2025}, } @article{19499, abstract = {Quantum hardware is inherently fragile and noisy. We find that the accuracy of traditional quantum error correction algorithms can be improved depending on the hardware. Given different hardware specifications, we automatically synthesize hardware-optimal algorithms for parity correction, qubit resetting, and GHZ (Greenberger–Horne–Zeilinger) state preparation. Using stochastic techniques from computer science, our method presents a computational tool to compute exact accuracy guarantees and synthesize optimal algorithms that are often different from traditional ones. We also show that improvements can be gained with respect to the Qiskit transpiler as we compute the hardware-optimal qubit mapping for the GHZ state-preparation problem.}, author = {Muroya Lei, Stefanie and Chatterjee, Krishnendu and Henzinger, Thomas A}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences}, number = {12}, publisher = {National Academy of Sciences}, title = {{Hardware-optimal quantum algorithms}}, doi = {10.1073/pnas.2419273122}, volume = {122}, year = {2025}, } @article{19626, abstract = {Active regulation of gene expression, orchestrated by complex interactions of activators and repressors at promoters, controls the fate of organisms. In contrast, basal expression at uninduced promoters is considered to be a dynamically inert mode of nonfunctional “promoter leakiness,” merely a byproduct of transcriptional regulation. Here, we investigate the basal expression mode of the mar operon, the main regulator of intrinsic multiple antibiotic resistance in Escherichia coli, and link its dynamic properties to the noncanonical, yet highly conserved start codon of marR across Enterobacteriaceae. Real-time, single-cell measurements across tens of generations reveal that basal expression consists of rare stochastic gene expression pulses, which maximize variability in wildtype and, surprisingly, transiently accelerate cellular elongation rates. Competition experiments show that basal expression confers fitness advantages to wildtype across several transitions between exponential and stationary growth by shortening lag times. The dynamically rich basal expression of the mar operon has likely been evolutionarily maintained for its role in growth homeostasis of Enterobacteria within the gut environment, thereby allowing other ancillary gene regulatory roles to evolve, e.g., control of costly-to-induce multidrug efflux pumps. Understanding the complex selection forces governing genetic systems involved in intrinsic multidrug resistance is crucial for effective public health measures.}, author = {Jain, Kirti and Hauschild, Robert and Bochkareva, Olga and Römhild, Roderich and Tkačik, Gašper and Guet, Calin C}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences}, number = {15}, publisher = {National Academy of Sciences}, title = {{Pulsatile basal gene expression as a fitness determinant in bacteria}}, doi = {10.1073/pnas.2413709122}, volume = {122}, year = {2025}, } @article{19627, abstract = {Differentially private gradient descent (DP-GD) is a popular algorithm to train deep learning models with provable guarantees on the privacy of the training data. In the last decade, the problem of understanding its performance cost with respect to standard GD has received remarkable attention from the research community, which formally derived upper bounds on the excess population risk RP in different learning settings. However, existing bounds typically degrade with over-parameterization, i.e., as the number of parameters p gets larger than the number of training samples n -- a regime which is ubiquitous in current deep-learning practice. As a result, the lack of theoretical insights leaves practitioners without clear guidance, leading some to reduce the effective number of trainable parameters to improve performance, while others use larger models to achieve better results through scale. In this work, we show that in the popular random features model with quadratic loss, for any sufficiently large p , privacy can be obtained for free, i.e., |RP|=o(1) , not only when the privacy parameter ε has constant order, but also in the strongly private setting ε=o(1) . This challenges the common wisdom that over-parameterization inherently hinders performance in private learning.}, author = {Bombari, Simone and Mondelli, Marco}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences}, number = {15}, publisher = {National Academy of Sciences}, title = {{Privacy for free in the overparameterized regime}}, doi = {10.1073/pnas.2423072122}, volume = {122}, year = {2025}, } @article{19965, abstract = {Multiagent learning is challenging when agents face mixed-motivation interactions, where conflicts of interest arise as agents independently try to optimize their respective outcomes. Recent advancements in evolutionary game theory have identified a class of “zero-determinant” strategies, which confer an agent with significant unilateral control over outcomes in repeated games. Building on these insights, we present a comprehensive generalization of zero-determinant strategies to stochastic games, encompassing dynamic environments. We propose an algorithm that allows an agent to discover strategies enforcing predetermined linear (or approximately linear) payoff relationships. Of particular interest is the relationship in which both payoffs are equal, which serves as a proxy for fairness in symmetric games. We demonstrate that an agent can discover strategies enforcing such relationships through experience alone, without coordinating with an opponent. In finding and using such a strategy, an agent (“enforcer”) can incentivize optimal and equitable outcomes, circumventing potential exploitation. In particular, from the opponent’s viewpoint, the enforcer transforms a mixed-motivation problem into a cooperative problem, paving the way for more collaboration and fairness in multiagent systems.}, author = {Mcavoy, Alex and Sehwag, Udari Madhushani and Hilbe, Christian and Chatterjee, Krishnendu and Barfuss, Wolfram and Su, Qi and Leonard, Naomi Ehrich and Plotkin, Joshua B.}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences}, number = {25}, publisher = {National Academy of Sciences}, title = {{Unilateral incentive alignment in two-agent stochastic games}}, doi = {10.1073/pnas.2319927121}, volume = {122}, year = {2025}, } @article{20289, abstract = {Cell and tissue movement in development, cancer invasion, and immune response relies on chemical or mechanical guidance cues. In many systems, this behavior is locally directed by self-generated signaling gradients rather than long-range, prepatterned cues. However, how heterogeneous mixtures of cells interact nonreciprocally and navigate through self-generated gradients remains largely unexplored. Here, we introduce a theoretical framework for the self-organized chemotaxis of heterogeneous cell populations. We find that the relative chemotactic sensitivities of different cell populations control their long-time coupling and comigration dynamics, with boundary conditions such as external cell and attractant reservoirs substantially influencing the migration patterns. Our model predicts an optimal parameter regime that enables robust and colocalized migration. We test our theoretical predictions with in vitro experiments demonstrating the comigration of distinct immune cell populations, and quantitatively reproduce observed migration patterns under wild-type and perturbed conditions. Interestingly, immune cell comigration occurs close to the predicted optimal regime. Finally, we incorporate mechanical interactions into our framework, revealing a nontrivial interplay between chemotactic and mechanical nonreciprocity in driving collective migration. Together, our findings suggest that self-generated chemotaxis is a robust strategy for the navigation of mixed cell populations.}, author = {Ucar, Mehmet C and Zane, Alsberga and Alanko, Jonna H and Sixt, Michael K and Hannezo, Edouard B}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences}, number = {34}, publisher = {National Academy of Sciences}, title = {{Self-generated chemotaxis of mixed cell populations}}, doi = {10.1073/pnas.2504064122}, volume = {122}, year = {2025}, } @article{18849, abstract = {Many biological systems operate near the physical limits to their performance, suggesting that aspects of their behavior and underlying mechanisms could be derived from optimization principles. However, such principles have often been applied only in simplified models. Here, we explore a detailed mechanistic model of the gap gene network in the Drosophila embryo, optimizing its 50+ parameters to maximize the information that gene expression levels provide about nuclear positions. This optimization is conducted under realistic constraints, such as limits on the number of available molecules. Remarkably, the optimal networks we derive closely match the architecture and spatial gene expression profiles observed in the real organism. Our framework quantifies the tradeoffs involved in maximizing functional performance and allows for the exploration of alternative network configurations, addressing the question of which features are necessary and which are contingent. Our results suggest that multiple solutions to the optimization problem might exist across closely related organisms, offering insights into the evolution of gene regulatory networks.}, author = {Sokolowski, Thomas R and Gregor, Thomas and Bialek, William and Tkačik, Gašper}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences}, number = {1}, publisher = {National Academy of Sciences}, title = {{Deriving a genetic regulatory network from an optimization principle}}, doi = {10.1073/pnas.2402925121}, volume = {122}, year = {2025}, } @article{18850, abstract = {Biophysical constraints limit the specificity with which transcription factors (TFs) can target regulatory DNA. While individual nontarget binding events may be low affinity, the sheer number of such interactions could present a challenge for gene regulation by degrading its precision or possibly leading to an erroneous induction state. Chromatin can prevent nontarget binding by rendering DNA physically inaccessible to TFs, at the cost of energy-consuming remodeling orchestrated by pioneer factors (PFs). Under what conditions and by how much can chromatin reduce regulatory errors on a global scale? We use a theoretical approach to compare two scenarios for gene regulation: one that relies on TF binding to free DNA alone and one that uses a combination of TFs and chromatin-regulating PFs to achieve desired gene expression patterns. We find, first, that chromatin effectively silences groups of genes that should be simultaneously OFF, thereby allowing more accurate graded control of expression for the remaining ON genes. Second, chromatin buffers the deleterious consequences of nontarget binding as the number of OFF genes grows, permitting a substantial expansion in regulatory complexity. Third, chromatin-based regulation productively co-opts nontarget TF binding for ON genes in order to establish a “leaky” baseline expression level, which targeted activator or repressor binding subsequently up- or down-modulates. Thus, on a global scale, using chromatin simultaneously alleviates pressure for high specificity of regulatory interactions and enables an increase in genome size with minimal impact on global expression error.}, author = {Perkins, Mindy Liu and Crocker, Justin and Tkačik, Gašper}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences}, number = {1}, publisher = {National Academy of Sciences}, title = {{Chromatin enables precise and scalable gene regulation with factors of limited specificity}}, doi = {10.1073/pnas.2411887121}, volume = {122}, year = {2025}, } @article{19036, abstract = {Neuronal processing of external sensory input is shaped by internally generated top–down information. In the neocortex, top–down projections primarily target layer 1, which contains NDNF (neuron-derived neurotrophic factor)-expressing interneurons and the dendrites of pyramidal cells. Here, we investigate the hypothesis that NDNF interneurons shape cortical computations in an unconventional, layer-specific way, by exerting presynaptic inhibition on synapses in layer 1 while leaving synapses in deeper layers unaffected. We first confirm experimentally that in the auditory cortex, synapses from somatostatin-expressing (SOM) onto NDNF neurons are indeed modulated by ambient Gamma-aminobutyric acid (GABA). Shifting to a computational model, we then show that this mechanism introduces a distinct mutual inhibition motif between NDNF interneurons and the synaptic outputs of SOM interneurons. This motif can control inhibition in a layer-specific way and introduces competition between NDNF and SOM interneurons for dendritic inhibition onto pyramidal cells on different timescales. NDNF interneurons can thereby control cortical information flow by redistributing dendritic inhibition from fast to slow timescales and by gating different sources of dendritic inhibition.}, author = {Naumann, Laura B and Hertäg, Loreen and Müller, Jennifer and Letzkus, Johannes J. and Sprekeler, Henning}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences}, number = {4}, publisher = {National Academy of Sciences}, title = {{Layer-specific control of inhibition by NDNF interneurons}}, doi = {10.1073/pnas.2408966122}, volume = {122}, year = {2025}, } @article{20635, abstract = {Plants have evolved sophisticated mechanisms to adapt to environmental changes, with root gravitropism playing a pivotal role in nutrient and water acquisition. Our study reveals that SnRK2 kinases (SnRK2.2 and SnRK2.3) are critical regulators of root gravitropism through their direct phosphorylation of the auxin transporter PIN2 at S259. We demonstrate that SnRK2s-mediated phosphorylation modulates both the polar localization and transport activity of PIN2. Importantly, SnRK2s function antagonistically to the AGCVIII kinase PID, which phosphorylates PIN2 at a distinct site (S258), establishing a regulatory balance essential for adaptive root growth. Structural modeling and phosphorylation assays further suggest that SnRK2s-mediated phosphorylation at S259 sterically hinders access of PID to S258, providing a mechanistic basis for their antagonistic relationship. These findings uncover a novel regulatory mechanism, by which plants fine-tune root developmental programs to adapt to environmental stimuli, highlighting the evolutionary significance of multilayered kinase-mediated regulation in plant adaptation.}, author = {Sheng, F and Gao, Y and Wang, Y and Li, Y and Zhang, JA and Zhang, Z and Qin, X and Zhang, S and Song, W and Li, J and Guo, Y and Friml, Jiří and Gong, Z and Zhang, Q and Zhang, J}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences}, number = {39}, pages = {e2512274122}, publisher = {National Academy of Sciences}, title = {{Antagonistic SnRK2 and PID kinases' action on auxin transport-mediated root gravitropism}}, doi = {10.1073/pnas.2512274122}, volume = {122}, year = {2025}, } @article{20795, abstract = {The tropical climate variability is characterized by various oscillations across a range of timescales. Oscillations that imprint the tropical mean state are generally attributed to slow processes, such as the seasonal cycle or interannual variability. Here, we identify a pronounced tropics-wide intraseasonal oscillation (TWISO) in satellite observations and reanalyses. This oscillation, with a period of 30 to 60 d, is evident across multiple variables and involves interactions between convection, radiation, surface fluxes, and large-scale circulation. It is primarily manifested as convective perturbations in the tropical Indo-Pacific warm pool accompanied by oscillations in the large-scale tropical overturning circulation. Here, we examine the relationship between TWISO, the Madden–Julian Oscillation (MJO), and the instability of radiative-convective equilibrium. Certain phases of TWISO coincide with specific phases of the MJO, suggesting a potential connection between the two. However, although the MJO can amplify the oscillation amplitude of TWISO, it is not essential for TWISO to occur. Finally, due to its broad manifestation across the tropics, TWISO potentially exerts widespread influence on tropical weather and climate at regional scales.}, author = {Bao, Jiawei and Bony, Sandrine and Takasuka, Daisuke and Muller, Caroline J}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences}, number = {48}, publisher = {National Academy of Sciences}, title = {{Tropics-wide intraseasonal oscillations}}, doi = {10.1073/pnas.2511549122}, volume = {122}, year = {2025}, } @article{19809, abstract = {In many physical situations in which many-body assemblies exist at temperature T, a characteristic quantum-mechanical time scale of approximately h/kbT can be identified in both theory and experiment, leading to speculation that it may be the shortest meaningful time in such circumstances. This behavior can be investigated by probing the scattering rate of electrons in a broad class of materials often referred to as “strongly correlated metals”. It is clear that in some cases only electron–electron scattering can be its cause, while in others it arises from high-temperature scattering of electrons from quantized lattice vibrations, i.e., phonons. In metallic oxides, which are among the most studied materials, analysis of electrical transport does not satisfactorily identify the relevant scattering mechanism at “high” temperatures near room temperature. We therefore employ a contactless optical method to measure thermal diffusivity in two Ru-based layered perovskites, Sr3Ru2O7 and Sr2RuO4, and use the measurements to extract the dimensionless Lorenz ratio. By comparing our results to the literature data on both conventional and unconventional metals, we show how the analysis of high-temperature thermal transport can both give important insight into dominant scattering mechanisms and be offered as a stringent test of theories attempting to explain anomalous scattering.}, author = {Sun, Fei and Mishra, Simli and Stockert, Ulrike and Daou, Ramzy and Kikugawa, Naoki and Perry, Robin S. and Hassinger, Elena and Hartnoll, Sean A. and Mackenzie, Andrew P. and Sunko, Veronika}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences}, number = {35}, publisher = {National Academy of Sciences}, title = {{The Lorenz ratio as a guide to scattering contributions to transport in strongly correlated metals}}, doi = {10.1073/pnas.2318159121}, volume = {121}, year = {2024}, } @article{18525, abstract = {As their statistical power grows, genome-wide association studies (GWAS) have identified an increasing number of loci underlying quantitative traits of interest. These loci are scattered throughout the genome and are individually responsible only for small fractions of the total heritable trait variance. The recently proposed omnigenic model provides a conceptual framework to explain these observations by postulating that numerous distant loci contribute to each complex trait via effect propagation through intracellular regulatory networks. We formalize this conceptual framework by proposing the “quantitative omnigenic model” (QOM), a statistical model that combines prior knowledge of the regulatory network topology with genomic data. By applying our model to gene expression traits in yeast, we demonstrate that QOM achieves similar gene expression prediction performance to traditional GWAS with hundreds of times less parameters, while simultaneously extracting candidate causal and quantitative chains of effect propagation through the regulatory network for every individual gene. We estimate the fraction of heritable trait variance in cis- and in trans-, break the latter down by effect propagation order, assess the trans- variance not attributable to transcriptional regulation, and show that QOM correctly accounts for the low-dimensional structure of gene expression covariance. We furthermore demonstrate the relevance of QOM for systems biology, by employing it as a statistical test for the quality of regulatory network reconstructions, and linking it to the propagation of nontranscriptional (including environmental) effects.}, author = {Ruzickova, Natalia and Hledik, Michal and Tkačik, Gašper}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, number = {44}, publisher = {National Academy of Sciences}, title = {{Quantitative omnigenic model discovers interpretable genome-wide associations}}, doi = {10.1073/pnas.2402340121}, volume = {121}, year = {2024}, } @article{18526, abstract = {Multivesicular endosomes (MVEs) sequester membrane proteins destined for degradation within intralumenal vesicles (ILVs), a process mediated by the membrane-remodeling action of Endosomal Sorting Complex Required for Transport (ESCRT) proteins. In Arabidopsis, endosomal membrane constriction and scission are uncoupled, resulting in the formation of extensive concatenated ILV networks and enhancing cargo sequestration efficiency. Here, we used a combination of electron tomography, computer simulations, and mathematical modeling to address the questions of when concatenated ILV networks evolved in plants and what drives their formation. Through morphometric analyses of tomographic reconstructions of endosomes across yeast, algae, and various land plants, we have found that ILV concatenation is widespread within plant species, but only prevalent in seed plants, especially in flowering plants. Multiple budding sites that require the formation of pores in the limiting membrane were only identified in hornworts and seed plants, suggesting that this mechanism has evolved independently in both plant lineages. To identify the conditions under which these multiple budding sites can arise, we used particle-based molecular dynamics simulations and found that changes in ESCRT filament properties, such as filament curvature and membrane binding energy, can generate the membrane shapes observed in multiple budding sites. To understand the relationship between membrane budding activity and ILV network topology, we performed computational simulations and identified a set of membrane remodeling parameters that can recapitulate our tomographic datasets.}, author = {Weiner, Ethan and Berryman, Elizabeth and Frey, Felix F and Solís, Ariadna González and Leier, André and Lago, Tatiana Marquez and Šarić, Anđela and Otegui, Marisa S.}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, number = {44}, publisher = {National Academy of Sciences}, title = {{Endosomal membrane budding patterns in plants}}, doi = {10.1073/pnas.2409407121}, volume = {121}, year = {2024}, } @article{18703, abstract = {Spatial games provide a simple and elegant mathematical model to study the evolution of cooperation in networks. In spatial games, individuals reside in vertices, adopt simple strategies, and interact with neighbors to receive a payoff. Depending on their own and neighbors’ payoffs, individuals can change their strategy. The payoff is determined by the Prisoners’ Dilemma, a classical matrix game, where players cooperate or defect. While cooperation is the desired behavior, defection provides a higher payoff for a selfish individual. There are many theoretical and empirical studies related to the role of the network in the evolution of cooperation. However, the fundamental question of whether there exist networks that for low initial cooperation rate ensure a high chance of fixation, i.e., cooperation spreads across the whole population, has remained elusive for spatial games with strong selection. In this work, we answer this fundamental question in the affirmative by presenting network structures that ensure high fixation probability for cooperators in the strong selection regime. Besides, our structures have many desirable properties: (a) they ensure the spread of cooperation even for a low initial density of cooperation and high temptation of defection, (b) they have constant degrees, and (c) the number of steps, until cooperation spreads, is at most quadratic in the size of the network.}, author = {Svoboda, Jakub and Chatterjee, Krishnendu}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, number = {50}, publisher = {National Academy of Sciences}, title = {{Density amplifiers of cooperation for spatial games}}, doi = {10.1073/pnas.2405605121}, volume = {121}, year = {2024}, } @article{18938, abstract = {The synthesis of proteins as encoded in the genome depends critically on translational fidelity. Nevertheless, errors inevitably occur, and those that result in reading frame shifts are particularly consequential because the resulting polypeptides are typically nonfunctional. Despite the generally maladaptive impact of such errors, the proper decoding of certain mRNAs, including many viral mRNAs, depends on a process known as programmed ribosomal frameshifting. The fact that these programmed events, commonly involving a shift to the –1 frame, occur at specific evolutionarily optimized “slippery” sites has facilitated mechanistic investigation. By contrast, less is known about the scope and nature of error (i.e., nonprogrammed) frameshifting. Here, we examine error frameshifting by monitoring spontaneous frameshift events that suppress the effects of single base pair deletions affecting two unrelated test proteins. To map the precise sites of frameshifting, we developed a targeted mass spectrometry–based method called “translational tiling proteomics” for interrogating the full set of possible –1 slippage events that could produce the observed frameshift suppression. Surprisingly, such events occur at many sites along the transcripts, involving up to one half of the available codons. Only a subset of these resembled canonical “slippery” sites, implicating alternative mechanisms potentially involving noncognate mispairing events. Additionally, the aggregate frequency of these events (ranging from 1 to 10% in our test cases) was higher than we might have anticipated. Our findings point to an unexpected degree of mechanistic diversity among ribosomal frameshifting events and suggest that frameshifted products may contribute more significantly to the proteome than generally assumed.}, author = {Springstein, Benjamin L and Paulo, Joao A. and Park, Hankum and Henry, Kemardo and Fleming, Eleanor and Feder, Zoë and Harper, J. Wade and Hochschild, Ann}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, number = {6}, publisher = {National Academy of Sciences}, title = {{Systematic analysis of nonprogrammed frameshift suppression in E.coli via translational tiling proteomics}}, doi = {10.1073/pnas.2317453121}, volume = {121}, year = {2024}, } @article{14478, abstract = {Entire chromosomes are typically only transmitted vertically from one generation to the next. The horizontal transfer of such chromosomes has long been considered improbable, yet gained recent support in several pathogenic fungi where it may affect the fitness or host specificity. To date, it is unknown how these transfers occur, how common they are and whether they can occur between different species. In this study, we show multiple independent instances of horizontal transfers of the same accessory chromosome between two distinct strains of the asexual entomopathogenic fungusMetarhizium robertsiiduring experimental co-infection of its insect host, the Argentine ant. Notably, only the one chromosome – but no other – was transferred from the donor to the recipient strain. The recipient strain, now harboring the accessory chromosome, exhibited a competitive advantage under certain host conditions. By phylogenetic analysis we further demonstrate that the same accessory chromosome was horizontally transferred in a natural environment betweenM. robertsiiand another congeneric insect pathogen,M. guizhouense. Hence horizontal chromosome transfer is not limited to the observed frequent events within species during experimental infections but also occurs naturally across species. The transferred accessory chromosome contains genes that might be involved in its preferential horizontal transfer, encoding putative histones and histone-modifying enzymes, but also putative virulence factors that may support its establishment. Our study reveals that both intra- and interspecies horizontal transfer of entire chromosomes is more frequent than previously assumed, likely representing a not uncommon mechanism for gene exchange.Significance StatementThe enormous success of bacterial pathogens has been attributed to their ability to exchange genetic material between one another. Similarly, in eukaryotes, horizontal transfer of genetic material allowed the spread of virulence factors across species. The horizontal transfer of whole chromosomes could be an important pathway for such exchange of genetic material, but little is known about the origin of transferable chromosomes and how frequently they are exchanged. Here, we show that the transfer of accessory chromosomes - chromosomes that are non-essential but may provide fitness benefits - is common during fungal co-infections and is even possible between distant pathogenic species, highlighting the importance of horizontal gene transfer via chromosome transfer also for the evolution and function of eukaryotic pathogens.}, author = {Habig, Michael and Grasse, Anna V and Müller, Judith and Stukenbrock, Eva H. and Leitner, Hanna and Cremer, Sylvia}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, number = {11}, publisher = {National Academy of Sciences}, title = {{Frequent horizontal chromosome transfer between asexual fungal insect pathogens}}, doi = {10.1073/pnas.2316284121}, volume = {121}, year = {2024}, } @article{15083, abstract = {Direct reciprocity is a powerful mechanism for cooperation in social dilemmas. The very logic of reciprocity, however, seems to require that individuals are symmetric, and that everyone has the same means to influence each others’ payoffs. Yet in many applications, individuals are asymmetric. Herein, we study the effect of asymmetry in linear public good games. Individuals may differ in their endowments (their ability to contribute to a public good) and in their productivities (how effective their contributions are). Given the individuals’ productivities, we ask which allocation of endowments is optimal for cooperation. To this end, we consider two notions of optimality. The first notion focuses on the resilience of cooperation. The respective endowment distribution ensures that full cooperation is feasible even under the most adverse conditions. The second notion focuses on efficiency. The corresponding endowment distribution maximizes group welfare. Using analytical methods, we fully characterize these two endowment distributions. This analysis reveals that both optimality notions favor some endowment inequality: More productive players ought to get higher endowments. Yet the two notions disagree on how unequal endowments are supposed to be. A focus on resilience results in less inequality. With additional simulations, we show that the optimal endowment allocation needs to account for both the resilience and the efficiency of cooperation.}, author = {Hübner, Valentin and Staab, Manuel and Hilbe, Christian and Chatterjee, Krishnendu and Kleshnina, Maria}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, number = {10}, publisher = {National Academy of Sciences}, title = {{Efficiency and resilience of cooperation in asymmetric social dilemmas}}, doi = {10.1073/pnas.2315558121}, volume = {121}, year = {2024}, } @article{15116, abstract = {Water is known to play an important role in collagen self-assembly, but it is still largely unclear how water–collagen interactions influence the assembly process and determine the fibril network properties. Here, we use the H2O/D2O isotope effect on the hydrogen-bond strength in water to investigate the role of hydration in collagen self-assembly. We dissolve collagen in H2O and D2O and compare the growth kinetics and the structure of the collagen assemblies formed in these water isotopomers. Surprisingly, collagen assembly occurs ten times faster in D2O than in H2O, and collagen in D2O self-assembles into much thinner fibrils, that form a more inhomogeneous and softer network, with a fourfold reduction in elastic modulus when compared to H2O. Combining spectroscopic measurements with atomistic simulations, we show that collagen in D2O is less hydrated than in H2O. This partial dehydration lowers the enthalpic penalty for water removal and reorganization at the collagen–water interface, increasing the self-assembly rate and the number of nucleation centers, leading to thinner fibrils and a softer network. Coarse-grained simulations show that the acceleration in the initial nucleation rate can be reproduced by the enhancement of electrostatic interactions. These results show that water acts as a mediator between collagen monomers, by modulating their interactions so as to optimize the assembly process and, thus, the final network properties. We believe that isotopically modulating the hydration of proteins can be a valuable method to investigate the role of water in protein structural dynamics and protein self-assembly.}, author = {Giubertoni, Giulia and Feng, Liru and Klein, Kevin and Giannetti, Guido and Rutten, Luco and Choi, Yeji and Van Der Net, Anouk and Castro-Linares, Gerard and Caporaletti, Federico and Micha, Dimitra and Hunger, Johannes and Deblais, Antoine and Bonn, Daniel and Sommerdijk, Nico and Šarić, Anđela and Ilie, Ioana M. and Koenderink, Gijsje H. and Woutersen, Sander}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, number = {11}, publisher = {National Academy of Sciences}, title = {{Elucidating the role of water in collagen self-assembly by isotopically modulating collagen hydration}}, doi = {10.1073/pnas.2313162121}, volume = {121}, year = {2024}, } @article{17123, abstract = {A key feature of many developmental systems is their ability to self-organize spatial patterns of functionally distinct cell fates. To ensure proper biological function, such patterns must be established reproducibly, by controlling and even harnessing intrinsic and extrinsic fluctuations. While the relevant molecular processes are increasingly well understood, we lack a principled framework to quantify the performance of such stochastic self-organizing systems. To that end, we introduce an information-theoretic measure for self-organized fate specification during embryonic development. We show that the proposed measure assesses the total information content of fate patterns and decomposes it into interpretable contributions corresponding to the positional and correlational information. By optimizing the proposed measure, our framework provides a normative theory for developmental circuits, which we demonstrate on lateral inhibition, cell type proportioning, and reaction–diffusion models of self-organization. This paves a way toward a classification of developmental systems based on a common information-theoretic language, thereby organizing the zoo of implicated chemical and mechanical signaling processes.}, author = {Brückner, David and Tkačik, Gašper}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, number = {23}, publisher = {National Academy of Sciences}, title = {{Information content and optimization of self-organized developmental systems}}, doi = {10.1073/pnas.2322326121}, volume = {121}, year = {2024}, }