École Normale Supérieure

Abstract The catalytic mechanism of the hairpin ribozyme has remained controversial for more than two decades, with different experimental approaches often supporting distinct mechanistic interpretations. In this work, we investigate the conformational landscape of the active site along several proposed reaction pathways using all-atom molecular dynamics simulations in explicit solvent combined with enhanced sampling techniques. Specifically, we employ Hamiltonian replica exchange simulations to extensively explore active-site conformations without relying on predefined collective variables, enabling a broad characterization of the structural ensembles associated with multiple protonation states along three candidate reaction mechanisms. Our simulations suggest that a dianionic general acid/general base pathway involving direct participation of A38 and G8 is unlikely to proceed through well-defined intermediates with catalytically competent geometries. In particular, states associated with G8 deprotonation and subsequent O2’ deprotonation exhibit strongly distorted active-site arrangements that appear poorly suited for reaction progression. Although highly synchronous protontransfer steps cannot be excluded, the required deprotonation of G8 remains difficult to reconcile with neutral pH conditions. In contrast, monoanionic pathways in which the non-bridging oxygens of the scissile phosphate act as transient proton relays produce intermediates that sample geometries favorable for the nucleophilic addition and leaving-group elimination steps of the reaction. These mechanisms do not require direct catalytic involvement of G8 while remaining compatible with potential acid catalysis by protonated A38 + . Our results provide a unified conformational perspective on competing mechanistic scenarios. The ensembles generated here offer a foundation for future QM/MM and ML/MM calculations aimed at quantitatively resolving the free-energy landscapes governing hairpin ribozyme catalysis. Finally, the present strategy could easily be applied to other biomolecular systems with high conformational plasticity, including other ribozymes.

Earthquake rupture propagation speed is an essential source factor that largely controls hazard and risk. However, measuring rupture speeds of natural earthquakes is often challenging and ambiguous. Near-fault seismic waveforms (recorded within several km) are believed to have high capability for resolving rupture process. In this study, we probe the feasibility of using near-fault data signatures to directly infer rupture speeds in continental strike-slip earthquakes. To thoroughly understand near-fault features, we synthesize the near-fault seismic waves for kinematic source models on a strike-slip fault under different rupture speeds in a 3D medium. We identify the dependence of velocity waveform and particle motion on rupture speed in both amplitude and shape. In addition, we compare our results with the analytical solution with steady-state constant rupture speed. The discrepancies between the kinematic model and the analytical model indicate the contribution of radiation from different configurations. With inspecting the near-fault dataset of eight M>7 strike-slip earthquakes, we find that instead of dealing with the velocity waveforms with multiple high-frequency spikes, the features of the particle motion shape are easier to identify. Then we apply the particle-motion-based criterion to identify signatures associated with supershear, subshear, and other complexities such as multiple rupture fronts and initial-stage rupture phase. Our study highlights the further application of near-fault seismic data in studying earthquake sources.

B cells and the antibodies they produce are vital to health and survival, motivating research on the details of the mutational and evolutionary processes in the germinal centers (GCs) from which mature B cells arise. It is known that B cells with higher affinity for their cognate antigen (Ag) will, on average, tend to have more offspring. However, the exact form of this relationship between affinity and fecundity, which we call the “affinity-fitness response function”, is not known. Here we use deep learning and simulation-based inference to learn this function from a unique experiment that replays a particular combination of GC conditions many times. All code is freely available at , while datasets and inference results can be found at .

2026 a rendez-vous avec la Lune, et la Lune attend… Au-delà des retards traditionnels des lancements à hauts enjeux, l’actuelle course à la Lune témoigne de grands changements dans la conquête de l’espace.

The longitudinal variations of temperature and pressure in the upper atmosphere of Mars provide important observational constraints on atmospheric waves, including thermal tides. This study aims to characterize the longitudinal harmonic components associated with non-migrating thermal tides between 80 and 130 km and to examine their dominant tidal contributions. We analyzed nightside temperature and pressure profiles obtained by the Spectroscopy for the Investigation of the Characteristics of the Atmosphere of Mars (SPICAM) instrument on board Mars Express during Mars years 26–30, excluding the global dust storm period. We used simulations from the Mars Planetary Climate Model (PCM) to interpret the observed longitudinal structures. Wave--2 and wave--3 are the dominant longitudinal components in the SPICAM observations. In contrast, wave--1 is generally weak and its longitudinal variability is consistent with that in the PCM, including the diurnal zonal-mean tide (D0), the stationary planetary wave with zonal wavenumber 1 (SPW1), and the westward propagating semidiurnal tide with zonal wavenumber 1 (SW1). Above 110 , we also identify a robust wave--4 component. The mode decomposition further indicates that wave--2 and wave--3 are primarily associated with the eastward--propagating diurnal tide with zonal wavenumber 1 (DE1) and the eastward--propagating semidiurnal tide with zonal wavenumber 2 (DE2), respectively. Wave--4 mainly arises from contributions of the eastward-propagating diurnal tide with zonal wavenumber 3 (DE3) and the eastward--propagating semidiurnal tide with zonal wavenumber 2 (SE2). km These results provide new observational constraints on non-migrating thermal tides in the Martian upper atmosphere and show that higher-order longitudinal components, such as wave--4, become increasingly important above 110 km, particularly during dusty seasons. The combined observational and model-based analysis highlights both the robustness of the dominant tidal structures and the limitations of current models in capturing the full complexity of longitudinal variability in the upper atmosphere.

Diversity-Generating Retroelements (DGRs) create rapid, targeted variation within specific genomic regions in phages and bacteria. They operate through stochastic retro-transcription of a template region (TR) into a variable region (VR), which typically encodes ligand-binding proteins. Despite their prevalence, the evolutionary conditions that maintain such hypermutating systems remain unclear. Here we introduce a two-timescale framework separating fast VR diversification from slow TR evolution, allowing the dynamics of DGR-controlled loci to be analytically understood from the TR design point of view. We quantity the fitness gain provided by the diversification mechanism of DGR in the presence of environmental switching with respect to standard mutagenesis. Our framework accounts for observed patterns of DGR activity in human-gut Bacteroides and clarifies when constitutive DGR activation is evolutionarily favored.

Ejaculation in male mice and humans requires intravaginal thrusting movements following penile intromission, yet the underlying neural mechanisms remain poorly understood. In this study, we used fiber photometry to record real-time activity of dopamine (DA) neurons in the ventral tegmental area (VTA) of male mice during copulation across six sexual interactions, in order to investigate how these dynamics change with experience and to examine their functional significance. Contrary to expectations, phasic VTA DA activity remained stable across sessions, showing time-locked responses to mounts, penile intromission, individual thrusts, and ejaculation, indicating experience-independent neural representations of all copulatory events. Notably, thrusting-related activity sharply declined just before ejaculation. Optogenetic inhibition of DA neurons disrupted thrusting behavior, but did not block ejaculation, suggesting DA signaling is critical for sustaining copulatory actions rather than triggering ejaculation itself. While prevailing theories frame VTA DA activity as primarily experience-dependent or centered on reward prediction, we here highlight its role in behavioral persistence during copulation. More broadly, our findings extend understanding of DA function beyond classical reward paradigms to the regulation of innate complex, goal-directed behaviors.

Abstract As artificial intelligence (AI) increasingly mediates human decision-making, there is growing concern about its impact on the human sense of agency (SoA)—the subjective experience of controlling one’s actions and their outcomes. Opacity and automation may undermine this experience, raising both ethical and cognitive challenges. In this study, we systematically examined how varying levels of automation, explanatory transparency, user engagement, and decision conflict shape explicit (Feeling of Control) and implicit (Intentional Binding) measures of agency. Participants interacted with an AI system in a simulated autonomous driving scenario, where we manipulated the degree of automation ( Motor-control vs AI-assisted condition ), the presence and type of explanation ( Proximal , Distal , Combined , No-Explanation ), and the level of conflict between user intentions and AI choices. Automation significantly reduced explicit agency, but explanatory cues—especially when combining Proximal and Distal rationales—partially restored it. Critically, explanation effectiveness depended on user engagement and goal-outcome conflict: transparency lost some of its restorative effect when participants declared their intentions but outcomes mismatched, yet reinforced predictive integration under high cognitive involvement. These findings highlight the need for adaptive, user-sensitive transparency strategies to preserve agency in automated environments.