eLife

The recent movement history shapes motor performance, that is, previous movements can affect current movement characteristics such as trajectory shape. History effects are commonly attributed to carryover of motor-related activity. However, action execution entails sensory feedback; therefore, an alternative is that history effects stem from the sensory information produced by previous movements. To dissociate motor and sensory contributions, we assessed whether history effects emerge from imagined movements, which involve movement planning but not sensory feedback. Overt reaches around an obstacle led to systematic adjustment of the initial reach direction of following reaches - a hallmark of motor history. Imagined reaches around obstacles induced similar biases, albeit with smaller magnitude, presumably due to the need to inhibit overt execution during imagery. By contrast, execution but not imagery induced biases in late, feedback-related measures, suggesting that these history effects depended on sensory rather than motor aspects of the movement history. Thus, motor and sensory signals make distinct and complementary contributions to movement history: recent motor states shape feedforward planning, whereas recent sensory states shape feedback-related movement refinement. Significance StatementRecent movements bias upcoming ones, but these so-called history effects may have their origin either in planning motor commands or in the executed movements sensory consequences. By leveraging motor imagery to retain movement planning but remove movement-related sensory feedback, we show that feedforward, planning-related biases persist without sensory consequences, whereas feedback-dependent biases only emerge from prior sensory feedback. Thus, motor and sensory processes induce specific histories that affect distinct aspects of the current movement.

Persistent detection of high-risk human papillomavirus (HPV) is required for cervical carcinogenesis, yet the metabolic phenotype associated with distinct HPV transition states remains incompletely defined. We analyzed vaginal metabolomics data from 71 HIV-negative, non-smoking, premenopausal women without other sexually transmitted infections, grouped by three-visit HPV trajectories: persistent negative (NNN, n=20), late incident positivity (NNP, n=9), conversion with persistence (NPP, n=13), clearance after prior positivity (PPN, n=16), and persistent positive (PPP, n=13). After detection-based filtering, 186 putative and 64 quantitatively estimated metabolites were retained for integrated univariate, multivariate, network, pathway, and machine learning analyses. Global class separation was weak by PERMANOVA and by five-class classification, indicating that the vaginal metabolome does not reorganize broadly across all HPV states. In contrast, trajectory-specific signals were reproducible. The strongest pairwise contrast was NNP versus PPP (best cross-validated ROC AUC 0.778; permutation p=0.039). Glycolic acid was the dominant single metabolite, particularly for NNP versus PPP (Mann-Whitney p=6.96x10^-4, FDR=0.0446, AUROC=0.902; detection 88.9% versus 15.4%; combined abundance+detection FDR=0.0010). Persistent positivity was characterized by a focused uracil-high, methyl-donor/redox-low signature, including lower glycolic acid, S-adenosylmethionine, NAD+, and betaine, together with higher uracil. Ratio mining further sharpened discrimination, with uracil/S-adenosylmethionine and uracil/creatinine among the best PPP classifiers, and glucose 1-phosphate/isovaleric acid-valeric acid strongly separating NNP from NPP. These data support a model in which HPV trajectory is encoded by targeted metabolic states rather than a diffuse HPV-positive versus HPV-negative metabolomic shift.

An animals nervous system enables it to detect and respond to stimuli to navigate its environment. To enhance sensory acquisition, animals can actively position sensors, altering how they extract information from the external world. However, active sensing, and movement in general, produces sensory feedback, requiring mechanisms for integrating predictive motor signals with externally generated sensations. Despite the importance of these mechanisms for guiding coordinated behavior, the cellular and circuit basis of motor control and sensory processing during active movements are not fully understood. Here, we investigate how mechanosensory information contributes to motor output in the Drosophila antenna, a sensor that can be actively positioned. We combine electrophysiology, quantitative behavior, optogenetics, and connectomics to characterize APN2, a nonspiking interneuron in Drosophila that encodes both mechanosensory stimuli and motor commands. We show that these neurons receive input from two classes of antennal mechanosensors, enabling responses to mechanical perturbations in both quiescence and flight. We then demonstrate how these neurons integrate higher-order motor commands with mechanosensory input to shape antennal movement. Together, this work reveals a previously uncharacterized sensory-motor circuit in the antennal mechanosensory system. These findings provide insight into how nervous systems integrate sensation with motor commands to guide the movement of active sensors, highlighting circuit mechanisms that may broadly support sensory acquisition during movement.

Multisensory perception is a cornerstone paradigm for understanding how the brain constructs coherent representations of the world from noisy, fragmented sensory inputs. For decades, researchers have used the magnitude of crossmodal illusions, the width of the temporal binding window, and related behavioral indices as direct proxies for integration strength, and have leveraged these measures to compare multisensory function across developmental, clinical, and aging populations. Here we argue that this descriptive practice is fundamentally compromised: behavioral readouts of multisensory integration are composite measures jointly shaped by unisensory precision, amodal priors, and the binding process itself, and cannot be interpreted in isolation. Drawing on simulations within a Bayesian Causal Inference framework, we show how identical behavioral patterns can arise from very different underlying causes, leading to systematic misattribution of group differences to deficits or enhancements in integration. We review complementary computational frameworks, including drift diffusion, multisensory correlation detection, and statistical facilitation models, and outline their respective explanatory limits. Finally, we provide a model-based inference pipeline, from experimental design and unisensory baselines to parameter estimation and interpretation, that disentangles sensory fidelity, prior expectations, and integrative tendency. Adopting this normative approach is essential for cumulative progress in basic multisensory research and for its translation to neuropsychiatric assessment, lifespan research, and artificial perceptual systems.

A long-standing hypothesis in sensory neuroscience suggests that the evolutionary expansion of cortex in mammals may contribute to sensory-dependent adaptation by acting on subcortical pathways that drive innate behavior. However, direct experimental evidence is lacking. Taking the visual system as a model, it is known that there is significant interaction between the evolutionarily conserved Superior Colliculus (SC) and the comparatively modern Visual Cortex (VC), key structures in the mammalian visual system. In the SC, local alignment is established between a retinotopic map of the visual field and a map of orienting movement vectors during development and drives accurate visually guided orienting behavior throughout an organisms lifespan. Interestingly mammals, like humans and non-human primates, readily adapt to altered visual experiences, while evolutionarily older vertebrates, like amphibians, lack this behavioral plasticity. To address this outstanding question, we have developed a novel behavioral paradigm for inducing visuomotor adaptation in freely moving mice that is analogous to paradigms utilized in primates. Our paradigm combines a visually guided orienting task and a novel mouse prism goggle system to shift the visual field. Using this paradigm, we demonstrate for the first time that mice gradually adapt to a chronic shift of their full visual field, suggesting this type of behavioral plasticity is conserved across mammalian species. Furthermore, we show that lesioning primary visual cortex (V1) prior to shifting the visual field disrupts normal visuomotor adaptation, suggesting that VC may play a generative role in the plasticity of fundamental visually guided behaviors. These findings lend support to the hypothesis that a particular evolutionary benefit of sensory cortex is the allowance for experience-dependent behavioral plasticity.

Ribonucleotides are frequently incorporated into our genome during replication. Canonically, RNase H2 is responsible for the removal of these embedded ribonucleotides. Alternatively, DNA topoisomerase 1 (TOP1) has also been shown to have genomic ribonucleotide processing activity. When this process occurs at short tandem repeat (STR) sequences, it can lead to 2-5 bp deletions. These deletions are the result of two sequential cuts by TOP1 at sites of ribonucleotide incorporation. In this study, we have determined that PARP1 regulates the TOP1-mediated excision of ribonucleotides by preventing the formation of TOP1-DNA adducts that occur through a second cleavage following the initial ribonucleotide cut by TOP1. We biochemically defined the mechanism by which this regulatory inhibition of TOP1 occurs, which involves both PARP1 physically restricting TOP1 from the cleavage site followed by the inhibitory PARylation of TOP1. We also show that this activity means that PARP1 prevents the TOP1-dependent deletions at STRs in cells. In the absence of both a functional RNase H2 complex and PARP1, we demonstrated that cells appear to be in a senescent state provoked by the accumulation of TOP1-DNA adducts, which are a result of TOP1 being unimpeded to remove genomic ribonucleotides. Our work has elucidated the role of PARP1 in preventing the deleterious consequences of the processing of genomic ribonucleotides by TOP1. Understanding this mechanism could help us develop therapies that better sensitize tumors to PARP inhibitors, especially in cancers that present loss-of-function RNase H2 mutations (seen in certain chronic lymphocytic leukemia and prostate cancers).

HIV escapes sterilizing immunity through a variety of mechanisms, including the downregulation of MHC-I expression by HIV Nef and Vpu to counteract CD8+ T cell responses. While reduced MHC-I expression would be expected to support targeting by NK cells, a subpopulation of infected CD4+ T cells consistently resists multiple rounds of NK cell natural and antibody-dependent cytotoxicity. Studies further reveal that the HIV accessory protein Vpr induces expression of TNFRSF10B (TRAIL-R2) in CD4+ T cells, with survivors of NK cell targeting exhibiting relatively higher MHC-I and weaker expression of TRAIL-R2. In fact, reverse TRAIL signaling in NK cells leads to the release of perforin and granzymes, a pathway limited when TRAIL-R2 expression is diminished. Thus, independent of canonical death receptor signaling, TRAIL-R2 serves as an activating ligand that augments NK cell killing. These observations demonstrate that through Vpr, HIV can regulate the TRAIL/TRAIL-R2 axis to control NK cell functionality.

Childhood obesity remains a pressing global health challenge, yet the impact of dynamic adiposity changes during active developmental window retains poorly understood. Leveraging longitudinal data from the Adolescent Brain Cognitive Development (ABCD) Study (N=8519 at baseline; N=1873 at 4-year follow-up), our study reveals distinct neurodevelopmental implications of central fat dynamics during adolescence. At baseline, central fat indices (body roundness index, BRI / waist-to-height ratio, WHtR) outperformed BMI in predicting cognitive deficits, showing robust associations with impaired inhibitory control and episodic memory. The prediction effect was partially mediated by cortical changes in prefrontal and temporal regions. Longitudinally, the rate of fat accumulation ({Delta}) emerged as a critical predictor: faster adiposity accrual predicted attenuated cortical thinning (i.e., slower development) in parietal lobes and poorer executive function at follow-up, while baseline adiposity showed no significant effects on the follow-up brain morphology or cognitive development. Notably, subgroup analyses uncovered that obese adolescents with central fat reduction exhibited accelerated cortical thinning in posterior cingulate (change difference p=0.006-0.029) alongside rapid improvement in inhibitory control (Flanker slope difference p<0.05), whereas those with persistent adiposity showed delayed thinning in the postcentral gyrus. The study reveals that central fat (BRI/WHtR) is closely linked to neurocognitive risks, and longitudinal fat accumulation?rather than baseline adiposity?drives cortical alteration. Notably, fat reduction activated adaptive neural change in obese adolescents, underscoring the importance of weigh regulation during neurodevelopment.

Planarian flatworms represent one of the most evolutionarily informative nervous systems for an account of ancient bilaterian brains. Likewise, the unparalleled regenerative ability of planarians makes possible certain investigations of neural development, memory, and behavior that are simply impossible with other model organisms. Despite these facts, learning and memory are today underexplored in planarians, likely due in part to the shadow of controversial 20th-century experiments on the transfer of memories between individual flatworms. Here, we attempted to replicate and extend the classical conditioning experiments in planarians that were the basis of the later memory transfer work. We failed to find evidence for classical conditioning in any of our procedural variations and obtained similar results using computer vision methods to avoid subjectivity in manual video annotation. Our results cast doubt on the suitability of planarian flatworms for studying primitive learning processes and the molecular basis of memory using classical conditioning.

Chronological age is a potent determinant of clinical events, but it is conventionally treated as a linear function of time rather than a dynamic process shaped by genetics and tissue-specific senescence. Deep learning models derived from cardiovascular imaging offer an opportunity to quantify biological age across multiple domains and to examine the extent to which these measures capture shared or distinct vulnerabilities. Here, we applied deep learning to estimate biological age from electrocardiograms, cardiac MRI, carotid ultrasound, and retinal imaging, capturing electrical, structural, macrovascular, and microvascular domains in more than 100,000 UK Biobank participants. Genome-wide association and cross-trait heritability analyses showed that cardiovascular aging is not a singular process but a modular phenotype with distinct genetic determinants across modalities. Polygenic risk scores supported these distinct trajectories, showing that different biological age measures capture partly divergent biological processes with corresponding differences in clinical associations. Modality-specific genes also showcased distinct cell-type enrichment patterns. By deconvoluting aging into electrical, structural, macrovascular, and microvascular components, our results demonstrate that AI-derived age metrics capture distinct, disease-specific aging pathways. Ultimately, this modular framework positions deep learning-derived aging models not as holistic measures of health, but as domain-specific biomarkers of cardiovascular vulnerability.

Energy homeostasis at the organismal level requires balancing energy storage and mobilization to provide sufficient fuel for energy-intensive processes like development without depleting or accumulating excess stores. Fluctuations in the nutritional content of the diet present a challenge to the pathways that maintain energy balance. We previously identified the Drosophila melanogaster counterpart of human ARC (activity-regulated cytoskeleton-associated protein) as a brain-expressed protein that regulates energy storage in the major fat storage tissue of the fly, the fat body. Here we show that Arc1 expression in the brain responds to changes in diet and insulin-like peptide levels. Mutating Arc1 perturbs the ability of larvae to maintain normal body fat and rates of development upon dietary changes: mutants develop slower or faster than wild-type on nutrient-poor or nutrient-rich diets, respectively. Excess fat storage in Arc1 mutants becomes an advantage upon starvation, prolonging survival relative to the wild type. In addition to metabolic and neuronal genes, transcriptomic analysis revealed changes in key developmental drivers of development, in both diet-dependent and - independent manners. This study supports a model in which nutrient regulation of Arc1 via insulin-like peptide signaling couples dietary changes to changes in metabolism -- to maintain energy homeostasis -- and production of hormone signals, to support timely development. In this role, Arc1 is a central player in a buffering mechanism that coordinates nutrient availability, organismal metabolism, and developmental rate.

This updated systematic review and network meta-analysis evaluated the efficacy and safety of obesity management medications (OMMs) in terms of reducing body weight and obesity related complications. Medline and Embase were searched up to 21 November 2025 for randomized controlled trials comparing OMMs versus placebo or active comparators in adults. The primary endpoint was percentage total body weight loss (TBWL%) at the end of the study. Secondary endpoints were TBWL% at 1, 2 and 3 years, anthropometric, metabolic, mental health and quality of life outcomes, cardiovascular morbidity and mortality, remission of obesity related complications, serious adverse events and all cause mortality. Sixty six RCTs (66 comparisons) were identified: orlistat (22), semaglutide (18), liraglutide (11), tirzepatide (8), naltrexone/bupropion (5) and phentermine/topiramate (2), enrolling 63,909 patients (34,861 and 29,048 with active compound and placebo, respectively). All OMMs showed significantly greater TBWL% versus placebo; tirzepatide and semaglutide exceeded 10% TBWL and showed the most favourable glycaemic effects. Semaglutide reduced major adverse cardiovascular events and all cause mortality. In dedicated complication specific trials, semaglutide and tirzepatide showed benefit on heart failure related outcomes; tirzepatide was associated with improved obstructive sleep apnoea syndrome and semaglutide with knee osteoarthritis pain remission. Tirzepatide and semaglutide were associated with improvements in metabolic dysfunction-associated steatohepatitis remission, and semaglutide with improvement in liver fibrosis. No OMMs were associated with an increased risk of serious adverse events. These updated results reinforce the need to individualize OMMs selection according to weight loss efficacy, complication profile and safety.

Diet is an important ecological modulator of the oral microbiome, yet population-level evidence on a broader spectrum of food components remains limited. This cross-sectional study investigated associations among dietary intake, oral rinse microbiome, and oral disease conditions in a nationally representative sample of United States adults from the National Health and Nutrition Examination Survey. A total of 3,254 participants with oral rinse microbiome sequencing data were included, with oral conditions classified as oral health, caries-only, periodontitis-only, or co-existing disease. Dietary intake was assessed using 24-hour dietary recalls and summarized as dietary indices and energy-adjusted food components. Associations between diet and the oral microbiome were evaluated using community-level analyses, regression models, mediation analyses, and unsupervised clustering, while accounting for oral conditions. This study found that dietary intake, as a combined variable set, explained 3.6% of the variance in oral rinse microbial community structure; this was comparable to oral disease status or smoking and larger than sociodemographic factors. Healthier dietary profiles, including higher health-associated dietary index scores and greater vegetable and fruit intake, were associated with taxa commonly linked to oral health (e.g., Neisseria, Cardiobacterium and Lautropia). In contrast, added sugars, alcoholic drinks, cured meat, potatoes, dairy products, and higher dietary inflammatory index scores showed opposite association patterns. Mediation analyses suggested that coordinated microbial groups may partly link dietary exposures with oral disease outcomes, particularly for vegetables and added sugars. Additionally, three population-level dietary patterns were identified, among which the plant-rich pattern was associated with more favorable oral health and microbial profiles enriched in nitrate-reducing commensals, including Neisseria and Haemophilus. Overall, dietary intake was associated with oral microbiota composition and oral health conditions, supporting ecological influences of dietary components beyond sugar on oral bacteria and dental diseases. Longitudinal studies are needed to clarify the direction and causality of these relationships.

Scratching provides transient relief from itch, yet the neural circuit mechanisms that transform scratching into itch relief remain poorly understood. Midbrain dopaminergic neurons and their downstream targets in the lateral shell of the nucleus accumbens (NAc LaSh) are implicated in itch-scratch processing. Previous studies show that pharmacological manipulation of dopamine D1 and D2 receptors in the NAc LaSh alters scratching behavior, but the specific contributions of D1R- and D2R-expressing neurons during acute and chronic itch remain unclear. Here, we show that NAc LaShD1R and D2R neurons bidirectionally regulate scratching behavior across itch states. NAc LaShD1R neurons activity promotes scratching bouts, whereas NAc LaShD2R neurons preferentially facilitate scratch termination. Anterograde viral tracing revealed distinct brain-wide projection patterns of NAc LaShD1R and D2R neurons, which we functionally tested using projection-specific optogenetic manipulations. We found that NAc LaShD2R neurons terminate scratching by inhibiting neurons in the lateral parabrachial nucleus (LPBN), a key hub for itch processing. Furthermore, dopamine levels in the NAc LaSh were elevated during chronic itch compared with acute itch, suggesting enhanced dopaminergic signaling contributes to persistent scratching. Together, these findings identify circuit mechanisms linking reward pathways to itch regulation.

The type VI secretion system (T6SS) is a contractile nanoweapon widely employed by Gram-negative bacteria to gain competitive advantages by injecting effector proteins into recipient cells. Although the biochemical activities of T6SS effectors have been well characterized, how recipient factors modulate effector toxicity remains poorly understood. Using Agrobacterium C58 as a model, previous work identified the Escherichia coli ClpAP protease as a recipient susceptibility (RS) factor that enhances T6SS-mediated interbacterial competition. Agrobacterium C58 deploys two DNase effectors, Tde1 and Tde2, as the major antibacterial weapon. Here, we demonstrate that the recipient ClpAP protease and its adaptor ClpS enhanced C58-mediated interbacterial competition in a Tde2-dependent manner in both intra- and interspecies competition. Ectopic expression of Tde2 in E. coli caused growth inhibition and DNA cleavage in the presence of a functional ClpAPS protease complex, but not in any of the clpP, clpA or clpS mutants. Notably, Tde2 accumulated in these mutants but not in wild-type cells, whereas a catalytic variant accumulated regardless of ClpAPS status, suggesting that Tde2 is not directly degraded by ClpAPS. Instead, Tde2 depends on ClpAPS for full toxicity, likely through degradation of inhibitory N-degron substrate(s). Affinity purification of His-tagged Tde2 in a clpP mutant background, followed by mass spectrometry, identified eight N-degron substrate candidates. Tde2-mediated interbacterial competition was significantly reduced by overexpression of three candidates. Among them, the Tde2 DNase domain directly associated with guanosine 5-monophosphate reductase GuaC, supporting a model in which Tde2 toxicity is blocked by binding of GuaC. Collectively, our findings reveal an unanticipated layer of recipient-mediated regulation in T6SS competition and highlight proteolytic control of inhibitory substrates as a determinant of bacterial susceptibility during interbacterial conflict.

Protein synthesis in cell-free protein synthesis systems often exhibits non-intuitive input-output relationships. In the PURE system, a reconstituted cell-free system, protein production peaked at low elongation factor Tu (EF-Tu) concentrations and decreased at higher concentrations, resulting in a characteristic bell-shaped profile. Here, we investigated the origin of this behavior using a detailed mechanistic model of translation in the PURE system, designated as ePURE, which describes reaction dynamics of hundreds of molecular species and reactions. Our computational analysis suggested that excess EF-Tu sequesters the initiator tRNA (tRNAfMet) into non-productive EF-Tu{middle dot}GTP{middle dot}Met-tRNAfMet complexes, thereby depleting the pool of initiator tRNA available for translation initiation. This suppression arises from competition for a limited molecular resource rather than from direct inhibition. Based on this mechanism, we predicted that increasing the concentrations of tRNAfMet and methionyl-tRNA formyl-transferase would eliminate the bell-shaped dependence, and experimentally confirmed this prediction. Under these modified conditions, the bell-shaped response disappeared and protein production was enhanced. These findings demonstrate how mechanistic computational models can reveal hidden constraints underlying non-intuitive input-output relationships in complex biochemical networks and guide the rational optimization of cell-free protein synthesis systems.

Retinitis Pigmentosa (RP) is a group of inherited retinal degenerations for which most subtypes lack effective drug treatments. This challenge is particularly critical for autosomal dominant (ad) RP, which is often unsuitable for gene replacement therapy. To address this challenge, we screened an FDA-approved compound library using a zebrafish adRP model expressing a human RHODOPSIN transgene with the Q344X mutation. The screen evaluated drug effects on larval visual behavior by assessing the visual-motor response (VMR). Four compounds significantly improved VMR in Q344X zebrafish: amitriptyline, difluprednate, maprotiline, and prednisolone. Further characterization revealed that these hits act through distinct mechanisms, including reducing rod death, promoting rod neogenesis, and enhancing the function of extraocular photoreceptors. Together, these findings demonstrate the potential to repurpose these drugs for adRP caused by the RHO Q344X mutation, providing preclinical candidates and revealing potential targets for future drug development.

Major surface antigens in many pathogens are encoded by rapidly diversifying multigene families, generating fitness variation through antigenic and functional differences. These variations align with the niche and absolute fitness axes of Modern Coexistence Theory (MCT). Yet, how such gene families evolve along these axes under competition for hosts and across transmission gradients remains poorly understood, as prior MCT studies have not explicitly accounted for evolutionary dynamics in high dimensions. We use a stochastic computational model of Plasmodium falciparum transmission to examine how transmission intensity and selection shape var multigene family evolution and composition within parasite genomes. Results show that selection alone cannot maintain the observed stable ratio of two gene groups within parasite genomes, indicating that group-based classifications do not clearly reflect transmission strategy or virulence. When a trade-off exists between diversification rates and absolute fitness, strong immune selection under high transmission favors fast-recombining genes while attenuating functional selection on R0-associated traits. In general, stronger immune selection increases the invasion probability of novel antigens and the niche differentiation among parasite genomes, while reducing the variance in gene-level transmissibility and expression duration, and therefore R0. This outcome, combining enhanced niche differentiation and reduced absolute fitness variation, departs from MCT predictions.

GLP-1 agonists are an emerging treatment for disorders of consumption. They are most prominent as treatments for obesity, but recent literature suggests that they are effective at reducing the consumption of all types of hedonic substances. This clearly suggests a central, cognitive, mechanism rather than a peripheral mechanism or an interaction with a single signalling pathway, but the specific site or sites for this mechanism remain to be discovered. Candidate brain regions for this reward-modulating activity have a relative paucity of GLP-1 receptors, with the exception of lateral septum, which expresses an abundance of them. In these experiments we recorded local field potential from lateral septum while animals received either saline control or the GLP-1R agonist liraglutide. We find that liraglutide significantly reduced the power of both high-frequency oscillations and theta rhythm in the lateral septum, suggesting that GLP-1R agonism changes how lateral septum communicates with its network. In addition, we show that liraglutide causes animals to wait longer to respond for reward in a differential reinforcement of low rates paradigm. Together, these results suggest that a primary region in the control of the anticonsumptive action of GLP-1 agonists is the lateral septum, and that the coding of reward by this region is a central node in the network responsible for cognition about and behaviour with respect to reward.

Perturbative X-ray crystallography can visualize functional dynamics and conformational changes in proteins at atomic resolution. During a typical perturbative crystallography experiment, only a fraction of protein molecules in a crystal will be perturbed, or "excited". As a result, the observed data represent a mixture of excited and ground states. The conventional approach to estimating the excited-state structure factor amplitudes is to linearly extrapolate the difference between the structure factor amplitudes of the perturbed and unperturbed data. This approach often fails to yield well-refined structural models because it amplifies experimental errors and neglects phase differences between the ground and excited states. Here, we introduce an approach to estimating excited-state structure factor amplitudes that starts from a statistical prior for the correlations between excited and ground states. Using benchmarks from time-resolved crystallography and a drug-fragment screen, we illustrate how this approach effectively addresses the limitations of traditional extrapolation.