pharmaceutical development teams

Abstract: Prioritizing central nervous system (CNS) interventions requires predicting how a dose, route, and schedule act on a partially observed microenvironment, then choosing the measurement that would change the decision. Action-conditioned predictors reduce a regimen to an identity token or a scalar exposure, discarding where and when the target is engaged; handing a point estimate to a separate planner then discards the joint uncertainty that makes a measurement worth running. We therefore treat decision quality as a property of the intervention interface, not of controller placement. NeuronSifter compiles regimens into state-conditional target-occupancy fields with support masks, propagates them through microenvironment dynamics with an occupancy-conditioned diffusion operator, and selects measurements by their expected reduction in intervention loss, assimilating typed outcomes into the same posterior. In a declared synthetic Alzheimer's disease (AD) evaluation over 64 paired scenario blocks, occupancy conditioning lowers trajectory continuous ranked probability score from 0.165 to 0.110 and raises intervention ordering accuracy from 0.760 to 0.880, and every paired benchmark contrast remains separated after Holm correction. Decision-directed acquisition attains terminal risk 0.160 against 0.166 for a matched numerical Bayesian experimental design planner, and reaches the target risk at 0.796 $[0.732,0.873]$ of an earlier design control's cost, while the corresponding ratio against the matched planner, 0.963 $[0.907,1.025]$, is not separated from equality; point-state and dependence-ablated interfaces instead raise risk to 0.220 and 0.199, and a full-posterior external controller ties exactly. Published AD trials supply a separate retrospective endpoint bridge.

Abstract: Proteins populate conformational ensembles, yet structure-based biomolecular design typically optimizes candidates against a single target conformation. Consequently, a candidate that fits one state can lose favorable interactions or develop steric clashes when the target adopts another. We introduce FlexEvo, a model-agnostic evolutionary framework that adapts candidates once at inference time from a single target conformation to improve compatibility with alternative natural conformations unseen during adaptation, without retraining the source model or requiring a conformational ensemble. FlexEvo casts cross-state adaptation as geometry-constrained bi-objective optimization, balancing preservation of input-state interactions against robustness to plausible conformational perturbations. To limit the search space and reduce invalid structural edits, geometry-derived FlexBoxes define protected anchor regions, adaptable regions for local exploration, and forbidden regions for clash avoidance. A unified all-atom representation supports topology-preserving adaptation across diverse binder categories, while Pareto selection preserves nondominated candidates across the two objectives. We evaluate FlexEvo across multiple generation baselines and nine representative binder categories spanning diverse molecular sizes and structural topologies. FlexEvo reduces the category-balanced mean relative performance degradation from 47.8% to 4.4%, while adding only 1.4--3.1 minutes of adaptation per sample. These results establish single-state inference-time adaptation as a practical route toward robust biomolecular complex design across protein conformational landscapes.

Abstract: Representation learning from medical code sequences in electronic health records and medical claims data has been successful in various clinical applications, such as those regarding disease prediction. However, significant challenges remain in extending this approach to the discovery of scientific hypotheses. One reason is that many existing BERT-based models fail to adequately capture the hierarchical structure of medical codes and the complex interactions between diagnoses and treatments. To address these limitations, we propose a new unified pre-training framework that explicitly integrates hierarchical sub-token aggregation, partial masking, and cross-reference mechanisms. The proposed model consistently outperformed existing methods on both pre-training objectives and downstream clinical event prediction tasks, including the onset of dementia and hospitalization. We also conducted an in silico drug repositioning case study targeting Alzheimer's disease. In the hypothesis generation step, our approach successfully rediscovered known promising drugs in a data-driven manner without relying on such external knowledge sources as the literature. Subsequently, in the hypothesis prioritization step, we introduced a Task-Adaptive Representation Approach to alleviate the over-encoding of historical prescription information within diagnostic vectors, enabling the robust prioritization of generated hypotheses. This study establishes an exploratory screening workflow for hypothesis generation and prioritization based on observational associations. Importantly, this framework is not intended to provide causal evidence, but rather to identify promising candidates for subsequent rigorous causal inference. Overall, this study demonstrates that domain-informed representation learning combined with task-adaptive representation control can enable a practical hypothesis discovery workflow.

Abstract: In practical molecular characterization, small-molecule structure identification benefits from complementary spectroscopic evidence, but missing, degraded, or mismatched spectra challenge multimodal models. Herein, we incorporate domain knowledge from spectroscopy and chemistry into mixed-condition training for candidate structure reranking, using a reproducible evaluation protocol and mixture-of-experts (MoE) fusion. The protocol incorporates perturbations tailored to each spectroscopic modality and chemically informed spectrum replacements to cover variations in spectral availability, quality, and consistency. A total of 79,462 test samples were evaluated across 30 predefined conditions using simulated spectra from the Multimodal Spectroscopic Dataset (MSSD) for mass spectrometry (MS), infrared (IR) spectroscopy, and 1H and 13C nuclear magnetic resonance (NMR), with up to 128 hard candidate structures per sample. A controlled two-by-two factorial comparison of complete-input training versus mixed-condition training and vanilla concatenation versus MoE fusion, with matched evaluation conditions, showed that mixed-condition training provided the main gains in both architectures. For MoE, mean reciprocal rank (MRR), averaged equally across conditions, increased from 0.9203 to 0.9763, a relative increase of 6.08%. Recall at rank 1 (R@1), averaged over the same conditions, increased from 89.50% to 96.36%, an increase of 6.86 percentage points and a relative increase of 7.67%. IR-only and MS/MS-only MRR increased from 0.4337 to 0.9307 and from 0.3711 to 0.8575, reaching 2.15 and 2.31 times their respective baseline values, while complete-input performance remained high. These results support integrating domain knowledge into training-condition design to improve robustness, with further gains from MoE under mixed-condition training.