#01Nov 10, 2026
cs.LG
Emergent Biological Capabilities in a Foundation Model for Molecular Interactions
Adi Mashiach
Foundation models trained on large unlabeled corpora develop emergent capabilities, tasks that go beyond the training objective. We extend this paradigm to multimodal biology with Bonbon, a foundation model for molecular interactions trained on approximately 3.2 trillion tokens of paired protein-ligand sequences. From a single representation space, Bonbon exhibits three zero-shot emergent capabilities at hierarchical levels of resolution: functional (mechanism of action), residue (binding site localization, including orthosteric/allosteric discrimination), and bond (covalent versus non-covalent engagement). All three capabilities generalize to out-of-distribution complexes. Bonbon was trained on protein-ligand sequences alone, without any task-specific supervision and without structural coordinates. We conducted controlled scaling experiments across six model scales from 42M to 1.6B parameters; every capability evaluated shows a sharp jump at the largest scale on continuous metrics, even as pretraining loss decreases smoothly. This demonstrates that loss-based scaling laws alone are insufficient to predict when zero-shot emergent capabilities become available. The capabilities reported here emerge after training at a 1:2,000 parameter-to-token ratio to accommodate the sparsity of paired biological interaction data. The same frozen representations achieve state-of-the-art binding and affinity prediction at five orders of magnitude greater speed than co-folding methods. In prospective wet-lab validation across nine disease targets spanning seven protein families, Bonbon achieves a 61.5% dose-response hit rate on de novo compounds, yielding structurally novel molecules not previously reported to inhibit these proteins, including for out-of-distribution targets.
#02Nov 10, 2026
cs.CV
C$^2$-Routing: Complementary Cropping and Compression for Efficient Vision-Language Inference
Guorui Lu, Qinyu Chen
Visual Question Answering (VQA) imposes substantial computational overhead on vision-language models (VLMs), motivating model-agnostic input reduction methods that can be readily applied across diverse VLMs, including in black-box settings. Simply enforcing a visual-token cap reduces computation, but it can discard information needed to answer the question. A single reduction strategy also struggles to accommodate different scenarios. Our key observation is that cropping and compression are complementary: cropping highlights small targets and local details, whereas whole-image compression better preserves context for large targets or distributed evidence. Based on this observation, we propose C$^2$-Routing, which adaptively selects cropping or compression according to the input image and question. Since both strategies may still discard key information, we further design a safety gate that uses the predicted joint correctness distribution under original and reduced inputs to guide fallback and protect accuracy. To accommodate consumer GPU resource constraints, all training and evaluation experiments run on RTX 3090 GPUs. To measure gains beyond token capping, we use full-image baselines with the same cap of 1,024 visual tokens. We conduct extensive evaluation on three VLMs and 18 datasets spanning local details, global scenes, scene text, and documents. With the visual budget already capped, C$^2$-Routing further reduces end-to-end FLOPs by 36.53% and visual tokens by 42.36% on average, with a mean relative task-score decrease of only 0.77%.
#03Nov 10, 2026
stat.ML
A Theory of Cross-Validation Variance
Nathaniel S. O'Connell, Jaime L. Speiser
Cross-validation estimates predictive performance by repeatedly splitting the data into training and validation sets, fitting the model on the first and evaluating it on the second. Every observation influences the estimate in two roles, through its own evaluation when it is held out and through the models it helps fit when it trains. The random splits determine its weight in each role. From this representation, we prove an exact finite-sample identity for the variance of the cross-validated estimate. For a given splitting scheme with a common training set size, the variance is a function of these weights, with constants of the model, the metric, and the population. It covers metrics averaged over observations, such as mean squared error, and over case--control pairs, such as the AUC. The identity shows which schemes to use. The variance decomposes into sampling variance, which depends only on the training size, and variance due to the random fold splitting, which arises when the weights change from one draw of the splits to the next. K-fold cross-validation, whose weights are equal across observations by design, is therefore variance optimal at first order; Monte Carlo and bootstrap cross-validation are not. The first-order variance of K-fold does not depend on K, and under reasonable conditions on the model leave-one-out has the smallest variance of any K-fold scheme. For the AUC the same holds for leave-pair-out, which evaluates every case--control pair. Finally, we show the cross-validated estimate is asymptotically normal with the identity's full variance. Together, these results provide a general theoretical foundation for inference on cross-validated performance and establish principles for selecting variance-optimal cross-validation designs.
#04Nov 10, 2026
cs.LG
When Does the Real Wiring Win? Testing connectome structure-function claims against unmeasured physiology
Yeyuan Liu
Connectome-constrained models are often used to argue that a measured wiring diagram outperforms shuffled or rewired wiring, and hence that structure shapes function. Such comparisons can confound wiring with how the models are tuned: a connectome fixes who connects to whom, not the excitability, gains or plasticity rates the model also needs, and modellers often tune these until the real-wiring model works. We separate three estimands: physiology tuned on the real wiring and transferred to nulls (P1), each wiring tuned on its own (P2), and P2 restricted to physiology consistent with independent data (P3). The biases involved are known in machine learning (under-tuned baselines, inherited weights, winner's curse); we measure what they do to biological conclusions, using synthetic ground truth, placebo nulls and three Drosophila circuit models. Some claims survive every protocol we test: segregated reward and punishment dopamine improves learning, and head-direction topography is required for a persistent bump. Others do not. In the mushroom body, the real Kenyon-cell output wiring beats a cross-subtype identity shuffle by 0.09 under P1 and P2 but loses to it by 0.09 under P3 (95% CIs exclude zero; held-out runs confirm). The verdict is set by the share of alpha'beta' cells among active Kenyon cells, which P1 selects low; at the share implied by imaging (about 44%) the real-wiring model fails to learn, exposing a model inadequacy rather than a deficit of the fly's wiring. In flyvis, P1 penalises a mirrored connectome, which has a constructed solution within 0.07 (median) of the real error, more than a spatially shuffled one in 50 of 50 members; the ranking survives ten-fold longer retraining but depends on the checkpoint at fifty-fold. A credible structural claim needs matched optimisation, data-constrained physiology and a model that still works there.
#05Nov 10, 2026
math.AP
Bayesian inverse problems and epidemic-threshold uncertainty for a heterogeneous SIS reaction-diffusion model
Duc-Lam Duong
We study Bayesian inference of persistence from early observations of a heterogeneous susceptible--infected--susceptible (SIS) reaction--diffusion model with standard incidence. We show that the leading prevalence dynamics depend on the unknown coefficients only through the difference between the transmission and recovery rates and the infected diffusivity. The same pair determines the principal eigenvalue whose sign governs persistence, so early prevalence can inform the threshold even when the individual rates remain uncertain. We prove global weak well-posedness and quantitative parameter stability for the SIS system and use the resulting observation-map estimates to establish Bayesian well-posedness. For an initial infection of size $\varepsilon$, we derive a uniform second-order expansion that describes how the separate rates enter prevalence. Incidence depends explicitly on transmission at leading order. When the noise standard deviation is proportional to $\varepsilon$, we prove $O(\varepsilon)$ convergence in Hellinger distance of the nonlinear posteriors to their low-prevalence limits for both prevalence alone and joint prevalence and incidence data. We bound the principal eigenvalue using the growth rate of the infected $L^2$ norm between two times. This rate gives a lower bound for the full nonlinear system, and the upper bound separates spatial transients from nonlinear saturation. Uniform spectral estimates and bounds on infection size and measurement error give sufficient conditions for persistence and extinction. We also bound the error in posterior persistence probabilities under forward and eigenvalue approximation, accounting for posterior mass near the threshold. Numerical examples illustrate threshold inference and the predicted \(O(\varepsilon)\) convergence of the nonlinear posteriors to their low-prevalence limits in Hellinger distance.