Daily Papers

AIVC (AI Virtual Cell) is a learned simulator of cellular behavior across conditions. Predicting how a cell population responds transcriptionally to a genetic perturbation is a core task. Perturb-seq records that response by destructive sequencing, so a control cell and a perturbed cell are never observed as a pair, and cells under one condition remain heterogeneous and noisy. Regression on individual cells absorbs sampling variation into the estimated effect, whereas interpretation requires the reproducible population effect. P2P (Perturbation-to-Perturbation) takes a stochastic cell-set view as its supervision unit. Two views drawn from the same condition share a reproducible population effect and differ by view-specific variation. A permutation-invariant set encoder summarizes the control population, a structured encoder represents perturbation tokens, cellular context, dose, and combination interactions, and a gate blends empirical condition-effect memory with a neural residual. A heteroscedastic head predicts the population mean and gene-wise response variance. Under one protocol and five seeds, P2P attains the lowest expression RMSE and the highest Effect Pearson, DEG F1, and DEG average precision on each of Adamson, Norman, Replogle K562, and Replogle RPE1 relative to GenePert, LinearPert, SLIM, Scouter, and scPILOT. On Replogle K562, Effect Pearson rises from 0.643 to 0.702 and DEG F1 rises from 0.067 to 0.178 relative to Scouter, the strongest baseline on both metrics.

Predicting transcriptional responses to genetic perturbations could reduce the experimental burden of functional genomics, but extrapolation to genes that were never perturbed during training remains difficult. We present Stable-Shift, a structured method for estimating unseen-gene responses. Stable-Shift aggregates single-cell measurements into perturbation-level expression shifts, fits a low-rank response basis using training perturbations only, and predicts an unseen gene's coordinates in that basis from biological context. The context combines STRING interactions, network structure, control-cell expression statistics, and Gene Ontology annotations; the evaluated implementation uses graph convolution to integrate these inputs. On the supplied K562 Perturb-seq benchmark, Stable-Shift obtained 0.592 cosine similarity, compared with 0.569 for GEARS, together with higher Spearman correlation and top-gene precision among the evaluated methods. Its mean cosine similarity over five unseen-gene splits was 0.589 +/- 0.008. The same ordering was observed in the supplied graph-aware, residualized, gene-space, and Norman-dataset comparisons. These results support further study of biologically structured latent-response prediction, while the lower gene-space accuracy and sensitivity to sparse graph neighborhoods limit the scope of the present conclusions.

Single-cell perturbation screens are used to train and evaluate models that predict perturbation effects, and model scores are judged against how reproducible the measured effects are. Reproducibility is usually judged by splitting each perturbation's cells into two random halves. This assumes that the halves are independent replicates. In pooled screens such as Perturb-seq, however, the cells carrying a guide RNA descend from a limited number of transduced cells, so two random halves contain the same clones: pseudoreplication whose unit is not marked in the data. Using perturbations that should have no effect as controls, we compared random halves with independent replicates from separate transductions, and tested directly with halves that differ only in their clones. In a genome-scale screen of primary T cells, null perturbations agreed between random halves almost always and between independent replicates only half the time, the rate expected from noise alone; measuring more cells did not remove this agreement. Splitting the cells into halves that share no clone, by the T-cell receptor constant region or by a clone barcode, largely removed the excess agreement. Its size equals the share of expression differences set by clones divided by the effective number of clones per perturbation; across 16 screens it was largest in T cells transferred into mice and in a genome-scale primary T-cell screen, one to two orders of magnitude smaller in cell lines, and smallest in non-dividing neurons. Shared clones inflate benchmark ceilings and reliability labels, and when a model's input and its scoring answer come from one transduction, published models that predict perturbation effects in a new cell state appear better than a baseline that ignores the perturbation; against cells from another transduction, most fall below it. Reproducibility should be judged across separate transductions.

Learning how local perturbations affect a network is important for identifying which components drive or absorb a system's response. We formulate this as seed-conditioned response ranking: given a perturbation at one seed node, ranking all other nodes by response strength. This is challenging when the model is given only the interaction topology, while the mechanism governing how perturbations propagate must be learned from data. We present VQIL (Visible Quantum Interference Learning), a trainable Szegedy quantum walk for seed-conditioned ranking. Edge weights, link phases, and per-node phase rotations are optimized end-to-end by backpropagation while the walk operator remains unitary throughout training. Node scores are obtained from a geometrically discounted coherent sum of quantum-walk amplitudes, enabling quantum interference before the final squared-norm readout. Because each learned parameter is attached to a named edge or node, the trained model provides directly inspectable hypotheses about the roles of individual graph components in the propagation mechanism. On AC power-flow perturbations over six transmission grids, with electrical parameters withheld from the model, VQIL improves Spearman rank correlation from 0.147 for the untrained walk to 0.831 and outperforms an identically trained random-walk model. On gene perturbation over five protein-protein interaction networks with Perturb-seq supervision, VQIL improves rank correlation from 0.171 to 0.620, outperforming the strongest learned classical and neural baselines. These results show that trainable quantum-walk interference provides a scalable and interpretable inductive bias for learning seed-conditioned response rankings on graphs.

Single-cell CRISPR screens summarize each perturbation by how far cells move from their unperturbed state, averaging over cell-to-cell variation. Whether the cells moved together is not captured: two perturbations with identical effect magnitude can differ qualitatively, one driving cells along a shared trajectory, the other scattering them around the same mean. We define SheshaP coherence (S_p), the mean cosine similarity between individual cell displacement vectors and their mean, and ask what it adds across six Perturb-seq datasets (2,285 perturbations; CRISPRa, CRISPRi, Cas9 knockout). Coherence and effect magnitude are closely coupled (Spearman ρ=0.84--0.98), and the coupling persists in a foundation-model embedding, under alternative effect-size definitions, and when analysis is restricted to responding cells. Associations reported without conditioning on effect size largely recover it, shown here for two comparisons that vanish under conditioning. Effect size accounts for 89--96\% of coherence variance; within the remainder, coherence is negatively associated with apoptosis and p53 signalling in the two largest screens. Two standard responder classifiers agree on only 68\% of cells. Directional coherence is largely a restatement of effect magnitude, and heterogeneity measures should report their redundancy with effect size as a matter of course. S_p is implemented in the open-source shesha-geometry Python package.

Predicting how a cell will change its transcriptional state under a developmental signal or a genetic perturbation is the computational core of in-silico biology and the AI Virtual Cell program. Existing approaches either fit static control-to-treated maps that discard time, or solve multi-step ODE / Schrödinger-bridge problems on each dataset independently. We introduce Chreode, a one-step cell world model that predicts action-conditioned cell-state transitions through a structured residual transition operator. It shifts distributional evolution from inference time to training time, enabling single-pass generation while preserving a Waddington-inspired decomposition into downhill landscape flow, rotational in-tangent dynamics, and stochastic spread. The model is pretrained with a shared scVI encoder and a DiT-based dynamics backbone on a 2.4M-cell mouse embryonic atlas spanning 7 datasets. As a fine-tuning initialization, Chreode improves per-target Sinkhorn distance on Weinreb hematopoiesis and Veres islet differentiation over matched scratch models, PI-SDE, and PRESCIENT. As a transferable gene-state embedding for GEARS, the pretrained dynamics representation reduces shared-vocabulary DE20 mean squared error on Norman Perturb-seq from 0.2121 to 0.1858, a 12.4% relative improvement, without changing the GEARS training procedure. We interpret this transfer to perturbation prediction as evidence that pretrained developmental-trajectory dynamics encode differentiation primitives transferable to CRISPR-induced state shifts, since both involve cell-state transitions in a shared latent geometry. The pretrained backbone additionally produces zero-shot clonal fate scores on Weinreb that are competitive with strong dynamic-OT baselines.

Single-cell and spatial foundation models promise transferable biological representations, yet their generality remains largely untested across modalities, biological domains and analytical tasks. We benchmarked six representative models, Nicheformer, CellPLM, scGPT-spatial, GenePT, scELMo and Novae, using a harmonised framework spanning scRNA-seq, spatial transcriptomics and Perturb-seq. We evaluated zero-shot and continually pretrained clustering, supervised annotation, marker-gene concordance and perturbation prediction. Model performance was strongly conditional: expression-trained cell-level transformers best resolved many cell-identity tasks, spatial and graph-aware models better preserved tissue architecture, and language-derived gene embeddings were competitive for selected perturbation-response metrics. No model dominated across tasks, and rankings shifted with modality, preprocessing, tokenisation, biological prior, domain shift and metric choice. This benchmark provides practical guidance for model selection and argues that future models should be judged by biological generalisation, interpretability and perturbation-grounded validity, not by scale or leaderboard performance alone.

Single-cell perturbation atlases rarely measure every intervention in every cellular context: a query perturbation is often observed in one or more source contexts but missing in the recipient context where its effect is needed. Ignoring those measured responses discards query-specific experimental evidence, whereas copying or weakly calibrating them across contexts risks transferring the wrong signal. We propose PerturbMap, which predicts a missing recipient-context effect by combining a recipient-local low-rank base with accepted proposals that transport the same perturbation's measured source responses through source-to-recipient ridge experts fit on paired training perturbations, with proposal weights determined by route reliability estimated on validation anchors. On the Perturb-CITE-seq melanoma cohort, PerturbMap improves full-effect MSE by 4.1\% over a recipient-local low-rank base and achieves lower MSE than FedAvg, zero-response, raw-copy, calibrated-copy, and identity-shuffled affine controls. It remains within 2.82times10^{-6} MSE of our centralized token-matched pooled reference, which uses a stronger training interface. A condition-mean specificity diagnostic shows the same direction: same-recipient top-10 counterpart retrieval by cosine increases from 74.5\% for the low-rank base to 80.5\% for PerturbMap.

State-space models (SSMs) have recently emerged as a framework for learning long-range sequence tasks. An example is the structured state-space sequence (S4) layer, which uses the diagonal-plus-low-rank structure of the HiPPO initialization framework. However, the complicated structure of the S4 layer poses challenges; and, in an effort to address these challenges, models such as S4D and S5 have considered a purely diagonal structure. This choice simplifies the implementation, improves computational efficiency, and allows channel communication. However, diagonalizing the HiPPO framework is itself an ill-posed problem. In this paper, we propose a general solution for this and related ill-posed diagonalization problems in machine learning. We introduce a generic, backward-stable "perturb-then-diagonalize" (PTD) methodology, which is based on the pseudospectral theory of non-normal operators, and which may be interpreted as the approximate diagonalization of the non-normal matrices defining SSMs. Based on this, we introduce the S4-PTD and S5-PTD models. Through theoretical analysis of the transfer functions of different initialization schemes, we demonstrate that the S4-PTD/S5-PTD initialization strongly converges to the HiPPO framework, while the S4D/S5 initialization only achieves weak convergences. As a result, our new models show resilience to Fourier-mode noise-perturbed inputs, a crucial property not achieved by the S4D/S5 models. In addition to improved robustness, our S5-PTD model averages 87.6% accuracy on the Long-Range Arena benchmark, demonstrating that the PTD methodology helps to improve the accuracy of deep learning models.

Short-term bike-sharing demand forecasting is complicated by spatial-temporal non-stationarity and the practical difficulty of incorporating unstructured external text into numerical pipelines. Conventional approaches rely on historical flow sequences and fixed graph structures, thereby constraining their accuracy when anomalous social events perturb normal travel patterns. We propose a forecasting framework in which a Large Language Model (LLM) drives a semantic shockwave mechanism that converts free-form urban text, such as municipal event schedules, local news, and transit bulletins, into quantified spatial-temporal perturbation fields. The LLM extracts three physically interpretable parameters per event (intensity, spatial reach, and temporal lag), from which Gaussian decay fields are constructed and injected into a Zero-Inflated Adaptive Spatio-Temporal Graph Convolutional Network (ZI-ASTGCN). To handle the pronounced sparsity of grid-level measurements, the model couples a dual-branch output head with a multi-task zero-inflated loss that jointly trains a gating probability and a conditional flow intensity. Experiments on the operational Barcelona Bicing dataset show that ZI-ASTGCN outperforms established neural baselines, with particularly strong gains during high-demand periods, validating the utility of physics-grounded semantic signals in spatial-temporal mobility forecasting.

Reducing audio-encoder depth lowers the inference cost of speech large language models, but removing complete blocks perturbs the embeddings consumed by the decoder and can cause deletion and premature end-of-sequence errors. We introduce X-AuT, a progressive framework that selects layer combinations through short behavioral probes and restores the pruned model through representation alignment, cross-scale distillation, scheduled student-policy supervision, and LoRA finetuning. The language-model backbone remains frozen, while attention LoRA adapters and the tied output embedding adapt during distillation. Training uses the highest-agreement tier from a transcript-consistency pipeline, followed by source reweighting during finetuning. On ten public Chinese--English benchmarks, compressing Qwen3-ASR-0.6B from 18 to 16 audio-encoder layers reduces macro-average error from 5.61% to 5.27%. The 14-layer model reaches 5.75% with 20.7% fewer audio-tower parameters. Under the matched recipe, the 1.7B teacher yields 5.55% mean error, compared with 8.45% for self-distillation, and progressive 18rightarrow14 pruning outperforms direct pruning (5.75% vs. 6.73%). These single-run results establish two practical operating points and show that the accuracy effects vary across benchmarks. Project website: https://xpeng-ai.github.io/x-aut