Single-cell (sc)RNA-seq, together with RNA velocity and metabolic labeling, reveals cellular states and transitions at unprecedented resolution. Fully exploiting these data, however, requires kinetic models capable of unveiling governing regulatory functions. Here, we introduce an analytical framework dynamo (https://github.com/aristoteleo/dynamo-release), which infers absolute RNA velocity, reconstructs continuous vector fields that predict cell fates, employs differential geometry to extract underlying regulations, and ultimately predicts optimal reprogramming paths and perturbation outcomes. We highlight dynamo’s power to overcome fundamental limitations of conventional splicing-based RNA velocity analyses to enable accurate velocity estimations on a metabolically labeled human hematopoiesis scRNA-seq dataset. Furthermore, differential geometry analyses reveal mechanisms driving early megakaryocyte appearance and elucidate asymmetrical regulation within the PU.1-GATA1 circuit. Leveraging the least-action-path method, dynamo accurately predicts drivers of numerous hematopoietic transitions. Finally, in silico perturbations predict cell-fate diversions induced by gene perturbations. Dynamo, thus, represents an important step in advancing quantitative and predictive theories of cell-state transitions.

The commonly used spatial entropy hr(U) of the multi-dimensional shift space U is the limit of growth rate of admissible local patterns on finite rectangular sublattices which expands to whole space Zd, d ≥ 2. This work studies spatial entropy hΩ(U) of shift space U on general expanding system Ω = {Ω(n)}∞ n=1 where Ω(n) is increasing finite sublattices and expands to Zd. Ω is called genuinely d-dimensional if Ω(n) contains no lower-dimensional part whose size is comparable to that of its d-dimensional part. We show that hr(U) is the supremum of hΩ(U) for all genuinely two-dimensional Ω. Furthermore, when Ω is genuinely d-dimensional and satisfies certain conditions, then hΩ(U) = hr(U). On the contrary, when Ω(n) contains a lower-dimensional part, then hr(U) < hΩ(U) for some U. Therefore, hr(U) is appropriate to be the d-dimensional spatial entropy.

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Let M be a compact Riemannian manifold, π : \tilde{M} → M be the universal covering and ω be a smooth 2-form on M with π^∗ω cohomologous to zero. Suppose the fundamental group π_1(M) satisfies certain radial quadratic (resp. linear) isoperimetric inequality, we show that there exists a smooth 1-form η on \tilde{M} of linear (resp. bounded) growth such that π^∗ω = dη. As applications, we prove that on a compact Kahler manifold (M,ω) with π^∗ω cohomologous to zero, if π_1(M) is CAT(0) or automatic (resp. hyperbolic), then M is Kahler non-elliptic (resp. Kahler hyperbolic) and the Euler characteristic (−1)^{dim_RM/2χ(M) ≥ 0 (resp. >0).

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