Many cellular processes are governed by stochastic reaction events. These events do not necessarily occur in single steps of individual molecules, and, conversely, each birth or death of a macromolecule (e.g., protein) could involve several small reaction steps, creating a memory between individual events and thus leading to nonmarkovian reaction kinetics. Characterizing this kinetics is challenging. Here, we develop a systematic approach for a general reaction network with arbitrary intrinsic waiting-time distributions, which includes the stationary generalized chemical-master equation (sgCME), the stationary generalized Fokker–Planck equation, and the generalized linear-noise approximation. The first formulation converts a nonmarkovian issue into a markovian one by introducing effective transition rates (that explicitly decode the effect of molecular memory) for the reactions in an equivalent reaction network with the same substrates but without molecular memory. Nonmarkovian features of the reaction kinetics can be revealed by solving the sgCME. The latter 2 formulations can be used in the fast evaluation of fluctuations. These formulations can have broad applications, and, in particular, they may help us discover new biological knowledge underlying memory effects. When they are applied to generalized stochastic models of gene-expression regulation, we find that molecular memory is in effect equivalent to a feedback and can induce bimodality, fine-tune the expression noise, and induce switch.

Prochlorococcus marinus, one of the most abundant marine cyanobacteria in the global ocean, is classified into low-light (LL) and high-light (HL) adapted ecotypes. These two adapted ecotypes differ in their ecophysiological characteristics, especially whether adapted for growth at high-light or low-light intensities. However, some evolutionary relationships of Prochlorococcus phylogeny remain to be resolved, such as whether the strains SS120 and MIT9211 form a monophyletic group. We use the Natural Vector (NV) method to represent the sequence in order to identify the phylogeny of the Prochlorococcus. The natural vector method is alignment free without any model assumptions. This study added the covariances of amino acids in protein sequence to the natural vector method. Based on these new natural vectors, we can compute the Hausdorff distance between the two clades which represents the dissimilarity. This method enables us to systematically analyze both the dataset of ribosomal proteomes and the dataset of 16s-23s rRNA sequences in order to reconstruct the phylogeny of Prochlorococcus. Furthermore, we apply classification to inspect the relationship of SS120 and MIT9211. From the reconstructed phylogenetic trees and classification results, we may conclude that the SS120 does not cluster with MIT9211. This study demonstrates a new method for performing phylogenetic analysis. The results confirm that these two strains do not form a monophyletic clade in the phylogeny of Prochlorococcus.

Cryo-electron microscopy (cryo-EM) has recently emerged as a powerful tool for obtaining three-dimensional (3D) structures of biological macromolecules in native states. A minimum cryo-EM image data set for deriving a meaningful reconstruction is comprised of thousands of randomly orientated projections of identical particles photographed with a small number of electrons. The computation of 3D structure from 2D projections requires clustering, which aims to enhance the signal to noise ratio in each view by grouping similarly oriented images. Nevertheless, the prevailing clustering techniques are often compromised by three characteristics of cryo-EM data: high noise content, high dimensionality and large number of clusters. Moreover, since clustering requires registering images of similar orientation into the same pixel coordinates by 2D alignment, it is desired that the clustering algorithm can label misaligned images as outliers. Herein, we introduce a clustering algorithm γ-SUP to model the data with a q-Gaussian mixture and adopt the minimum γ-divergence for estimation, and then use a self-updating procedure to obtain the numerical solution. We apply γ-SUP to the cryo-EM images of two benchmark macromolecules, RNA polymerase II and ribosome. In the former case, simulated images were chosen to decouple clustering from alignment to demonstrate γ-SUP is more robust to misalignment outliers than the existing clustering methods used in the cryo-EM community. In the latter case, the clustering of real cryo-EM data by our γ-SUP method eliminates noise in many views to reveal true structure features of ribosome at the projection level.

Processing streaming data as they arrive is often necessary for high dimensional data analysis. In this paper, we analyze the convergence of a subspace online PCA iteration, as a followup of the recent work of Li, Wang, Liu, and Zhang [Math. Program., Ser. B, DOI 10.1007/s10107-017-1182-z] who considered the case for the most significant principal component only, i.e., a single vector. Under the sub-Gaussian assumption, we obtain a finite-sample error bound that closely matches the minimax information lower bound of Vu and Lei [Ann. Statist. 41:6 (2013), 2905-2947].

Randomness often plays an important role in the spatial and temporal dynamics of biological systems. General stochastic simulation methods may lead to excessive computational cost for a system in which a large number of molecules involved. Therefore, multi-scale hybrid simulation methods become important for stochastic simulations. Here we build a spatially hybrid method which couples two approaches: discrete stochastic simulation and continuous stochastic differential equations. In our method, the locations of the interfaces between the two approaches are changing according to the distribution of molecules in a one-dimensional domain. To balance the accuracy and efficiency, the time step of the numerical method for the continuous stochastic differential equations is adapted to the dynamics of the molecules near the adaptive interfaces. The simulation results for a linear system and two nonlinear biological systems in different one-dimensional domains demonstrate the effectiveness and advantage of our new hybrid method with the adaptive time step control.