Cryo-electron microscopy (cryo-EM), the subject of the 2017 Nobel Prize in Chemistry, is a technology for determining the 3-D structure of macromolecules from many noisy 2-D projections of instances of these macromolecules, whose orientations and positions are unknown. The molecular structures are not rigid objects, but flexible objects involved in dynamical processes. The different conformations are exhibited by different instances of the macromolecule observed in a cryo-EM experiment, each of which is recorded as a particle image. The range of conformations and the conformation of each particle are not known a priori; one of the great promises of cryo-EM is to map this conformation space. Remarkable progress has been made in determining rigid structures from homogeneous samples of molecules in spite of the unknown orientation of each particle image and significant progress has been made in recovering a few distinct states from mixtures of rather distinct conformations, but more complex heterogeneous samples remain a major challenge. We introduce the hyper-molecule'' framework for modeling structures across different states of heterogeneous molecules, including continuums of states. The key idea behind this framework is representing heterogeneous macromolecules as high-dimensional objects, with the additional dimensions representing the conformation space. This idea is then refined to model properties such as localized heterogeneity. In addition, we introduce an algorithmic framework for recovering such maps of heterogeneous objects from experimental data using a Bayesian formulation of the problem and Markov chain Monte Carlo (MCMC) algorithms to address the computational challenges in recovering these high dimensional hyper-molecules. We demonstrate these ideas in a prototype applied to synthetic data.
The covariance estimation approach proposed in @cite_39 does not rely on a particular model for heterogeneity, be it discrete or continuous. Indeed, the authors present a method for characterizing continuous variability in synthetic data. However, the covariance approach is adapted to a linear model of variability and is therefore not well-suited for continuous, and necessarily non-linear, variability. Furthermore, the limited resolution of the reconstruction precludes the study of heterogeneity at higher level of detail. Another approach has been to study the normal modes of perturbation of a macromolecular structure @cite_45 @cite_13 .
@cite_45 @cite_13 @cite_39
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Statistical inference and information processing of high-dimensional data often require an efficient and accurate estimation of their second-order statistics. With rapidly changing data, limited processing power and storage at the acquisition devices, it is desirable to extract the covariance structure from a single pass over the data and a small number of stored measurements. In this paper, we explore a quadratic (or rank-one) measurement model which imposes minimal memory requirements and low computational complexity during the sampling process, and is shown to be optimal in preserving various low-dimensional covariance structures. Specifically, four popular structural assumptions of covariance matrices, namely, low rank, Toeplitz low rank, sparsity, jointly rank-one and sparse structure, are investigated, while recovery is achieved via convex relaxation paradigms for the respective structure. The proposed quadratic sampling framework has a variety of potential applications, including streaming data processing, high-frequency wireless communication, phase space tomography and phase retrieval in optics, and noncoherent subspace detection. Our method admits universally accurate covariance estimation in the absence of noise, as soon as the number of measurements exceeds the information theoretic limits. We also demonstrate the robustness of this approach against noise and imperfect structural assumptions. Our analysis is established upon a novel notion called the mixed-norm restricted isometry property (RIP- @math ), as well as the conventional RIP- @math for near-isotropic and bounded measurements. In addition, our results improve upon the best-known phase retrieval (including both dense and sparse signals) guarantees using PhaseLift with a significantly simpler approach. A method for simultaneous modelling of the Cholesky decomposition of several covariance matrices is presented. We highlight the conceptual and computational advantages of the unconstrained parameterization of the Cholesky decomposition and compare the results with those obtained using the classical spectral (eigenvalue) and variance-correlation decompositions. All these methods amount to decomposing complicated covariance matrices into ''dependence'' and ''variance'' components, and then modelling them virtually separately using regression techniques. The entries of the ''dependence'' component of the Cholesky decomposition have the unique advantage of being unconstrained so that further reduction of the dimension of its parameter space is fairly simple. Normal theory maximum likelihood estimates for complete and incomplete data are presented using iterative methods such as the EM (Expectation-Maximization) algorithm and their improvements. These procedures are illustrated using a dataset from a growth hormone longitudinal clinical trial. Statistical and balance features of forecast errors are generally incorporated in the background constraint of variational data assimilation. Forecast error covariances are here estimated with a spectral approach and from a set of forecast differences; autocovariances are calculated with a nonseparable scheme, and multiple linear regressions are used in the formulation of cross covariances. Such an approach was first developed for global models; it is here adapted to ALADIN, a bi-Fourier high-resolution limited-area model, and extended to a multivariate study of humidity forecast errors. Results for autocovariances confirm the importance of nonseparability, in terms of both vertical variability of horizontal correlations and dependence of vertical correlations with horizontal scale; high-resolution spatial correlations are obtained, which should enable a high-resolution analysis. Moreover nonnegligible relationships are found between forecast errors of humidity and those of mass and wind fields. Abstract Estimation of the covariance structure of spatial processes is a fundamental prerequisite for problems of spatial interpolation and the design of monitoring networks. We introduce a nonparametric approach to global estimation of the spatial covariance structure of a random function Z(x, t) observed repeatedly at times ti (i = 1, …, T) at a finite number of sampling stations xi (i = 1, 2, …, N) in the plane. Our analyses assume temporal stationarity but do not assume spatial stationarity (or isotropy). We analyze the spatial dispersions var(Z(xi, t) − Z(xj, t)) as a natural metric for the spatial covariance structure and model these as a general smooth function of the geographic coordinates of station pairs (xi, xj ). The model is constructed in two steps. First, using nonmetric multidimensional scaling (MDS) we compute a two-dimensional representation of the sampling stations for which a monotone function of interpoint distances δij approximates the spatial dispersions. MDS transforms the problem...