Cryo-electron microscopy (cryo-EM) is a widely used technique for recovering the three-dimensional (3-D) structure of biological molecules from a large number of experimentally generated noisy 2-D tomographic projection images of the 3-D structure, taken from unknown viewing angles. Through computationally intensive algorithms, these observed images are processed to reconstruct the 3-D structures. Many popular computational methods rely on estimating the unknown angles as part of the reconstruction process, which becomes particularly challenging at low signal-to-noise ratios. The method of moments offers an alternative approach that circumvents the estimation of viewing orientations of individual projection images by instead estimating the underlying distribution of the viewing angles, and is robust to noise given sufficiently many images. However, the method of moments typically entails computing higher-order moments of the projection images, incurring significant computational and memory costs. To mitigate this, we propose a new approach called the subspace method of moments (SubspaceMoM), which compresses the first three moments using data-driven low-rank tensor techniques as well as expansion into a suitable function basis. The compressed moments can be efficiently computed from the set of projection images using numerical quadrature and can be employed to jointly reconstruct the 3-D structure and the distribution of viewing orientations. We illustrate the practical applicability of SubspaceMoM through numerical experiments using up to the third-order moment on synthetic datasets with a simplified cryo-EM image formation model, which significantly improves the reconstruction resolution compared to previous MoM approaches.

Single-particle cryo-electron microscopy (cryo-EM) has recently joined X-ray crystallography and NMR spectroscopy as a high-resolution structural method to resolve biological macromolecules. In a cryo-EM experiment, the microscope produces images called micrographs. Projections of the molecule of interest are embedded in the micrographs at unknown locations, and under unknown viewing directions. Standard imaging techniques first locate these projections (detection) and then reconstruct the 3-D structure from them. Unfortunately, high noise levels hinder detection. When reliable detection is rendered impossible, the standard techniques fail. This is a problem, especially for small molecules. In this paper, we pursue a radically different approach: we contend that the structure could, in principle, be reconstructed directly from the micrographs, without intermediate detection. The aim is to bring small molecules within reach for cryo-EM. To this end, we design an autocorrelation analysis technique that allows one to go directly from the micrographs to the sought structures. This involves only one pass over the micrographs, allowing online, streaming processing for large experiments. We show numerical results and discuss challenges that lay ahead to turn this proof-of-concept into a complementary approach to state-of-the-art algorithms.

An introduction to the mathematical problem of cryo-electron microscopy (cryo-EM) is given, along with an overview of ASPIRE, an open-source Python package for processing cryo-EM image data. ASPIRE uses unique Fourier basis representations for images of cryo-EM particles. The challenge of representing these mathematical structures within the ASPIRE codebase was addressed by building an extensible class hierarchy using mixins.

Motivated by the problem of determining the atomic structure of macromolecules using single-particle cryo-electron microscopy (cryo-EM), we study the sample and computational complexities of the sparse multi-reference alignment (MRA) model: the problem of estimating a sparse signal from its noisy, circularly shifted copies. Based on its tight connection to the crystallographic phase retrieval problem, we establish that if the number of observations is proportional to the square of the variance of the noise, then the sparse MRA problem is statistically feasible for sufficiently sparse signals. To investigate its computational hardness, we consider three types of computational frameworks: projection-based algorithms, bispectrum inversion, and convex relaxations. We show that a state-of-the-art projection-based algorithm achieves the optimal estimation rate, but its computational complexity is exponential in the sparsity level. The bispectrum framework provides a statistical-computational trade-off : it requires more observations (so its estimation rate is suboptimal), but its computational complexity is provably polynomial in the signal's length. The convex relaxation approach provides polynomial-time algorithms (with a large exponent) that recover sufficiently sparse signals at the optimal estimation rate. We conclude the paper by discussing potential statistical and algorithmic implications for cryo-EM.

We consider the two-dimensional multi-target detection (MTD) problem of estimating a target image from a noisy measurement that contains multiple copies of the image, each randomly rotated and translated. The MTD model serves as a mathematical abstraction of the structure reconstruction problem in single-particle cryo-electron microscopy, the chief motivation of this study. We focus on high noise regimes, where accurate detection of image occurrences within a measurement is impossible. To estimate the image, we develop an expectation-maximization framework that aims to maximize an approximation of the likelihood function. We demonstrate image recovery in highly noisy environments, and show that our framework outperforms the previously studied autocorrelation analysis in a wide range of parameters.

We consider dimensionality reduction for data sets with two or more independent degrees of freedom. For example, measurements of deformable shapes with several parts that move independently fall under this characterization. Mathematically, if the space of each continuous independent motion is a manifold, then their combination forms a product manifold. In this paper, we present an algorithm for manifold factorization given a sample of points from the product manifold. Our algorithm is based on spectral graph methods for manifold learning and the separability of the Laplacian operator on product spaces. Recovering the factors of a manifold yields meaningful lower-dimensional representations, allowing one to focus on particular aspects of the data space while ignoring others. We demonstrate the potential use of our method for an important and challenging problem in structural biology: mapping the motions of proteins and other large molecules using cryo-electron microscopy data sets.

We target the problem of estimating the center of mass of objects in noisy two-dimensional images. We assume that the noise dominates the image, and thus many standard approaches are vulnerable to estimation errors, e.g., the direct computation of the center of mass and the geometric median which is a robust alternative to the center of mass. In this paper, we define a novel surrogate function to the center of mass. We present a mathematical and numerical analysis of our method and show that it outperforms existing methods for estimating the center of mass of an object in various realistic scenarios. As a case study, we apply our centering method to data from single-particle cryo-electron microscopy (cryo-EM), where the goal is to reconstruct the three-dimensional structure of macromolecules. We show how to apply our approach for a better translational alignment of molecule images picked from experimental data. In this way, we facilitate the succeeding steps of reconstruction and streamline the entire cryo-EM pipeline, saving computational time and supporting resolution enhancement.

We introduce a framework for recovering an image from its rotationally and translationally invariant features based on autocorrelation analysis. This work is an instance of the multi-target detection statistical model, which is mainly used to study the mathematical and computational properties of single-particle reconstruction using cryo-electron microscopy (cryo-EM) at low signal-to-noise ratios. We demonstrate with synthetic numerical experiments that an image can be reconstructed from rotational and translational invariants and show that the reconstruction is robust to noise. These results constitute an important step towards the goal of structure determination of small biomolecules using cryo-EM.

Motivated by the task of 2-D classification in single particle reconstruction by cryo-electron microscopy (cryo-EM), we consider the problem of heterogeneous multireference alignment of images. In this problem, the goal is to estimate a (typically small) set of target images from a (typically large) collection of observations. Each observation is a rotated, noisy version of one of the target images. For each individual observation, neither the rotation nor which target image has been rotated are known. As the noise level in cryo-EM data is high, clustering the observations and estimating individual rotations is challenging. We propose a framework to estimate the target images directly from the observations, completely bypassing the need to cluster or register the images. The framework consists of two steps. First, we estimate rotation-invariant features of the images, such as the bispectrum. These features can be estimated to any desired accuracy, at any noise level, provided sufficiently many observations are collected. Then, we estimate the images from the invariant features. Numerical experiments on synthetic cryo-EM datasets demonstrate the effectiveness of the method. Ultimately, we outline future developments required to apply this method to experimental data.

In photon-limited imaging, the pixel intensities are affected by photon count noise. Many applications require an accurate estimation of the covariance of the underlying 2-D clean images. For example, in X-ray free electron laser (XFEL) single molecule imaging, the covariance matrix of 2-D diffraction images is used to reconstruct the 3-D molecular structure. Accurate estimation of the covariance from low-photon-count images must take into account that pixel intensities are Poisson distributed, hence the classical sample covariance estimator is highly biased. Moreover, in single molecule imaging, including in-plane rotated copies of all images could further improve the accuracy of covariance estimation. In this paper we introduce an efficient and accurate algorithm for covariance matrix estimation of count noise 2-D images, including their uniform planar rotations and possibly reflections. Our procedure, steerable ePCA, combines in a novel way two recently introduced innovations. The first is a methodology for principal component analysis (PCA) for Poisson distributions, and more generally, exponential family distributions, called ePCA. The second is steerable PCA, a fast and accurate procedure for including all planar rotations when performing PCA. The resulting principal components are invariant to the rotation and reflection of the input images. We demonstrate the efficiency and accuracy of steerable ePCA in numerical experiments involving simulated XFEL datasets and rotated face images from Yale Face Database B.

In the multireference alignment model, a signal is observed by the action of a random circular translation and the addition of Gaussian noise. The goal is to recover the signal’s orbit by accessing multiple independent observations. Of particular interest is the sample complexity, i.e., the number of observations/samples needed in terms of the signal-to-noise ratio (SNR) (the signal energy divided by the noise variance) in order to drive the mean-square error to zero. Previous work showed that if the translations are drawn from the uniform distribution, then, in the low SNR regime, the sample complexity of the problem scales as$\omega (1/ \mathrm {SNR}^{3})$. In this paper, using a generalization of the Chapman–Robbins bound for orbits and expansions of the$\chi ^{2}$divergence at low SNR, we show that in the same regime the sample complexity for any aperiodic translation distribution scales as$\omega (1/ \mathrm {SNR}^{2})$. This rate is achieved by a simple spectral algorithm. We propose two additional algorithms based on non-convex optimization and expectation–maximization. We also draw a connection between the multireference alignment problem and the spiked covariance model.

We analyze the problem of estimating a signal from multiple measurements on a group action channel that linearly transforms a signal by a random group action followed by a fixed projection and additive Gaussian noise. This channel is motivated by applications such as multi-reference alignment and cryo-electron microscopy. We focus on the large noise regime prevalent in these applications. We give a lower bound on the mean square error (MSE) of any asymptotically unbiased estimator of the orbit in terms of the signal's moment tensors, which implies that the MSE is bounded away from 0 when N/σ2dis bounded from above, where N is the number of observations, σ is the noise standard deviation, and d is the so-called moment order cutoff. In contrast, the maximum likelihood estimator is shown to be consistent if N/σ2ddiverges.

In cryo-electron microscopy, the three-dimensional (3D) electric potentials of an ensemble of molecules are projected along arbitrary viewing directions to yield noisy two-dimensional images. The volume maps representing these potentials typically exhibit a great deal of structural variability, which is described by their 3D covariance matrix. Typically, this covariance matrix is approximately low rank and can be used to cluster the volumes or estimate the intrinsic geometry of the conformation space. We formulate the estimation of this covariance matrix as a linear inverse problem, yielding a consistent least-squares estimator. For $n$ images of size $N$-by-$N$ pixels, we propose an algorithm for calculating this covariance estimator with computational complexity $\mathcal{O}(nN^4+\sqrt{\kappa}N^6 \log N)$, where the condition number $\kappa$ is empirically in the range 10--200. Its efficiency relies on the observation that the normal equations are equivalent to a deconvolution problem in six dimensions. This is then solved by the conjugate gradient method with an appropriate circulant preconditioner. The result is the first computationally efficient algorithm for consistent estimation of the 3D covariance from noisy projections. It also compares favorably in runtime with respect to previously proposed nonconsistent estimators. Motivated by the recent success of eigenvalue shrinkage procedures for high-dimensional covariance matrix estimation, we incorporate a shrinkage procedure that improves accuracy at lower signal-to-noise ratios. We evaluate our methods on simulated datasets and achieve classification results comparable to state-of-the-art methods in shorter running time. We also present results on clustering volumes in an experimental dataset, illustrating the power of the proposed algorithm for practical determination of structural variability.

Accurate estimation of camera matrices is an important step in structure from motion algorithms. In this paper we introduce a novel rank constraint on collections of fundamental matrices in multi-view settings. We show that in general, with the selection of proper scale factors, a matrix formed by stacking fundamental matrices between pairs of images has rank 6. Moreover, this matrix forms the symmetric part of a rank 3 matrix whose factors relate directly to the corresponding camera matrices. We use this new characterization to produce better estimations of fundamental matrices by optimizing an L1-cost function using Iterative Re-weighted Least Squares and Alternate Direction Method of Multiplier. We further show that this procedure can improve the recovery of camera locations, particularly in multi-view settings in which fewer images are available.

The Boolean multireference alignment problem consists in recovering a Boolean signal from multiple shifted and noisy observations. In this paper we obtain an expression for the error exponent of the maximum A posteriori decoder. This expression is used to characterize the number of measurements needed for signal recovery in the low SNR regime, in terms of higher order autocorrelations of the signal. The characterization is explicit for various signal dimensions, such as prime and even dimensions.

Dynamical processes in biology are studied using an ever-increasing number of techniques, each of which brings out unique features of the system. One of the current challenges is to develop systematic approaches for fusing heterogeneous datasets into an integrated view of multivariable dynamics. We demonstrate that heterogeneous data fusion can be successfully implemented within a semi-supervised learning framework that exploits the intrinsic geometry of high-dimensional datasets. We illustrate our approach using a dataset from studies of pattern formation in Drosophila. The result is a continuous trajectory that reveals the joint dynamics of gene expression, subcellular protein localization, protein phosphorylation, and tissue morphogenesis. Our approach can be readily adapted to other imaging modalities and forms a starting point for further steps of data analytics and modeling of biological dynamics.

3D structure recovery from a collection of 2D images requires the estimation of the camera locations and orientations, i.e. the camera motion. For large, irregular collections of images, existing methods for the location estimation part, which can be formulated as the inverse problem of estimating n locations t1, t2, ..., tn in ℝ3from noisy measurements of a subset of the pairwise directions ti-tj/∥ti-tj∥, are sensitive to outliers in direction measurements. In this paper, we firstly provide a complete characterization of well-posed instances of the location estimation problem, by presenting its relation to the existing theory of parallel rigidity. For robust estimation of camera locations, we introduce a two-step approach, comprised of a pairwise direction estimation method robust to outliers in point correspondences between image pairs, and a convex program to maintain robustness to outlier directions. In the presence of partially corrupted measurements, we empirically demonstrate that our convex formulation can even recover the locations exactly. Lastly, we demonstrate the utility of our formulations through experiments on Internet photo collections.

In this paper, we describe an algorithm for sensor network localization (SNL) that proceeds by dividing the whole network into smaller subnetworks, then localizes them in parallel using some fast and accurate algorithm, and finally registers the localized subnetworks in a global coordinate system. We demonstrate that this divide-and-conquer algorithm can be used to leverage existing high-precision SNL algorithms to large-scale networks, which could otherwise only be applied to small-to-medium sized networks. The main contribution of this paper concerns the final registration phase. In particular, we consider a least-squares formulation of the registration problem (both with and without anchor constraints) and demonstrate how this otherwise non-convex problem can be relaxed into a tractable convex program. We provide some preliminary simulation results for large-scale SNL demonstrating that the proposed registration algorithm (together with an accurate localization scheme) offers a good tradeoff between run time and accuracy.

In cryo-electron microscopy (cryo-EM), a microscope generates a top view of a sample of randomly oriented copies of a molecule. The problem of single particle reconstruction (SPR) from cryo-EM is to use the resulting set of noisy two-dimensional projection images taken at unknown directions to reconstruct the three-dimensional (3D) structure of the molecule. In some situations, the molecule under examination exhibits structural variability, which poses a fundamental challenge in SPR. The heterogeneity problem is the task of mapping the space of conformational states of a molecule. It has been previously suggested that the leading eigenvectors of the covariance matrix of the 3D molecules can be used to solve the heterogeneity problem. Estimating the covariance matrix is challenging, since only projections of the molecules are observed, but not the molecules themselves. In this paper, we formulate a general problem of covariance estimation from noisy projections of samples. This problem has intimate connections with matrix completion problems and high-dimensional principal component analysis. We propose an estimator and prove its consistency. When there are finitely many heterogeneity classes, the spectrum of the estimated covariance matrix reveals the number of classes. The estimator can be found as the solution to a certain linear system. In the cryo-EM case, the linear operator to be inverted, which we term the projection covariance transform, is an important object in covariance estimation for tomographic problems involving structural variation. Inverting it involves applying a filter akin to the ramp filter in tomography. We design a basis in which this linear operator is sparse and thus can be tractably inverted despite its large size. We demonstrate via numerical experiments on synthetic datasets the robustness of our algorithm to high levels of noise.

We study the inverse problem of estimating $n$ locations $\mathbf{t}_1, \mathbf{t}_2, \ldots, \mathbf{t}_n$ (up to global scale, translation, and negation) in $\mathbb{R}^d$ from noisy measurements of a subset of the (unsigned) pairwise lines that connect them, that is, from noisy measurements of $\pm \frac{\mathbf{t}_i - \mathbf{t}_j}{\|\mathbf{t}_i - \mathbf{t}_j \|_2}$ for some pairs $(i,j)$ (where the signs are unknown). This problem is at the core of the structure from motion (SfM) problem in computer vision, where the $\mathbf{t}_i$ represent camera locations in $\mathbb{R}^3$. The noiseless version of the problem, with exact line measurements, has been considered previously under the general title of parallel rigidity theory, mainly in order to characterize the conditions for unique realization of locations. For noisy pairwise line measurements, current methods tend to produce spurious solutions that are clustered around a few locations. This sensitivity of the location estimates is a well-known problem in SfM, especially for large, irregular collections of images. In this paper we introduce a semidefinite programming (SDP) formulation, specially tailored to overcome the clustering phenomenon. We further identify the implications of parallel rigidity theory for the location estimation problem to be well-posed, and prove exact (in the noiseless case) and stable location recovery results. We also formulate an alternating direction method to solve the resulting semidefinite program, and provide a distributed version of our formulation for large numbers of locations. Specifically for the camera location estimation problem, we formulate a pairwise line estimation method based on robust camera orientation and subspace estimation. Finally, we demonstrate the utility of our algorithm through experiments on real images.

We have observed an interesting, yet unexplained, phenomenon: Semidefinite programming (SDP) based relaxations of maximum likelihood estimators (MLE) tend to be tight in recovery problems with noisy data, even when MLE cannot exactly recover the ground truth. Several results establish tightness of SDP based relaxations in the regime where exact recovery from MLE is possible. However, to the best of our knowledge, their tightness is not understood beyond this regime. As an illustrative example, we focus on the generalized Procrustes problem.

The multireference alignment problem consists of estimating a signal from multiple noisy shifted observations. Inspired by existing Unique-Games approximation algorithms, we provide a semidefinite program (SDP) based relaxation which approximates the maximum likelihood estimator (MLE) for the multireference alignment problem. Although we show this MLE problem is Unique-Games hard to approximate within any constant, we observe that our poly-time approximation algorithm for this problem appears to perform quite well in typical instances, outperforming existing methods. In an attempt to explain this behavior we provide stability guarantees for our SDP under a random noise model on the observations. This case is more challenging to analyze than traditional semi-random instances of Unique-Games: the noise model is on vertices of a graph and translates into dependent noise on the edges.

This paper considers the inverse problem with observed variables Y = BGX ⊕ Z, where BGis the incidence matrix of a graph G, X is the vector of unknown vertex variables with a uniform prior, and Z is a noise vector with Bernoulli(ε) i.i.d. entries. All variables and operations are Boolean. This model is motivated by coding, synchronization, and community detection problems. In particular, it corresponds to a stochastic block model or a correlation clustering problem with two communities and censored edges. Without noise, exact recovery of X is possible if and only the graph G is connected, with a sharp threshold at the edge probability log(n)=n for Erdös-Rényi random graphs. The first goal of this paper is to determine how the edge probability p needs to scale to allow exact recovery in the presence of noise. Defining the degree (oversampling) rate of the graph by α = np= log(n), it is shown that exact recovery is possible if and only if α > 2/(1-2ε)2+o(1/(1-2ε)2). In other words, 2/(1-2ε)2is the information theoretic threshold for exact recovery at low-SNR. In addition, an efficient recovery algorithm based on semidefinite programming is proposed and shown to succeed in the threshold regime up to twice the optimal rate. Full version available in [1].

It was recently demonstrated in [13] that the denoising performance of Non-Local Means (NLM) can be improved at large noise levels by replacing the mean by the robust Euclidean median. Numerical experiments on synthetic and natural images showed that the latter consistently performed better than NLM beyond a certain noise level, and significantly so for images with sharp edges. The Euclidean mean and median can be put into a common regression (on the patch space) framework, in which the ℓ2norm of the residuals is considered in the former, while the ℓ1norm is considered in the latter. The natural question then is what happens if we consider ℓp(0 <; p <; 1) regression? We investigate this possibility in this paper.

Computerized tomography is a standard method for obtaining internal structure of objects from their projection images. While CT reconstruction requires the knowledge of the imaging directions, there are some situations in which the imaging directions are unknown, for example, when imaging a moving object. It is therefore desirable to design a reconstruction method from projection images taken at unknown directions. Another difficulty arises from the fact that the projections are often contaminated by noise, practically limiting all current methods, including the recently proposed diffusion map approach. In this paper, we introduce two denoising steps that allow reconstructions at much lower signal-to-noise ratios (SNRs) when combined with the diffusion map framework. In the first denoising step we use principal component analysis (PCA) together with classical Wiener filtering to derive an asymptotically optimal linear filter. In the second step, we denoise the graph of similarities between the filtered projections using a network analysis measure such as the Jaccard index. Using this combination of PCA, Wiener filtering, graph denoising, and diffusion maps, we are able to reconstruct the two-dimensional (2-D) Shepp-Logan phantom from simulative noisy projections at SNRs well below their currently reported threshold values. We also report the results of a numerical experiment corresponding to an abdominal CT. Although the focus of this paper is the 2-D CT reconstruction problem, we believe that the combination of PCA, Wiener filtering, graph denoising, and diffusion maps is potentially useful in other signal processing and image analysis applications.

A major challenge in single particle reconstruction from cryo-electron microscopy is to establish a reliable ab initio three-dimensional model using two-dimensional projection images with unknown orientations. Common-lines--based methods estimate the orientations without additional geometric information. However, such methods fail when the detection rate of common-lines is too low due to the high level of noise in the images. An approximation to the least squares global self-consistency error was obtained in [A. Singer and Y. Shkolnisky, SIAM J. Imaging Sci., 4 (2011), pp. 543--572] using convex relaxation by semidefinite programming. In this paper we introduce a more robust global self-consistency error and show that the corresponding optimization problem can be solved via semidefinite relaxation. In order to prevent artificial clustering of the estimated viewing directions, we further introduce a spectral norm term that is added as a constraint or as a regularization term to the relaxed minimization problem. The resulting problems are solved using either the alternating direction method of multipliers or an iteratively reweighted least squares procedure. Numerical experiments with both simulated and real images demonstrate that the proposed methods significantly reduce the orientation estimation error when the detection rate of common-lines is low.

A central task in recovering the structure of a macromolecule from cryo-electron microscopy (cryo-EM) images is to determine a three-dimensional model of the macromolecule given many of its two-dimensional projection images. The direction from each image taken the images which was is unknown, and are small and extremely noisy. The goal is to determine the direction from which each image was taken and then to combine the images into a three-dimensional model of the molecule. We present an algorithm for determining the viewing direction of all cryo-EM images at once, which is robust to high levels of noise. The algorithm is based on formulating the problem as a synchronization problem; that is, we estimate the relative spatial configuration of pairs of images and then estimate a global assignment of orientations that maximizes the number of satisfied pairwise relations. Information about the spatial relation between pairs of images is extracted from common lines between triplets of images. These noisy pairwise relations are combined into a single consistent assignment of orientations by constructing a matrix whose entries encode the pairwise relations. This matrix is shown to have rank 3, and its nontrivial eigenspace is shown to reveal the projection orientation of each image. In particular, we show that the nontrivial eigenvectors encode the rotation matrix that corresponds to each image.

In this letter, we note that the denoising performance of Non-Local Means (NLM) can be improved at large noise levels by replacing the mean by the Euclidean median. We call this new denoising algorithm the Non-Local Euclidean Medians (NLEM). At the heart of NLEM is the observation that the median is more robust to outliers than the mean. In particular, we provide a simple geometric insight that explains why NLEM performs better than NLM in the vicinity of edges, particularly at large noise levels. NLEM can be efficiently implemented using iteratively reweighted least squares, and its computational complexity is comparable to that of NLM. We provide some preliminary results to study the proposed algorithm and to compare it with NLM.

We present a new approach to localization of sensors from noisy measurements of a subset of their Euclidean distances. Our algorithm starts by finding, embedding, and aligning uniquely realizable subsets of neighboring sensors called patches. In the noise-free case, each patch agrees with its global positioning up to an unknown rigid motion of translation, rotation, and possibly reflection. The reflections and rotations are estimated using the recently developed eigenvector synchronization algorithm, while the translations are estimated by solving an overdetermined linear system. The algorithm is scalable as the number of nodes increases and can be implemented in a distributed fashion. Extensive numerical experiments show that it compares favorably to other existing algorithms in terms of robustness to noise, sparse connectivity, and running time. While our approach is applicable to higher dimensions, in the current article, we focus on the two-dimensional case.

The cryo-electron microscopy reconstruction problem is to find the three-dimensional (3D) structure of a macromolecule given noisy samples of its two-dimensional projection images at unknown random directions. Present algorithms for finding an initial 3D structure model are based on the "angular reconstitution" method in which a coordinate system is established from three projections, and the orientation of the particle giving rise to each image is deduced from common lines among the images. However, a reliable detection of common lines is difficult due to the low signal-to-noise ratio of the images. In this paper we describe two algorithms for finding the unknown imaging directions of all projections by minimizing global self-consistency errors. In the first algorithm, the minimizer is obtained by computing the three largest eigenvectors of a specially designed symmetric matrix derived from the common lines, while the second algorithm is based on semidefinite programming (SDP). Compared with existing algorithms, the advantages of our algorithms are five-fold: first, they accurately estimate all orientations at very low common-line detection rates; second, they are extremely fast, as they involve only the computation of a few top eigenvectors or a sparse SDP; third, they are nonsequential and use the information in all common lines at once; fourth, they are amenable to a rigorous mathematical analysis using spectral analysis and random matrix theory; and finally, the algorithms are optimal in the sense that they reach the information theoretic Shannon bound up to a constant for an idealized probabilistic model.

The cryo-electron microscopy (cryo-EM) reconstruction problem is to find the three-dimensional structure of a macromolecule given noisy versions of its two-dimensional projection images at unknown random directions. We introduce a new algorithm for identifying noisy cryo-EM images of nearby viewing angles. This identification is an important first step in three-dimensional structure determination of macromolecules from cryo-EM, because once identified, these images can be rotationally aligned and averaged to produce "class averages" of better quality. The main advantage of our algorithm is its extreme robustness to noise. The algorithm is also very efficient in terms of running time and memory requirements, because it is based on the computation of the top few eigenvectors of a specially designed sparse Hermitian matrix. These advantages are demonstrated in numerous numerical experiments.

We present here an efficient algorithm to compute the Principal Component Analysis (PCA) of a large image set consisting of images and, for each image, the set of its uniform rotations in the plane. We do this by pointing out the block circulant structure of the covariance matrix and utilizing that structure to compute its eigenvectors. We also demonstrate the advantages of this algorithm over similar ones with numerical experiments. Although it is useful in many settings, we illustrate the specific application of the algorithm to the problem of cryo-electron microscopy.

Nonlocal neighborhood filters are modern and powerful techniques for image and signal denoising. In this paper, we give a probabilistic interpretation and analysis of the method viewed as a random walk on the patch space. We show that the method is intimately connected to the characteristics of diffusion processes, their escape times over potential barriers, and their spectral decomposition. In particular, the eigenstructure of the diffusion operator leads to novel insights on the performance and limitations of the denoising method, as well as a proposal for an improved filtering algorithm.

We introduce a graph Laplacian-based algorithm for the tomographic reconstruction of a planar object from its projections taken at random unknown directions. A Laplace-type operator is constructed on the data set of projections, and the eigenvectors of this operator reveal the projection orientations. The algorithm is shown to successfully reconstruct the Shepp-Logan phantom from its noisy projections. Such a reconstruction algorithm is desirable for the structuring of certain biological proteins using cryo-electron microscopy.