Publications

Multisite protein phosphorylation plays a critical role in cell regulation [1, 2, 3]. It is widely appreciated that the functional capabilities of multisite phosphorylation depend on the order and kinetics of phosphorylation steps, but kinetic aspects of multisite phosphorylation remain poorly understood [4, 5, 6]. Here, we focus on what appears to be the simplest scenario, when a protein is phosphorylated on only two sites in a strict, well-defined order. This scenario describes the activation of ERK, a highly conserved cell-signaling enzyme. We use Bayesian parameter inference in a structurally identifiable kinetic model to dissect dual phosphorylation of ERK by MEK, a kinase that is mutated in a large number of human diseases [7, 8, 9, 10, 11, 12]. Our results reveal how enzyme processivity and efficiencies of individual phosphorylation steps are altered by pathogenic mutations. The presented approach, which connects specific mutations to kinetic parameters of multisite phosphorylation mechanisms, provides a systematic framework for closing the gap between studies with purified enzymes and their effects in the living organism.

Multisite protein phosphorylation plays a critical role in cell regulation [1, 2, 3]. It is widely appreciated that the functional capabilities of multisite phosphorylation depend on the order and kinetics of phosphorylation steps, but kinetic aspects of multisite phosphorylation remain poorly understood [4, 5, 6]. Here, we focus on what appears to be the simplest scenario, when a protein is phosphorylated on only two sites in a strict, well-defined order. This scenario describes the activation of ERK, a highly conserved cell-signaling enzyme. We use Bayesian parameter inference in a structurally identifiable kinetic model to dissect dual phosphorylation of ERK by MEK, a kinase that is mutated in a large number of human diseases [7, 8, 9, 10, 11, 12]. Our results reveal how enzyme processivity and efficiencies of individual phosphorylation steps are altered by pathogenic mutations. The presented approach, which connects specific mutations to kinetic parameters of multisite phosphorylation mechanisms, provides a systematic framework for closing the gap between studies with purified enzymes and their effects in the living organism.

Principles that predict reactions or properties of materials define the discipline of chemistry. In this work, we derive chemical rules, based on atomic distances and chemical bond character, which predict topological materials in compounds that feature the structural motif of a square-net. Using these rules, we identify over 300 potential new topological materials. We show that simple chemical heuristics can be a powerful tool to characterize topological matter. In contrast to previous database-driven materials’ categorization, our approach allows us to identify candidates that are alloys, solid-solutions, or compounds with statistical vacancies. While previous material searches relied on density functional theory, our approach is not limited by this method and could also be used to discover magnetic and statistically disordered topological semimetals.

Gravitational wave echoes have been proposed as a smoking-gun signature of exotic compact objects with near-horizon structure. Recently there have been observational claims that echoes are indeed present in stretches of data from Advanced LIGO and Advanced Virgo immediately following gravitational wave signals from presumed binary black hole mergers, as well as a binary neutron star merger. In this paper we deploy a morphology-independent search algorithm for echoes introduced in Tsang et al., Phys. Rev. D 98, 024023 (2018), which (a) is able to accurately reconstruct a possible echoes signal with minimal assumptions about their morphology, and (b) computes Bayesian evidences for the hypotheses that the data contain a signal, an instrumental glitch, or just stationary, Gaussian noise. Here we apply this analysis method to all the significant events in the first Gravitational Wave Transient Catalog (GWTC-1), which comprises the signals from binary black hole and binary neutron star coalescences found during the first and second observing runs of Advanced LIGO and Advanced Virgo. In all cases, the ratios of evidences for signal versus noise and signal versus glitch do not rise above their respective "background distributions" obtained from detector noise, the smallest p-value being 3% (for event GW170823). Hence we find no statistically significant evidence for echoes in GWTC-1.

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 eigenvalues and eigenfunctions of the Stokes operator have been the subject of intense analytical investigation and have applications in the study and simulation of the Navier–Stokes equations. As the Stokes operator is second order and has the divergence-free constraint, computing these eigenvalues and the corresponding eigenfunctions is a challenging task, particularly in complex geometries and at high frequencies. The boundary integral equation (BIE) framework provides robust and scalable eigenvalue computations due to (a) the reduction in the dimension of the problem to be discretized and (b) the absence of high-frequency “pollution” when using Green’s function to represent propagating waves. In this paper, we detail the theoretical justification for a BIE approach to the Stokes eigenvalue problem on simply- and multiply-connected planar domains, which entails a treatment of the uniqueness theory for oscillatory Stokes equations on exterior domains. Then, using well-established techniques for discretizing BIEs, we present numerical results which confirm the analytical claims of the paper and demonstrate the efficiency of the overall approach.

The analysis of single-cell genomics data presents several statistical challenges, and extensive efforts have been made to produce methods for the analysis of this data that impute missing values, address sampling issues and quantify and correct for noise. In spite of such efforts, no consensus on best practices has been established and all current approaches vary substantially based on the available data and empirical tests. The k-Nearest Neighbor Graph (kNN-G) is often used to infer the identities of, and relationships between, cells and is the basis of many widely used dimensionality-reduction and projection methods. The kNN-G has also been the basis for imputation methods using, e.g., neighbor averaging and graph diffusion. However, due to the lack of an agreed-upon optimal objective function for choosing hyperparameters, these methods tend to oversmooth data, thereby resulting in a loss of information with regard to cell identity and the specific gene-to-gene patterns underlying regulatory mechanisms. In this paper, we investigate the tuning of kNN- and diffusion-based denoising methods with a novel non-stochastic method for optimally preserving biologically relevant informative variance in single-cell data. The framework, Denoising Expression data with a Weighted Affinity Kernel and Self-Supervision (DEWÄKSS), uses a self-supervised technique to tune its parameters. We demonstrate that denoising with optimal parameters selected by our objective function (i) is robust to preprocessing methods using data from established benchmarks, (ii) disentangles cellular identity and maintains robust clusters over dimension-reduction methods, (iii) maintains variance along several expression dimensions, unlike previous heuristic-based methods that tend to oversmooth data variance, and (iv) rarely involves diffusion but rather uses a fixed weighted kNN graph for denoising. Together, these findings provide a new understanding of kNN- and diffusion-based denoising methods and serve as a foundation for future research. Code and example data for DEWÄKSS is available at https://gitlab.com/Xparx/dewakss/-/tree/Tjarnberg2020branch.

We review the development of generative modeling techniques in machine learning for the purpose of reconstructing real, noisy, many-qubit quantum states. Motivated by its interpretability and utility, we discuss in detail the theory of the restricted Boltzmann machine. We demonstrate its practical use for state reconstruction, starting from a classical thermal distribution of Ising spins, then moving systematically through increasingly complex pure and mixed quantum states. Intended for use on experimental noisy intermediate-scale quantum (NISQ) devices, we review recent efforts in reconstruction of a cold atom wavefunction. Finally, we discuss the outlook for future experimental state reconstruction using machine learning, in the NISQ era and beyond.

CMB-HD is a proposed ultra-deep (0.5 uk-arcmin), high-resolution (15 arcseconds) millimeter-wave survey over half the sky that would answer many outstanding questions in both fundamental physics of the Universe and astrophysics. This survey would be delivered in 7.5 years of observing 20,000 square degrees, using two new 30-meter-class off-axis cross-Dragone telescopes to be located at Cerro Toco in the Atacama Desert. Each telescope would field 800,000 detectors (200,000 pixels), for a total of 1.6 million detectors.