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Background: Despite recent advances in cellular cryo-electron tomography (CET), developing automated tools for macromolecule identification in submolecular resolution remains challenging due to the lack of annotated data and high structural complexities. To date, the extent of the deep learning methods constructed for this problem is limited to conventional Convolutional Neural Networks (CNNs). Identifying macromolecules of different types and sizes is a tedious and time-consuming task. In this paper, we employ a capsule-based architecture to automate the task of macro- molecule identification, that we refer to as 3D-UCaps. In particular, the architecture is composed of three components: feature extractor, capsule encoder, and CNN decoder. The feature extractor converts voxel intensities of input sub-tomograms to activities of local features. The encoder is a 3D Capsule Network (CapsNet) that takes local features to generate a low-dimensional representation of the input. Then, a 3D CNN decoder reconstructs the sub-tomograms from the given representation by upsampling.
Results: We performed binary and multi-class localization and identification tasks on synthetic and experimental data. We observed that the 3D-UNet and the 3D-UCaps had an F1−score mostly above 60% and 70%, respectively, on the test data. In both network architectures, we observed degradation of at least 40% in the F1-score when identifying very small particles (PDB entry 3GL1) compared to a large particle (PDB entry 4D8Q). In the multi-class identification task of experimental data, 3D-UCaps had an F1-score of 91% on the test data in contrast to 64% of the 3D-UNet. The better F1-score of 3D-UCaps compared to 3D-UNet is obtained by a higher precision score. We speculate this to be due to the capsule network employed in the encoder. To study the effect of the CapsNet-based encoder architecture further, we performed an ablation study and perceived that the F1-score is boosted as network depth is increased which
is in contrast to the previously reported results for the 3D-UNet. To present a reproducible work, source code, trained models, data as well as visualization results are made publicly available.
Conclusion: Quantitative and qualitative results show that 3D-UCaps successfully perform various downstream tasks including identification and localization of macro- molecules and can at least compete with CNN architectures for this task. Given that the capsule layers extract both the existence probability and the orientation of the molecules, this architecture has the potential to lead to representations of the data that are better interpretable than those of 3D-UNet.
Structural properties of molecules are of primary concern in many fields. This report provides a comprehensive overview on techniques that have been developed in the fields of molecular graphics and visualization with a focus on applications in structural biology. The field heavily relies on computerized geometric and visual representations of three-dimensional, complex, large and time-varying molecular structures. The report presents a taxonomy that demonstrates which areas of molecular visualization have already been extensively investigated and where the field is currently heading. It discusses visualizations for molecular structures, strategies for efficient display regarding image quality and frame rate, covers different aspects of level of detail and reviews visualizations illustrating the dynamic aspects of molecular simulation data. The survey concludes with an outlook on promising and important research topics to foster further success in the development of tools that help to reveal molecular secrets.
In this report we review and structure the branch of molecular visualization that is concerned with the visual analysis of cavities in macromolecular protein structures. First the necessary background, the domain terminology, and the goals of analytical reasoning are introduced. Based on a comprehensive collection of relevant research works, we present a novel classification for cavity detection approaches and structure them into four distinct classes: grid-based, Voronoi-based, surface-based, and probe-based methods. The subclasses are then formed by their combinations. We match these approaches with corresponding visualization technologies starting with direct 3D visualization, followed with non-spatial visualization techniques that for example abstract the interactions between structures into a relational graph, straighten the cavity of interest to see its profile in one view, or aggregate the time sequence into a single contour plot. We also discuss the current state of methods for the visual analysis of cavities in dynamic data such as molecular dynamics simulations. Finally, we give an overview of the most common tools that are actively developed and used in the structural biology and biochemistry research. Our report is concluded by an outlook on future challenges in the field.
The historical importance of ancient manuscripts is unique since they provide information about the heritage of ancient cultures. Often texts are hidden in rolled or folded documents. Due to recent impro- vements in sensitivity and resolution, spectacular disclosures of rolled hidden texts were possible by X-ray tomography. However, revealing text on folded manuscripts is even more challenging. Manual unfolding is often too risky in view of the fragile condition of fragments, as it can lead to the total loss of the document. X-ray tomography allows for virtual unfolding and enables non-destructive access to hid- den texts. We have recently demonstrated the procedure and tested unfolding algorithms on a mockup sample. Here, we present results on unfolding ancient papyrus packages from the papyrus collection of the Musée du Louvre, among them objects folded along approximately orthogonal folding lines. In one of the packages, the first identification of a word was achieved, the Coptic word for “Lord”.
Two new species of cheilostome Bryozoa are described from continental-slope habitats off Mauritania, including canyon and coldwater-coral (mound) habitats. Internal structures of both species were visualised and quantified using micro-computed tomographic (micro-CT) methods. Cellaria bafouri n. sp. is characterised by the arrangement of zooids in alternating longitudinal rows, a smooth cryptocyst, and the presence of an ooecial plate with denticles. Smittina imragueni n. sp. exhibits many similarities with Smittina cervicornis (Pallas, 1766), but differs especially in the shape and orientation of the suboral avicularium. Observations on Smittina imragueni and material labelled as Smittina cervicornis suggest that the latter represents a species group, members of which have not yet been discriminated, possibly because of high intracolony variation and marked astogenetic changes in surface morphology. Both new species are known only from the habitats where they were collected, probably reflecting the paucity of bryozoan sampling from this geographic area and depth range. Both species are able to tolerate low oxygen concentration, which is assumed to be compensated by the high nutrient supply off Mauritania. The application of micro-CT for the semiautomatic quantification of zooidal skeletal characters was successfully tested. We were able to automatically distinguish individual zooidal cavities and acquire corresponding morphological datasets. Comparing the obtained results with conventional SEM measurements allowed ascertaining the reliability of this new method. The employment of micro-CT allows the observation and quantification of previously un- seen characters that can be used in describing and differentiating species that were previously indistinguishable. Further- more, this method might help elucidate processes of colony growth and the function of individual zooids during this process.
During cell division, kinetochore microtubules (KMTs) provide a physical linkage between the chromosomes and the rest of the spindle. KMTs in mammalian cells are organized into bundles, so-called kinetochore-fibers (k-fibers), but the ultrastructure of these fibers is currently not well characterized. Here we show by large-scale electron tomography that each k-fiber in HeLa cells in metaphase is composed of approximately nine KMTs, only half of which reach the spindle pole. Our comprehensive reconstructions allowed us to analyze the three-dimensional (3D) morphology of k-fibers and their surrounding MTs in detail. We found that k-fibers exhibit remarkable variation in circumference and KMT density along their length, with the pole-proximal side showing a broadening. Extending our structural analysis then to other MTs in the spindle, we further observed that the association of KMTs with non-KMTs predominantly occurs in the spindle pole regions. Our 3D reconstructions have implications for KMT growth and k-fiber self-organization models as covered in a parallel publication applying complementary live-cell imaging in combination with biophysical modeling (Conway et al., 2022). Finally, we also introduce a new visualization tool allowing an interactive display of our 3D spindle data that will serve as a resource for further structural studies on mitosis in human cells.
Thin, curved structures occur in many volumetric datasets. Their analysis using classical volume rendering is difficult because parts of such structures can bend away or hide behind occluding elements. This problem cannot be fully compensated by effective navigation alone, because structure-adapted navigation in the volume is cumbersome and only parts of the structure are visible in each view.
We solve this problem by rendering a spatially transformed view into the volume so that an unobscured visualization of the entire curved structure is obtained. As a result, simple and intuitive navigation becomes possible. The domain of the spatial transform is defined by a triangle mesh that is topologically equivalent to an open disc and that approximates the structure of interest. The rendering is based on ray-casting in which the rays traverse the original curved sub-volume. In order to carve out volumes of varying thickness, the lengths of the rays as well as the position of the mesh vertices can be easily modified in a view-controlled manner by interactive painting. We describe a prototypical implementation and demonstrate the interactive visual inspection of complex structures from digital humanities, biology, medicine, and materials science. Displaying the structure as a whole enables simple inspection of interesting substructures in their original spatial context.
Overall, we show that transformed views utilizing ray-casting-based volume rendering supported by guiding surface meshes and supplemented by local, interactive modifications of ray lengths and vertex positions, represent a simple but versatile approach to effectively visualize thin, curved structures in volumetric data.
Recent advances in connectomics research enable the acquisition of increasing amounts of data about the connectivity patterns of neurons. How can we use this wealth of data to efficiently derive and test hypotheses about the principles underlying these patterns? A common approach is to simulate neural networks using a hypothesized wiring rule in a generative model and to compare the resulting synthetic data with empirical data. However, most wiring rules have at least some free parameters and identifying parameters that reproduce empirical data can be challenging as it often requires manual parameter tuning. Here, we propose to use simulation-based Bayesian inference (SBI) to address this challenge. Rather than optimizing a single rule to fit the empirical data, SBI considers many parametrizations of a wiring rule and performs Bayesian inference to identify the parameters that are compatible with the data. It uses simulated data from multiple candidate wiring rules and relies on machine learning methods to estimate a probability distribution (the `posterior distribution over rule parameters conditioned on the data') that characterizes all data-compatible rules. We demonstrate how to apply SBI in connectomics by inferring the parameters of wiring rules in an in silico model of the rat barrel cortex, given in vivo connectivity measurements. SBI identifies a wide range of wiring rule parameters that reproduce the measurements. We show how access to the posterior distribution over all data-compatible parameters allows us to analyze their relationship, revealing biologically plausible parameter interactions and enabling experimentally testable predictions. We further show how SBI can be applied to wiring rules at different spatial scales to quantitatively rule out invalid wiring hypotheses. Our approach is applicable to a wide range of generative models used in connectomics, providing a quantitative and efficient way to constrain model parameters with empirical connectivity data.