CellVis2: a conference on visualizing the molecular cell.

In January 2024, a targeted conference, 'CellVis2', was held at Scripps Research in La Jolla, USA, the second in a series designed to explore the promise, practices, roadblocks, and prospects of creating, visualizing, sharing, and communicating physical representations of entire biological cells at scales down to the atom.

Adenita: interactive 3D modelling and visualization of DNA nanostructures.

DNA nanotechnology is a rapidly advancing field, which increasingly attracts interest in many different disciplines, such as medicine, biotechnology, physics and biocomputing. The increasing complexity of novel applications requires significant computational support for the design, modelling and analysis of DNA nanostructures. However, current in silico design tools have not been developed in view of these new applications and their requirements. Here, we present Adenita, a novel software tool for the modelling of DNA nanostructures in a user-friendly environment. A data model supporting different DNA nanostructure concepts (multilayer DNA origami, wireframe DNA origami, DNA tiles etc.) has been developed allowing the creation of new and the import of existing DNA nanostructures. In addition, the nanostructures can be modified and analysed on-the-fly using an intuitive toolset. The possibility to combine and re-use existing nanostructures as building blocks for the creation of new superstructures, the integration of alternative molecules (e.g. proteins, aptamers) during the design process, and the export option for oxDNA simulations are outstanding features of Adenita, which spearheads a new generation of DNA nanostructure modelling software. We showcase Adenita by re-using a large nanorod to create a new nanostructure through user interactions that employ different editors to modify the original nanorod.

Metabopolis: scalable network layout for biological pathway diagrams in urban map style.

BACKGROUND: Biological pathways represent chains of molecular interactions in biological systems that jointly form complex dynamic networks. The network structure changes from the significance of biological experiments and layout algorithms often sacrifice low-level details to maintain high-level information, which complicates the entire image to large biochemical systems such as human metabolic pathways. RESULTS: Our work is inspired by concepts from urban planning since we create a visual hierarchy of biological pathways, which is analogous to city blocks and grid-like road networks in an urban area. We automatize the manual drawing process of biologists by first partitioning the map domain into multiple sub-blocks, and then building the corresponding pathways by routing edges schematically, to maintain the global and local context simultaneously. Our system incorporates constrained floor-planning and network-flow algorithms to optimize the layout of sub-blocks and to distribute the edge density along the map domain. We have developed the approach in close collaboration with domain experts and present their feedback on the pathway diagrams based on selected use cases. CONCLUSIONS: We present a new approach for computing biological pathway maps that untangles visual clutter by decomposing large networks into semantic sub-networks and bundling long edges to create space for presenting relationships systematically.

COZOID: contact zone identifier for visual analysis of protein-protein interactions.

BACKGROUND: Studying the patterns of protein-protein interactions (PPIs) is fundamental for understanding the structure and function of protein complexes. The exploration of the vast space of possible mutual configurations of interacting proteins and their contact zones is very time consuming and requires the proteomic expert knowledge. RESULTS: In this paper, we propose a novel tool containing a set of visual abstraction techniques for the guided exploration of PPI configuration space. It helps proteomic experts to select the most relevant configurations and explore their contact zones at different levels of detail. The system integrates a set of methods that follow and support the workflow of proteomics experts. The first visual abstraction method, the Matrix view, is based on customized interactive heat maps and provides the users with an overview of all possible residue-residue contacts in all PPI configurations and their interactive filtering. In this step, the user can traverse all input PPI configurations and obtain an overview of their interacting amino acids. Then, the models containing a particular pair of interacting amino acids can be selectively picked and traversed. Detailed information on the individual amino acids in the contact zones and their properties is presented in the Contact-Zone list-view. The list-view provides a comparative tool to rank the best models based on the similarity of their contacts to the template-structure contacts. All these techniques are interactively linked with other proposed methods, the Exploded view and the Open-Book view, which represent individual configurations in three-dimensional space. These representations solve the high overlap problem associated with many configurations. Using these views, the structural alignment of the best models can also be visually confirmed. CONCLUSIONS: We developed a system for the exploration of large sets of protein-protein complexes in a fast and intuitive way. The usefulness of our system has been tested and verified on several docking structures covering the three major types of PPIs, including coiled-coil, pocket-string, and surface-surface interactions. Our case studies prove that our tool helps to analyse and filter protein-protein complexes in a fraction of the time compared to using previously available techniques.

Generalized box-plot for root growth ensembles.

BACKGROUND: In the field of root biology there has been a remarkable progress in root phenotyping, which is the efficient acquisition and quantitative description of root morphology. What is currently missing are means to efficiently explore, exchange and present the massive amount of acquired, and often time dependent root phenotypes. RESULTS: In this work, we present visual summaries of root ensembles by aggregating root images with identical genetic characteristics. We use the generalized box plot concept with a new formulation of data depth. In addition to spatial distributions, we created a visual representation to encode temporal distributions associated with the development of root individuals. CONCLUSIONS: The new formulation of data depth allows for much faster implementation close to interactive frame rates. This allows us to present the statistics from bootstrapping that characterize the root sample set quality. As a positive side effect of the new data-depth formulation we are able to define the geometric median for the curve ensemble, which was well received by the domain experts.

Interactively illustrating polymerization using three-level model fusion.

BACKGROUND: Research in cell biology is steadily contributing new knowledge about many aspects of physiological processes, both with respect to the involved molecular structures as well as their related function. Illustrations of the spatio-temporal development of such processes are not only used in biomedical education, but also can serve scientists as an additional platform for in-silico experiments. RESULTS: In this paper, we contribute a new, three-level modeling approach to illustrate physiological processes from the class of polymerization at different time scales. We integrate physical and empirical modeling, according to which approach best suits the different involved levels of detail, and we additionally enable a form of interactive steering, while the process is illustrated. We demonstrate the suitability of our approach in the context of several polymerization processes and report from a first evaluation with domain experts. CONCLUSION: We conclude that our approach provides a new, hybrid modeling approach for illustrating the process of emergence in physiology, embedded in a densely filled environment. Our approach of a complementary fusion of three systems combines the strong points from the different modeling approaches and is capable to bridge different spatial and temporal scales.

Dr. KID: Direct Remeshing and K-Set Isometric Decomposition for Scalable Physicalization of Organic Shapes.

Dr. KID is an algorithm that uses isometric decomposition for the physicalization of potato-shaped organic models in a puzzle fashion. The algorithm begins with creating a simple, regular triangular surface mesh of organic shapes, followed by iterative K-means clustering and remeshing. For clustering, we need similarity between triangles (segments) which is defined as a distance function. The distance function maps each triangle's shape to a single point in the virtual 3D space. Thus, the distance between the triangles indicates their degree of dissimilarity. K-means clustering uses this distance and sorts segments into k classes. After this, remeshing is applied to minimize the distance between triangles within the same cluster by making their shapes identical. Clustering and remeshing are repeated until the distance between triangles in the same cluster reaches an acceptable threshold. We adopt a curvature-aware strategy to determine the surface thickness and finalize puzzle pieces for 3D printing. Identical hinges and holes are created for assembling the puzzle components. For smoother outcomes, we use triangle subdivision along with curvature-aware clustering, generating curved triangular patches for 3D printing. Our algorithm was evaluated using various models, and the 3D-printed results were analyzed. Findings indicate that our algorithm performs reliably on target organic shapes with minimal loss of input geometry.

Nanomatrix: Scalable Construction of Crowded Biological Environments.

We present a novel method for the interactive construction and rendering of extremely large molecular scenes, capable of representing multiple biological cells in atomistic detail. Our method is tailored for scenes, which are procedurally constructed, based on a given set of building rules. Rendering of large scenes normally requires the entire scene available in-core, or alternatively, it requires out-of-core management to load data into the memory hierarchy as a part of the rendering loop. Instead of out-of-core memory management, we propose to procedurally generate the scene on-demand on the fly. The key idea is a positional- and view-dependent procedural scene-construction strategy, where only a fraction of the atomistic scene around the camera is available in the GPU memory at any given time. The atomistic detail is populated into a uniform-space partitioning using a grid that covers the entire scene. Most of the grid cells are not filled with geometry, only those are populated that are potentially seen by the camera. The atomistic detail is populated in a compute shader and its representation is connected with acceleration data structures for hardware ray-tracing of modern GPUs. Objects which are far away, where atomistic detail is not perceivable from a given viewpoint, are represented by a triangle mesh mapped with a seamless texture, generated from the rendering of geometry from atomistic detail. The algorithm consists of two pipelines, the construction-compute pipeline, and the rendering pipeline, which work together to render molecular scenes at an atomistic resolution far beyond the limit of the GPU memory containing trillions of atoms. We demonstrate our technique on multiple models of SARS-CoV-2 and the red blood cell.

Visual cavity analysis in molecular simulations.

Molecular surfaces provide a useful mean for analyzing interactions between biomolecules; such as identification and characterization of ligand binding sites to a host macromolecule. We present a novel technique, which extracts potential binding sites, represented by cavities, and characterize them by 3D graphs and by amino acids. The binding sites are extracted using an implicit function sampling and graph algorithms. We propose an advanced cavity exploration technique based on the graph parameters and associated amino acids. Additionally, we interactively visualize the graphs in the context of the molecular surface. We apply our method to the analysis of MD simulations of Proteinase 3, where we verify the previously described cavities and suggest a new potential cavity to be studied.

Molecumentary: Adaptable Narrated Documentaries Using Molecular Visualization.

We present a method for producing documentary-style content using real-time scientific visualization. We introduce molecumentaries, i.e., molecular documentaries featuring structural models from molecular biology, created through adaptable methods instead of the rigid traditional production pipeline. Our work is motivated by the rapid evolution of scientific visualization and it potential in science dissemination. Without some form of explanation or guidance, however, novices and lay-persons often find it difficult to gain insights from the visualization itself. We integrate such knowledge using the verbal channel and provide it along an engaging visual presentation. To realize the synthesis of a molecumentary, we provide technical solutions along two major production steps: (1) preparing a story structure and (2) turning the story into a concrete narrative. In the first step, we compile information about the model from heterogeneous sources into a story graph. We combine local knowledge with external sources to complete the story graph and enrich the final result. In the second step, we synthesize a narrative, i.e., story elements presented in sequence, using the story graph. We then traverse the story graph and generate a virtual tour, using automated camera and visualization transitions. We turn texts written by domain experts into verbal representations using text-to-speech functionality and provide them as a commentary. Using the described framework, we synthesize fly-throughs with descriptions: automatic ones that mimic a manually authored documentary or semi-automatic ones which guide the documentary narrative solely through curated textual input.

Nanotilus: Generator of Immersive Guided-Tours in Crowded 3D Environments.

Immersive virtual reality environments are gaining popularity for studying and exploring crowded three-dimensional structures. When reaching very high structural densities, the natural depiction of the scene produces impenetrable clutter and requires visibility and occlusion management strategies for exploration and orientation. Strategies developed to address the crowdedness in desktop applications, however, inhibit the feeling of immersion. They result in nonimmersive, desktop-style outside-in viewing in virtual reality. This article proposes Nanotilus-a new visibility and guidance approach for very dense environments that generates an endoscopic inside-out experience instead of outside-in viewing, preserving the immersive aspect of virtual reality. The approach consists of two novel, tightly coupled mechanisms that control scene sparsification simultaneously with camera path planning. The sparsification strategy is localized around the camera and is realized as a multi-scale, multi-shell, variety-preserving technique. When Nanotilus dives into the structures to capture internal details residing on multiple scales, it guides the camera using depth-based path planning. In addition to sparsification and path planning, we complete the tour generation with an animation controller, textual annotation, and text-to-visualization conversion. We demonstrate the generated guided tours on mesoscopic biological models - SARS-CoV-2 and HIV. We evaluate the Nanotilus experience with a baseline outside-in sparsification and navigational technique in a formal user study with 29 participants. While users can maintain a better overview using the outside-in sparsification, the study confirms our hypothesis that Nanotilus leads to stronger engagement and immersion.

Finding Nano-Ötzi: Cryo-Electron Tomography Visualization Guided by Learned Segmentation.

Cryo-electron tomography (cryo-ET) is a new 3D imaging technique with unprecedented potential for resolving submicron structural details. Existing volume visualization methods, however, are not able to reveal details of interest due to low signal-to-noise ratio. In order to design more powerful transfer functions, we propose leveraging soft segmentation as an explicit component of visualization for noisy volumes. Our technical realization is based on semi-supervised learning, where we combine the advantages of two segmentation algorithms. First, the weak segmentation algorithm provides good results for propagating sparse user-provided labels to other voxels in the same volume and is used to generate dense pseudo-labels. Second, the powerful deep-learning-based segmentation algorithm learns from these pseudo-labels to generalize the segmentation to other unseen volumes, a task that the weak segmentation algorithm fails at completely. The proposed volume visualization uses deep-learning-based segmentation as a component for segmentation-aware transfer function design. Appropriate ramp parameters can be suggested automatically through frequency distribution analysis. Furthermore, our visualization uses gradient-free ambient occlusion shading to further suppress the visual presence of noise, and to give structural detail the desired prominence. The cryo-ET data studied in our technical experiments are based on the highest-quality tilted series of intact SARS-CoV-2 virions. Our technique shows the high impact in target sciences for visual data analysis of very noisy volumes that cannot be visualized with existing techniques.

SpyDirect: A Novel Biofunctionalization Method for High Stability and Longevity of Electronic Biosensors.

Electronic immunosensors are indispensable tools for diagnostics, particularly in scenarios demanding immediate results. Conventionally, these sensors rely on the chemical immobilization of antibodies onto electrodes. However, globular proteins tend to adsorb and unfold on these surfaces. Therefore, self-assembled monolayers (SAMs) of thiolated alkyl molecules are commonly used for indirect gold-antibody coupling. Here, a limitation associated with SAMs is revealed, wherein they curtail the longevity of protein sensors, particularly when integrated into the state-of-the-art transducer of organic bioelectronics-the organic electrochemical transistor. The SpyDirect method is introduced, generating an ultrahigh-density array of oriented nanobody receptors stably linked to the gold electrode without any SAMs. It is accomplished by directly coupling cysteine-terminated and orientation-optimized spyTag peptides, onto which nanobody-spyCatcher fusion proteins are autocatalytically attached, yielding a dense and uniform biorecognition layer. The structure-guided design optimizes the conformation and packing of flexibly tethered nanobodies. This biolayer enhances shelf-life and reduces background noise in various complex media. SpyDirect functionalization is faster and easier than SAM-based methods and does not necessitate organic solvents, rendering the sensors eco-friendly, accessible, and amenable to scalability. SpyDirect represents a broadly applicable biofunctionalization method for enhancing the cost-effectiveness, sustainability, and longevity of electronic biosensors, all without compromising sensitivity.

Multi-Level Area Balancing of Clustered Graphs.

We present a multi-level area balancing technique for laying out clustered graphs to facilitate a comprehensive understanding of the complex relationships that exist in various fields, such as life sciences and sociology. Clustered graphs are often used to model relationships that are accompanied by attribute-based grouping information. Such information is essential for robust data analysis, such as for the study of biological taxonomies or educational backgrounds. Hence, the ability to smartly arrange textual labels and packing graphs within a certain screen space is therefore desired to successfully convey the attribute data . Here we propose to hierarchically partition the input screen space using Voronoi tessellations in multiple levels of detail. In our method, the position of textual labels is guided by the blending of constrained forces and the forces derived from centroidal Voronoi cells. The proposed algorithm considers three main factors: (1) area balancing, (2) schematized space partitioning, and (3) hairball management. We primarily focus on area balancing, which aims to allocate a uniform area for each textual label in the diagram. We achieve this by first untangling a general graph to a clustered graph through textual label duplication, and then coupling with spanning-tree-like visual integration. We illustrate the feasibility of our approach with examples and then evaluate our method by comparing it with well-known conventional approaches and collecting feedback from domain experts.

Data-Driven Colormap Adjustment for Exploring Spatial Variations in Scalar Fields.

Colormapping is an effective and popular visualization technique for analyzing patterns in scalar fields. Scientists usually adjust a default colormap to show hidden patterns by shifting the colors in a trial-and-error process. To improve efficiency, efforts have been made to automate the colormap adjustment process based on data properties (e.g., statistical data value or histogram distribution). However, as the data properties have no direct correlation to the spatial variations, previous methods may be insufficient to reveal the dynamic range of spatial variations hidden in the data. To address the above issues, we conduct a pilot analysis with domain experts and summarize three requirements for the colormap adjustment process. Based on the requirements, we formulate colormap adjustment as an objective function, composed of a boundary term and a fidelity term, which is flexible enough to support interactive functionalities. We compare our approach with alternative methods under a quantitative measure and a qualitative user study (25 participants), based on a set of data with broad distribution diversity. We further evaluate our approach via three case studies with six domain experts. Our method is not necessarily more optimal than alternative methods of revealing patterns, but rather is an additional color adjustment option for exploring data with a dynamic range of spatial variations.

Multiscale Unfolding: Illustratively Visualizing the Whole Genome at a Glance.

We present Multiscale Unfolding, an interactive technique for illustratively visualizing multiple hierarchical scales of DNA in a single view, showing the genome at different scales and demonstrating how one scale spatially folds into the next. The DNA's extremely long sequential structure-arranged differently on several distinct scale levels-is often lost in traditional 3D depictions, mainly due to its multiple levels of dense spatial packing and the resulting occlusion. Furthermore, interactive exploration of this complex structure is cumbersome, requiring visibility management like cut-aways. In contrast to existing temporally controlled multiscale data exploration, we allow viewers to always see and interact with any of the involved scales. For this purpose we separate the depiction into constant-scale and scale transition zones. Constant-scale zones maintain a single-scale representation, while still linearly unfolding the DNA. Inspired by illustration, scale transition zones connect adjacent constant-scale zones via level unfolding, scaling, and transparency. We thus represent the spatial structure of the whole DNA macro-molecule, maintain its local organizational characteristics, linearize its higher-level organization, and use spatially controlled, understandable interpolation between neighboring scales. We also contribute interaction techniques that provide viewers with a coarse-to-fine control for navigating within our all-scales-in-one-view representations and visual aids to illustrate the size differences. Overall, Multiscale Unfolding allows viewers to grasp the DNA's structural composition from chromosomes to the atoms, with increasing levels of "unfoldedness," and can be applied in data-driven illustration and communication.

GPU Accelerated 3D Tomographic Reconstruction and Visualization from Noisy Electron Microscopy Tilt-Series.

We present a novel framework for 3D tomographic reconstruction and visualization of tomograms from noisy electron microscopy tilt-series. Our technique takes as an input aligned tilt-series from cryogenic electron microscopy and creates denoised 3D tomograms using a proximal jointly-optimized approach that iteratively performs reconstruction and denoising, relieving the users of the need to select appropriate denoising algorithms in the pre-reconstruction or post-reconstruction steps. The whole process is accelerated by exploiting parallelism on modern GPUs, and the results can be visualized immediately after the reconstruction using volume rendering tools incorporated in the framework. We show that our technique can be used with multiple combinations of reconstruction algorithms and regularizers, thanks to the flexibility provided by proximal algorithms. Additionally, the reconstruction framework is open-source and can be easily extended with additional reconstruction and denoising methods. Furthermore, our approach enables visualization of reconstruction error throughout the iterative process within the reconstructed tomogram and on projection planes of the input tilt-series. We evaluate our approach in comparison with state-of-the-art approaches and additionally show how our error visualization can be used for reconstruction evaluation.

Homomorphic-Encrypted Volume Rendering.

Computationally demanding tasks are typically calculated in dedicated data centers, and real-time visualizations also follow this trend. Some rendering tasks, however, require the highest level of confidentiality so that no other party, besides the owner, can read or see the sensitive data. Here we present a direct volume rendering approach that performs volume rendering directly on encrypted volume data by using the homomorphic Paillier encryption algorithm. This approach ensures that the volume data and rendered image are uninterpretable to the rendering server. Our volume rendering pipeline introduces novel approaches for encrypted-data compositing, interpolation, and opacity modulation, as well as simple transfer function design, where each of these routines maintains the highest level of privacy. We present performance and memory overhead analysis that is associated with our privacy-preserving scheme. Our approach is open and secure by design, as opposed to secure through obscurity. Owners of the data only have to keep their secure key confidential to guarantee the privacy of their volume data and the rendered images. Our work is, to our knowledge, the first privacy-preserving remote volume-rendering approach that does not require that any server involved be trustworthy; even in cases when the server is compromised, no sensitive data will be leaked to a foreign party.

HyperLabels: Browsing of Dense and Hierarchical Molecular 3D Models.

We present a method for the browsing of hierarchical 3D models in which we combine the typical navigation of hierarchical structures in a 2D environment-using clicks on nodes, links, or icons-with a 3D spatial data visualization. Our approach is motivated by large molecular models, for which the traditional single-scale navigational metaphors are not suitable. Multi-scale phenomena, e. g., in astronomy or geography, are complex to navigate due to their large data spaces and multi-level organization. Models from structural biology are in addition also densely crowded in space and scale. Cutaways are needed to show individual model subparts. The camera has to support exploration on the level of a whole virus, as well as on the level of a small molecule. We address these challenges by employing HyperLabels: active labels that-in addition to their annotational role-also support user interaction. Clicks on HyperLabels select the next structure to be explored. Then, we adjust the visualization to showcase the inner composition of the selected subpart and enable further exploration. Finally, we use a breadcrumbs panel for orientation and as a mechanism to traverse upwards in the model hierarchy. We demonstrate our concept of hierarchical 3D model browsing using two exemplary models from meso-scale biology.

Modeling in the Time of COVID-19: Statistical and Rule-based Mesoscale Models.

We present a new technique for the rapid modeling and construction of scientifically accurate mesoscale biological models. The resulting 3D models are based on a few 2D microscopy scans and the latest knowledge available about the biological entity, represented as a set of geometric relationships. Our new visual-programming technique is based on statistical and rule-based modeling approaches that are rapid to author, fast to construct, and easy to revise. From a few 2D microscopy scans, we determine the statistical properties of various structural aspects, such as the outer membrane shape, the spatial properties, and the distribution characteristics of the macromolecular elements on the membrane. This information is utilized in the construction of the 3D model. Once all the imaging evidence is incorporated into the model, additional information can be incorporated by interactively defining the rules that spatially characterize the rest of the biological entity, such as mutual interactions among macromolecules, and their distances and orientations relative to other structures. These rules are defined through an intuitive 3D interactive visualization as a visual-programming feedback loop. We demonstrate the applicability of our approach on a use case of the modeling procedure of the SARS-CoV-2 virion ultrastructure. This atomistic model, which we present here, can steer biological research to new promising directions in our efforts to fight the spread of the virus.