Managing the life cycle of a portfolio of open data resources at the SIB Swiss Institute of Bioinformatics.

Data resources are essential for the long-term preservation of scientific data and the reproducibility of science. The SIB Swiss Institute of Bioinformatics provides the life science community with a portfolio of openly accessible, high-quality databases and software platforms, which vary from expert-curated knowledgebases, such as UniProtKB/Swiss-Prot (part of the UniProt consortium) and STRING, to online platforms such as SWISS-MODEL and SwissDrugDesign. SIB's mission is to ensure that these resources are available in the long term, as long as their return on investment and their scientific impact are high. To this end, SIB provides its resources, in addition to stable financial support, with a range of high-quality, innovative services that are, to our knowledge, unique in the field. Through this first-class management framework with central services, such as user-centric consulting activities, legal support, open-science guidance, knowledge sharing and training efforts, SIB supports the promotion of excellence in resource development and operation. This review presents the ecosystem of data resources at SIB; the process used for the identification, evaluation and development of resources; and the support activities that SIB provides. A set of indicators has been put in place to select the resources and establish quality standards, reflecting their multifaceted nature and complexity. Through this paper, the reader will discover how SIB's leading tools and databases are fostered by the institute, leading them to be best-in-class resources able to tackle the burning matters that society faces from disease outbreaks and cancer to biodiversity and open science.

Expasy, the Swiss Bioinformatics Resource Portal, as designed by its users.

The SIB Swiss Institute of Bioinformatics (https://www.sib.swiss) creates, maintains and disseminates a portfolio of reliable and state-of-the-art bioinformatics services and resources for the storage, analysis and interpretation of biological data. Through Expasy (https://www.expasy.org), the Swiss Bioinformatics Resource Portal, the scientific community worldwide, freely accesses more than 160 SIB resources supporting a wide range of life science and biomedical research areas. In 2020, Expasy was redesigned through a user-centric approach, known as User-Centred Design (UCD), whose aim is to create user interfaces that are easy-to-use, efficient and targeting the intended community. This approach, widely used in other fields such as marketing, e-commerce, and design of mobile applications, is still scarcely explored in bioinformatics. In total, around 50 people were actively involved, including internal stakeholders and end-users. In addition to an optimised interface that meets users' needs and expectations, the new version of Expasy provides an up-to-date and accurate description of high-quality resources based on a standardised ontology, allowing to connect functionally-related resources.

Cell shape dynamics reveal balance of elasticity and contractility in peripheral arcs.

The mechanical interaction between adherent cells and their substrate relies on the formation of adhesion sites and on the stabilization of contractile acto-myosin bundles, or stress fibers. The shape of the cell and the orientation of these fibers can be controlled by adhesive patterning. On nonadhesive gaps, fibroblasts develop thick peripheral stress fibers, with a concave curvature. The radius of curvature of these arcs results from the balance of the line tension in the arc and of the surface tension in the cell bulk. However, the nature of these forces, and in particular the contribution of myosin-dependent contractility, is not clear. To get insight into the force balance, we inhibit myosin activity and simultaneously monitor the dynamics of peripheral arc radii and traction forces. We use these measurements to estimate line and surface tension. We found that myosin inhibition led to a decrease in the traction forces and an increase in arc radius, indicating that both line tension and surface tension dropped, but the line tension decreased to a lesser extent than surface tension. These results suggest that myosin-independent force contributes to tension in the peripheral arcs. We propose a simple physical model in which the peripheral arc line tension is due to the combination of myosin II contractility and a passive elastic component, while surface tension is largely due to active contractility. Numerical solutions of this model reproduce well the experimental data and allow estimation of the contributions of elasticity and contractility to the arc line tension.

Funding knowledgebases: Towards a sustainable funding model for the UniProt use case.

Millions of life scientists across the world rely on bioinformatics data resources for their research projects. Data resources can be very expensive, especially those with a high added value as the expert-curated knowledgebases. Despite the increasing need for such highly accurate and reliable sources of scientific information, most of them do not have secured funding over the near future and often depend on short-term grants that are much shorter than their planning horizon. Additionally, they are often evaluated as research projects rather than as research infrastructure components. In this work, twelve funding models for data resources are described and applied on the case study of the Universal Protein Resource (UniProt), a key resource for protein sequences and functional information knowledge. We show that most of the models present inconsistencies with open access or equity policies, and that while some models do not allow to cover the total costs, they could potentially be used as a complementary income source. We propose the Infrastructure Model as a sustainable and equitable model for all core data resources in the life sciences. With this model, funding agencies would set aside a fixed percentage of their research grant volumes, which would subsequently be redistributed to core data resources according to well-defined selection criteria. This model, compatible with the principles of open science, is in agreement with several international initiatives such as the Human Frontiers Science Program Organisation (HFSPO) and the OECD Global Science Forum (GSF) project. Here, we have estimated that less than 1% of the total amount dedicated to research grants in the life sciences would be sufficient to cover the costs of the core data resources worldwide, including both knowledgebases and deposition databases.

Microsurgery-aided in-situ force probing reveals extensibility and viscoelastic properties of individual stress fibers.

Actin-myosin filament bundles (stress fibers) are critical for tension generation and cell shape, but their mechanical properties are difficult to access. Here we propose a novel approach to probe individual peripheral stress fibers in living cells through a microsurgically generated opening in the cytoplasm. By applying large deformations with a soft cantilever we were able to fully characterize the mechanical response of the fibers and evaluate their tension, extensibility, elastic and viscous properties.

Ultra-soft cantilevers and 3-D micro-patterned substrates for contractile bundle tension measurement in living cells.

Actin-myosin microfilament bundles or stress-fibers are the principal tension-generating structures in the cell. Their mechanical properties are critical for cell shape, motion, and interaction with other cells and extracellular matrix, but were so far difficult to access in a living cell. Here we propose a micro-fabricated two-component setup for direct tension measurement on a peripheral bundle within an intact cell. We used 3-D substrates made of silicon elastomer to elevate the cell making the filament bundle at its border accessible from the side, and employed an ultra-soft (spring constant 0.78 nN µm(-1)) epoxy-based cantilever for mechanical probing. With this setup we were able for the first time to measure the tension in peripheral actin bundles in living primary fibroblasts spread on a rigid substrate.

Contact angle at the leading edge controls cell protrusion rate.

Plasma membrane tension and the pressure generated by actin polymerization are two antagonistic forces believed to define the protrusion rate at the leading edge of migrating cells [1-5]. Quantitatively, resistance to actin protrusion is a product of membrane tension and mean local curvature (Laplace's law); thus, it depends on the local geometry of the membrane interface. However, the role of the geometry of the leading edge in protrusion control has not been yet investigated. Here, we manipulate both the cell shape and substrate topography in the model system of persistently migrating fish epidermal keratocytes. We find that the protrusion rate does not correlate with membrane tension, but, instead, strongly correlates with cell roundness, and that the leading edge of the cell exhibits pinning on substrate ridges-a phenomenon characteristic of spreading of liquid drops. These results indicate that the leading edge could be considered a triple interface between the substrate, membrane, and extracellular medium and that the contact angle between the membrane and the substrate determines the load on actin polymerization and, therefore, the protrusion rate. Our findings thus illuminate a novel relationship between the 3D shape of the cell and its dynamics, which may have implications for cell migration in 3D environments.

Dynamic measurement of the height and volume of migrating cells by a novel fluorescence microscopy technique.

We propose a new technique to measure the volume of adherent migrating cells. The method is based on a negative staining where a fluorescent, non-cell-permeant dye is added to the extracellular medium. The specimen is observed with a conventional fluorescence microscope in a chamber of uniform height. Given that the fluorescence signal depends on the thickness of the emitting layer, the objects excluding the fluorescent dye (i.e., cells) appear dark, and the decrease of the fluorescent signal with respect to the background is expected to give information about the height and the volume of the object. Using a glass microfabricated pattern with steps of defined heights, we show that the drop in fluorescence intensity is indeed proportional to the height of the step and obtain calibration curves relating fluorescence intensity to height. The technique, termed the fluorescence displacement method, is further validated by comparing our measurements with the ones obtained by atomic force microscopy (AFM). We apply our method to measure the real-time volume dynamics of migrating fish epidermal keratocytes subjected to osmotic stress. The fluorescence displacement technique allows fast and precise monitoring of cell height and volume, thus providing a valuable tool for characterizing the three-dimensional behaviour of migrating cells.