Recent advances in single-cell technologies have enabled high-throughput molecular profiling of cells across modalities and locations. Single-cell transcriptomics data can now be complemented by chromatin accessibility, surface protein expression, adaptive immune receptor repertoire profiling and spatial information. The increasing availability of single-cell data across modalities has motivated the development of novel computational methods to help analysts derive biological insights. As the field grows, it becomes increasingly difficult to navigate the vast landscape of tools and analysis steps. Here, we summarize independent benchmarking studies of unimodal and multimodal single-cell analysis across modalities to suggest comprehensive best-practice workflows for the most common analysis steps. Where independent benchmarks are not available, we review and contrast popular methods. Our article serves as an entry point for novices in the field of single-cell (multi-)omic analysis and guides advanced users to the most recent best practices.

During transmission of malaria‐causing parasites from mosquitoes to mammals, Plasmodium sporozoites migrate rapidly in the skin to search for a blood vessel. The high migratory speed and narrow passages taken by the parasites suggest considerable strain on the sporozoites to maintain their shape. Here, we show that the membrane‐associated protein, concavin, is important for the maintenance of the Plasmodium sporozoite shape inside salivary glands of mosquitoes and during migration in the skin. Concavin‐GFP localizes at the cytoplasmic periphery and concavin(−) sporozoites progressively round up upon entry of salivary glands. Rounded concavin(−) sporozoites fail to pass through the narrow salivary ducts and are rarely ejected by mosquitoes, while normally shaped concavin(−) sporozoites are transmitted. Strikingly, motile concavin(−) sporozoites disintegrate while migrating through the skin leading to parasite arrest or death and decreased transmission efficiency. Collectively, we suggest that concavin contributes to cell shape maintenance by riveting the plasma membrane to the subtending inner membrane complex. Interfering with cell shape maintenance pathways might hence provide a new strategy to prevent a malaria infection.

ABSTRACT During transmission of malaria-causing parasites from mosquitoes to mammals, Plasmodium sporozoites migrate rapidly in the skin to search for a blood vessel. The high migratory speed and narrow passages taken by the parasites suggest considerable strain on the sporozoites to maintain their shape. Here we report on a newly identified protein, concavin, that is important for maintenance of the sporozoite shape inside salivary glands of mosquitoes and during migration in the skin. Concavin-GFP localized at the cytoplasmic periphery of sporozoites and concavin(−) sporozoites progressively rounded up upon entry of salivary glands. These rounded concavin(−) sporozoites failed to pass through the narrow salivary ducts and were hence rarely ejected by mosquitoes. However, normally shaped concavin(−) sporozoites could be transmitted and migrated in the skin or skin like environments. Strikingly, motile concavin(−) sporozoites could disintegrate while migrating through narrow strictures in the skin leading to parasite arrest or death and decreased transmission efficiency. We suggest that concavin contributes to cell shape maintenance by riveting the plasma membrane to the subtending inner membrane complex. SIGNIFICANCE Malaria parasites are transmitted by Anopheles mosquitoes and rely on rapid migration for establishing an infection. We identified and characterized a protein, named concavin, essential for maintaining the shape of the sporozoite. Concavin is a membrane associated protein facing the cytoplasm suggesting that it contributes to riveting the plasma membrane to the subtending inner membrane complex. Sporozoites lacking concavin can round up in the salivary glands, are less well transmitted to mice and disintegrate while migrating in the skin. Hence, concavin is essential for parasite transmission and infectivity. Highlights - A membrane associated protein is essential for Plasmodium shape maintenance -Migrating parasites disintegrate in the absence of concavin -First protein essential for cellular integrity of Plasmodium sporozoites -Thickened and deformed Plasmodium sporozoites fail to be transmitted by mosquitoes

The last decade has witnessed a technological arms race to encode the molecular states of cells into DNA libraries, turning DNA sequencers into scalable single-cell microscopes. Single-cell measurement of chromatin accessibility (DNA), gene expression (RNA), and proteins has revealed rich cellular diversity across tissues, organisms, and disease states. However, single-cell data poses a unique set of challenges. A dataset may comprise millions of cells with tens of thousands of sparse features. Identifying biologically relevant signals from the background sources of technical noise requires innovation in predictive and representational learning. Furthermore, unlike in machine vision or natural language processing, biological ground truth is limited. Here we leverage recent advances in multi-modal single-cell technologies which, by simultaneously measuring two layers of cellular processing in each cell, provide ground truth analogous to language translation. We define three key tasks to predict one modality from another and learn integrated representations of cellular state. We also generate a novel dataset of the human bone marrow specifically designed for benchmarking studies. The dataset and tasks are accessible through an open-source framework that facilitates centralized evaluation of community-submitted methods.

Biology has become a data-intensive science. Recent technological advances in single-cell genomics have enabled the measurement of multiple facets of cellular state, producing datasets with millions of single-cell observations. While these data hold great promise for understanding molecular mechanisms in health and disease, analysis challenges arising from sparsity, technical and biological variability, and high dimensionality of the data hinder the derivation of such mechanistic insights. To promote the innovation of algorithms for analysis of multimodal single-cell data, we organized a competition at NeurIPS 2021 applying the Common Task Framework to multimodal single-cell data integration. For this competition we generated the first multimodal benchmarking dataset for single-cell biology and defined three tasks in this domain: prediction of missing modalities, aligning modalities, and learning a joint representation across modalities. We further specified evaluation metrics and developed a cloud-based algorithm evaluation pipeline. Using this setup, 280 competitors submitted over 2600 proposed solutions within a 3 month period, showcasing substantial innovation especially in the modality alignment task. Here, we present the results, describe trends of well performing approaches, and discuss challenges associated with running the competition.

ZusammenfassungMenschen in Ländern des globalen Südens sind einerseits von einem eigenen Spektrum an Krankheiten betroffen, andererseits stellen die Gesundheitskosten im Kontext der vorherrschenden Armut eine erhebliche Belastung dar. In diesen Ländern spielen außerdem auch nicht-übertragbare Krankheiten eine immer größere Rolle. Medikamentenforschung in Deutschland und die Preisgestaltung der Endprodukte rücken daher in einen globalen Kontext. Universitäten haben diesbezüglich aus 2 Gründen eine besondere Verantwortung. Erstens tragen sie zu einem nicht unerheblichen Teil, insbesondere durch geleistete Grundlagenforschung, zur Entwicklung neuer Medikamente bei. Zweitens ist die Universität eine gemeinnützige Institution und hat als solche die Verantwortung, neu erworbenes Wissen an die Öffentlichkeit zurückzugeben. Von der öffentlichen Gemeinschaft mitfinanzierte Innovationen sollten deshalb so verwertet werden, dass finanziell benachteiligte Individuen und Bevölkerungen weltweit Zugang dazu haben. Als ersten konkreten Schritt in diese Richtung fordern wir die Einführung einer global verantwortlichen Lizenzpolitik an deutschen Universitäten. Verschiedene Mechanismen unter dem Sammelbegriff „Equitable Licensing“ bieten eine Grundlage zur Realisierung dieses ambitionierten Vorhabens, wie es bereits von den Universitäten Tübingen, Münster und Freiburg praktiziert wird.

People in countries of the global south are affected by a unique spectrum of diseases, while costs for health care are a huge burden in the context of poverty. Furthermore, non-communicable diseases increasingly play a role in these countries. The management of translational research, potential clinical applications and marketing of new drugs in Germany is thus getting more and more important for global health. Regarding this, universities have a particular responsibility for two reasons. First, through basic research, they contribute significantly to the development of new medicines. Second, the university is a public institution and has thus the responsibility to return the gained knowledge to the public. Marketing of publicly funded innovations should provide benefits to patients in wealthy and poor countries alike. As a first step towards this goal, we demand the introduction of a globally responsible licensing policy at German universities. Different mechanisms which have been described in the German speaking areas such as "Equitable Licensing" provide a basis for the realization of this ambitious aim and have been introduced successfully at the universities of Muenster, Tuebingen and Freiburg.