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Single-cell genomics has enabled the study of biological processes at an unprecedented scale and resolution. These studies were enabled by innovative data generation technologies coupled with emerging computational tools specialized for single-cell data. As single-cell technologies have become more prevalent, so has the development of new analysis tools, which has resulted in over 1,700 published algorithms1 (as of February 2024). Thus, there is an increasing need to continually evaluate which algorithm performs best in which context to inform best practices2,3 that evolve with the field. In many fields of quantitative science, public competitions and benchmarks address this need by evaluating state-of-the-art methods against known criteria, following the concept of a common task framework4. Here, we present Open Problems, a living, extensive, community-guided platform including 12 current single-cell tasks that we envisage raising standards for the selection, evaluation and development of methods in single-cell analysis. 

Abstract The introduction of more effective and selective mRNA delivery systems is required for the advancement of many emerging biomedical technologies including the development of prophylactic and therapeutic vaccines, immunotherapies for cancer and strategies for genome editing. While polymers and oligomers have served as promising mRNA delivery systems, their efficacy in hard-to-transfect cells such as primary T lymphocytes is often limited as is their cell and organ tropism. To address these problems, considerable attention has been placed on structural screening of various lipid and cation components of mRNA delivery systems. Here, we disclose a class of charge-altering releasable transporters (CARTs) that differ from previous CARTs based on their beta-amido carbonate backbone (bAC) and side chain spacing. These bAC-CARTs exhibit enhanced mRNA transfection in primary T lymphocytes in vitro and enhanced protein expression in vivo with highly selective spleen tropism, supporting their broader therapeutic use as effective polyanionic delivery systems. 

Deep Neural Networks (DNNs) need to be both efficient and robust for practical uses. Quantization and structure simplification are promising ways to adapt DNNs to mobile devices, and adversarial training is one of the most successful methods to train robust DNNs. In this work, we aim to realize both advantages by applying a convergent relaxation quantization algorithm, i.e., Binary-Relax (BR), to an adversarially trained robust model, i.e. the ResNets Ensemble via Feynman-Kac Formalism (EnResNet). We discover that high-precision quantization, such as ternary (tnn) or 4-bit, produces sparse DNNs. However, this sparsity is unstructured under adversarial training. To solve the problems that adversarial training jeopardizes DNNs’ accuracy on clean images and break the structure of sparsity, we design a trade-off loss function that helps DNNs preserve natural accuracy and improve channel sparsity. With our newly designed trade-off loss function, we achieve both goals with no reduction of resistance under weak attacks and very minor reduction of resistance under strong adversarial attacks. Together with our model and algorithm selections and loss function design, we provide an integrated approach to produce robust DNNs with high efficiency and accuracy. Furthermore, we provide a missing benchmark on robustness of quantized models. 

We developed an integrated recurrent neural network and nonlinear regression spatio-temporal model for vector-borne disease evolution. We take into account climate data and seasonality as external factors that correlate with disease transmitting insects (e.g. flies), also spill-over infections from neighboring regions surrounding a region of interest. The climate data is encoded to the model through a quadratic embedding scheme motivated by recommendation systems. The neighboring regions’ influence is modeled by a long short-term memory neural network. The integrated model is trained by stochastic gradient descent and tested on leishmaniasis data in Sri Lanka from 2013-2018 where infection outbreaks occurred. Our model out-performed ARIMA models across a number of regions with high infections, and an associated ablation study renders support to our modeling hypothesis and ideas. 

As the COVID-19 pandemic evolves, reliable prediction plays an important role in policymaking. The classical infectious disease model SEIR (susceptible-exposed-infectious-recovered) is a compact yet simplistic temporal model. The data-driven machine learning models such as RNN (recurrent neural networks) can suffer in case of limited time series data such as COVID-19. In this paper, we combine SEIR and RNN on a graph structure to develop a hybrid spatiotemporal model to achieve both accuracy and efficiency in training and forecasting. We introduce two features on the graph structure: node feature (local temporal infection trend) and edge feature (geographic neighbor effect). For node feature, we derive a discrete recursion (called I-equation) from SEIR so that gradient descend method applies readily to its optimization. For edge feature, we design an RNN model to capture the neighboring effect and regularize the landscape of loss function so that local minima are effective and robust for prediction. The resulting hybrid model (called IeRNN) improves the prediction accuracy on state-level COVID-19 new case data from the US, out-performing standard temporal models (RNN, SEIR, and ARIMA) in 1-day and 7-day ahead forecasting. Our model accommodates various degrees of reopening and provides potential outcomes for policymakers. 

The outbreaks of Coronavirus Disease 2019 (COVID-19) have impacted the world significantly. Modeling the trend of infection and realtime forecasting of cases can help decision making and control of the disease spread. However, data-driven methods such as recurrent neural networks (RNN) can perform poorly due to limited daily samples in time. In this work, we develop an integrated spatiotemporal model based on the epidemic differential equations (SIR) and RNN. The former after simplification and discretization is a compact model of temporal infection trend of a region while the latter models the effect of nearest neighboring regions. The latter captures latent spatial information. We trained and tested our model on COVID-19 data in Italy, and show that it out-performs existing temporal models (fully connected NN, SIR, ARIMA) in 1-day, 3-day, and 1-week ahead forecasting especially in the regime of limited training data. 

The outbreaks of Coronavirus Disease 2019 (COVID-19) have impacted the world significantly. Modeling the trend of infection and real-time forecasting of cases can help decision making and control of the disease spread. However, data-driven methods such as recurrent neural networks (RNN) can perform poorly due to limited daily samples in time. In this work, we develop an integrated spatiotemporal model based on the epidemic differential equations (SIR) and RNN. The former after simplification and discretization is a compact model of temporal infection trend of a region while the latter models the effect of nearest neighboring regions. The latter captures latent spatial information. We trained and tested our model on COVID-19 data in Italy, and show that it out-performs existing temporal models (fully connected NN, SIR, ARIMA) in 1-day, 3-day, and 1-week ahead forecasting especially in the regime of limited training data. 

We study epidemic forecasting on real-world health data by a graph-structured recurrent neural network (GSRNN). We achieve state-of-the-art forecasting accuracy on the benchmark CDC dataset. To improve model efficiency, we sparsify the network weights via a transformed-1 penalty without losing prediction accuracy in numerical experiments.