Grit and Academic Resilience During the Covid-19 Pandemic (preprint)

Grit, a non-cognitive skill that indicates perseverance and passion for long-term goals, has been shown to predict academic achievement. This paper provides evidence that grit also predicts student outcomes during the challenging period of the Covid-19 pandemic. We use a unique dataset from a digital learning platform in the United Arab Emirates to construct a behavioral measure of grit. We find that controlling for baseline ability, students who were grittier according to this measure before the pandemic, register lower declines in math and science scores during the coronavirus period. Using machine learning, behavioral data in the platform prior to the pandemic can explain 77% of the variance in academic resilience. A survey measure of grit of the same students, on the other hand, does not have significant predictive power over performance changes. Our findings have implications for interventions on non-cognitive skills, as well as how data from digital learning platforms can be used to predict student behavior and outcomes, which we expect will be increasingly relevant as AI-based learning technologies become more common.

Transcriptome-wide Cas13 guide RNA design for model organisms and viral RNA pathogens

In brief To accelerate CRISPR-based targeting of RNA, Guo et al. present a resource with optimized RfxCas13d guide RNAs (gRNAs) to target messenger RNAs and noncoding RNAs in six common model organisms and four RNA virus families. An accompanying open access web-based platform and design tool enable optimal gRNA design for any RNA target.

Large libraries of single-chain trimer peptide-MHCs enable rapid antigen-specific CD8+ T cell discovery and analysis (preprint)

CD8 + cytotoxic T cell responses against viral infection represent a major element of the adaptive immune response. We describe the development of a peptide antigen – major histompatibility complex (pMHC) library representing the full SARS-CoV-2 viral proteome, and comprised of 634 pMHC multimers representing the A*02.01, A*24.02, and B*07.02 HLA alleles, as well as specific antigens associated with the cytomegalovirus (CMV). These libraries were used to capture non-expanded CD8 + T cells from blood samples collected from 64 infected individuals, and then analyzed using single cell RNA-seq. The discovery and characterization of antigen-specific CD8+ T cell clonotypes typically involves the labor-intensive synthesis and construction of peptide-MHC tetramers. We adapted single-chain trimer (SCT) technologies into a high throughput platform for pMHC library generation, showing that hundreds can be rapidly prepared across multiple Class I HLA alleles. We used this platform to explore the impact of peptide and SCT template mutations on protein expression yield, thermal stability, and functionality. SCT libraries were an efficient tool for identifying T cells recognizing commonly reported viral epitopes. We then constructed SCT libraries designed to capture SARS-CoV-2 specific CD8+ T cells from COVID-19 participants and healthy donors. The immunogenicity of these epitopes was validated by functional assays of T cells with cloned TCRs captured using SCT libraries. These technologies should enable the rapid analyses of peptide-based T cell responses across several contexts, including autoimmunity, cancer, or infectious disease.

Multiomic Immunophenotyping of COVID-19 Patients Reveals Early Infection Trajectories (preprint)

Host immune responses play central roles in controlling SARS-CoV2 infection, yet remain incompletely characterized and understood. Here, we present a comprehensive immune response map spanning 454 proteins and 847 metabolites in plasma integrated with single-cell multi-omic assays of 221,748 PBMCs in which whole transcriptome, 192 surface proteins, and T and B cell receptor sequence were analyzed within the context of clinical measures from 50 COVID19 patient samples. Our study reveals novel cellular subpopulations, such as proliferative exhausted CD8+ and CD4+ T cells, and cytotoxic CD4+ T cells, that may be features of severe COVID-19 infection. We condensed over 1 million immune features into a single immune response axis that independently aligns with many clinical features and is also strongly associated with disease severity. Our study represents an important resource towards understanding the heterogeneous immune responses of COVID-19 patients and may provide key information for informing therapeutic development.

A Multi-Phenotype System to Discover Therapies for Age-Related Dysregulation of the Immune Response to Viral Infections (preprint)

ABSTRACT Age-related immune dysregulation contributes to increased susceptibility to infection and disease in older adults. We combined high-throughput laboratory automation with machine learning to build a multi-phenotype aging profile that models the dysfunctional immune response to viral infection in older adults. From a single well, our multi-phenotype aging profile can capture changes in cell composition, physical cell-to-cell interaction, organelle structure, cytokines, and other hidden complexities contributing to age-related dysfunction. This system allows for rapid identification of new potential compounds to rejuvenate older adults’ immune response. We used our technology to screen thousands of compounds for their ability to make old immune cells respond to viral infection like young immune cells. We observed beneficial effects of multiple compounds, of which two of the most promising were disulfiram and triptonide. Our findings indicate that disulfiram could be considered as a treatment for severe coronavirus disease 2019 and other inflammatory infections.

Multiomic Immunophenotyping of COVID-19 Patients Reveals Early Infection Trajectories (preprint)

Host immune responses play central roles in controlling SARS-CoV2 infection, yet remain incompletely characterized and understood. Here, we present a comprehensive immune response map spanning 454 proteins and 847 metabolites in plasma integrated with single-cell multi-omic assays of PBMCs in which whole transcriptome, 192 surface proteins, and T and B cell receptor sequence were co-analyzed within the context of clinical measures from 50 COVID19 patient samples. Our study reveals novel cellular subpopulations, such as proliferative exhausted CD8+ and CD4+ T cells, and cytotoxic CD4+ T cells, that may be features of severe COVID-19 infection. We condensed over 1 million immune features into a single immune response axis that independently aligns with many clinical features and is also strongly associated with disease severity. Our study represents an important resource towards understanding the heterogeneous immune responses of COVID-19 patients and may provide key information for informing therapeutic development.

Statistical Network Analysis: A Review with Applications to the Coronavirus Disease 2019 Pandemic

As the coronavirus disease 2019 outbreak evolves, statistical network analysis is playing an essential role in informing policy decisions. Therefore, researchers who are new to such studies need to understand the techniques available to them. As a field, statistical network analysis aims to develop methods that account for the complex dependencies found in network data. Over the last few decades, the area has rapidly accumulated methods, including techniques for network modelling and simulating the spread of infectious disease. This article reviews these network modelling techniques and their applications to the coronavirus disease 2019 pandemic.