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This Perspective reviews tools developed over the past five years in the macromolecular modeling, docking and design software Rosetta.

The sexually transmitted human parasite Trichomonas vaginalis belongs to a clade of host-switching trichomonads that parasitize mammals, birds, livestock, and pets. Here the authors describe a chromosome-scale genome for T. vaginalis and assemblies of other bird and mammal-infecting species, identifying gene functions implicated in the spillover of trichomonads from birds to humans.

A group of microbiome researchers discuss some of the challenges in developing a new generation of microbiome therapies.

Analysis of snRNA genes in individuals with rare disorders identifies de novo and recurrent variants in RNU5B-1 and RNU5A-1, in addition to previously unreported cases with pathogenic or likely pathogenic variants in RNU4-2.

Computational methods are becoming an increasingly important part of biological research. Using the Rosetta framework as an example, the authors demonstrate how community-driven development of computational methods can be done in a reproducible and reliable fashion.

Generating new sensible molecular structures is a key problem in computer aided drug discovery. Here the authors propose a graph-based molecular generative model that outperforms previously proposed graph-based generative models of molecules and performs comparably to several SMILES-based models.

OpenFold is a trainable open-source implementation of AlphaFold2. It is fast and memory efficient, and the code and training data are available under a permissive license.

Autism spectrum disorder (ASD) is characterized by heterogeneous phenotypes. Disruption of the gut–brain axis (GBA) has been implicated in ASD although with limited reproducibility across studies. In this study, the authors propose a framework to leverage multi-omic datasets and investigate how the GBA influences ASD.

Protein sequence and structural similarities in large databases are rapidly identified using machine learning.

Here, using longitudinal survey and Twitter data, the authors examine the relationship between exposure to Russian Internet Research Agency activities on Twitter and voting behavior and attitudes in the 2016 US election.

Advances in protein structure prediction have led to a significant influx of protein structure data. Here the authors exploit this data to offer an unbiased overview of complex sequence-structure-function relationships in the protein universe. This work opens up new uses for 3D structure data repositories in meta-omics and other fields of biology.

The ability of the DEAD-box RNA helicase DDX5 to interact with master transcription factor RORγt is dependent on binding of the long noncoding RNA Rmrp; the DDX5–RORγt complex coordinates transcription of selective T_H17 genes and is required for the pathogenicity of T_H17 cells.

The transcriptional programs and chromatin accessibility changes that cause two related interneuronal subtypes to diverge from common developmental origins and acquire specialized properties are elucidated.

Genetic variants in ionotropic glutamate receptors have been implicated in neurodevelopmental disorders. Here, the authors report heterozygous de novo mutations in the GRIA2 gene in 28 individuals with intellectual disability and neurodevelopmental abnormalities associated with reduced Ca²⁺ transport and AMPAR currents.”

Most currently available statistical tools for the analysis of ATAC-seq data were repurposed from tools developed for other functional genomics data (e.g. ChIP-seq). Here, Gabitto et al develop ChromA, a Bayesian statistical approach for the analysis of both bulk and single-cell ATAC-seq data.

mmvec, a neural-network-based algorithm, uses paired multiomics data (microbial sequence counts and metabolite abundances) to compute the conditional probability of observing a metabolite in the presence of a specific microorganism.

Computational methods for the de novo design of conformationally restricted peptides produce exceptionally stable short peptides stabilized by backbone cyclization and/or internal disulfide bonds that are promising starting points for a new generation of peptide-based drugs.

The rapid increase in the number of proteins in sequence databases and the diversity of their functions challenge computational approaches for automated function prediction. Here, the authors introduce DeepFRI, a Graph Convolutional Network for predicting protein functions by leveraging sequence features extracted from a protein language model and protein structures.

In multiple myeloma, a 4;14 translocation induces overexpression of histone methyltransferase NSD2, resulting in expansion of H3K36me2 and shrinkage of H3K27me3 domains. Here the authors find that CTCF, H3K27ac and gene expression changes cluster within a subset of insulated domains implicating 3D chromosome organization as a key factor in the NSD2-mediated phenotype.

High or multiple doses of macrolide antibiotics, when given early in life, can perturb the metabolic and immunological development of lab mice. Here, Ruiz et al. show that even a single macrolide course, given early in life, leads to long-lasting changes in the gut microbiota and immune system of mice.

Small molecules and peptide inhibitors have their benefits and faults when it comes to inhibiting protein-protein interactions. Here, the authors designed a peptoid-peptide hybrid that inhibited β-catenin/TCF interactions, leading to inhibition of Wnt signalling in models of prostate cancer.

Screening of cells transduced with a lentivirus library harboring nucleosome-free regions of mammalian genomes identifies cis elements that regulate transcription.

Tr1 cells have potent regulatory effects in vitro and in vivo. Kuchroo and colleagues comprehensively describe the epigenetic, transcriptional and gene regulatory landscape that is essential for Tr1 cell differentiation.

The expression of CD4, a critical co-receptor providing T cell help in adaptive immunity, is finely tuned during development. Here the authors show that two enhancer elements, E4p and the newly-defined E4m, coordinate the expression and heritable demethylation of Cd4 in thymocytes but are dispensable for its sustained expression in peripheral T cells.

The HPN-DREAM community challenge assessed the ability of computational methods to infer causal molecular networks, focusing specifically on the task of inferring causal protein signaling networks in cancer cell lines.

The transcription factor c-MAF is required for the generation of Helicobacter-specific regulatory T cells that selectively restrain pro-inflammatory T_H17 cells; the absence of c-MAF in mouse regulatory T cells results in pathobiont-dependent inflammatory bowel disease.

A dense, spatially barcoded bead array captures RNA from histological tissue sections for spatially resolved gene expression analysis.

This Perspective lays out the impetus and goals of the Cellular Senescence Network established to comprehensively identify and characterize senescent cells (SnCs) across tissues and lifespan, providing a publicly available SnC atlas.

This analysis comprehensively compares methods for gene regulatory network inference submitted through the DREAM5 challenge. It demonstrates that integration of predictions from multiple methods shows the most robust performance across data sets.