Simultaneous profiling of multiomic modalities within a single cell is a grand challenge for single-cell biology. While there have been impressive technical innovations demonstrating feasibility—for example, generating paired measurements of single-cell transcriptome (single-cell RNA sequencing [scRNA-seq]) and chromatin accessibility (single-cell assay for transposase-accessible chromatin using sequencing [scATAC-seq])—widespread application of joint profiling is challenging due to its experimental complexity, noise, and cost. Here, we introduce BABEL, a deep learning method that translates between the transcriptome and chromatin profiles of a single cell. Leveraging an interoperable neural network model, BABEL can predict single-cell expression directly from a cell’s scATAC-seq and vice versa after training on relevant data. This makes it possible to computationally synthesize paired multiomic measurements when only one modality is experimentally available. Across several paired single-cell ATAC and gene expression datasets in human and mouse, we validate that BABEL accurately translates between these modalities for individual cells. BABEL also generalizes well to cell types within new biological contexts not seen during training. Starting from scATAC-seq of patient-derived basal cell carcinoma (BCC), BABEL generated single-cell expression that enabled fine-grained classification of complex cell states, despite having never seen BCC data. These predictions are comparable to analyses of experimental BCC scRNA-seq data for diverse cell types related to BABEL’s training data. We further show that BABEL can incorporate additional single-cell data modalities, such as protein epitope profiling, thus enabling translation across chromatin, RNA, and protein. BABEL offers a powerful approach for data exploration and hypothesis generation.

Decades of work have demonstrated that messenger RNAs (mRNAs) are localized and translated within neuronal dendrites and axons to provide proteins for remodeling and maintaining growth cones or synapses. It remains unknown, however, whether specific forms of plasticity differentially regulate the dynamics and translation of individual mRNA species. To address this, we targeted three individual synaptically localized mRNAs, CamkIIa, β-actin, Psd95, and used molecular beacons to track endogenous mRNA movements. We used reporters and CRISPR/Cas9 gene editing to track mRNA translation in cultured neurons. We found alterations in mRNA dynamic properties occurred during two forms of synaptic plasticity, long-term potentiation (cLTP) and depression (mGluR-LTD). Changes in mRNA dynamics following either form of plasticity resulted in an enrichment of mRNA in the vicinity of dendritic spines. Both the reporters and tagging of endogenous proteins revealed the transcript-specific stimulation of protein synthesis following cLTP or mGluR-LTD. As such, the plasticity-induced enrichment of mRNA near synapses could be uncoupled from its translational status. The enrichment of mRNA in the proximity of spines allows for localized signaling pathways to decode plasticity milieus and stimulate a specific translational profile, resulting in a customized remodeling of the synaptic proteome.

CD20 is a B cell-specific membrane protein and represents an attractive target for therapeutic antibodies. Despite widespread usage of anti-CD20 antibodies for B cell depletion therapies, the biological function of their target remains unclear. Here, we demonstrate that CD20 controls the nanoscale organization of receptors on the surface of resting B lymphocytes. CRISPR/Cas9-mediated ablation of CD20 in resting B cells resulted in relocalization and interaction of the IgM-class B cell antigen receptor with the coreceptor CD19. This receptor rearrangement led to a transient activation of B cells, accompanied by the internalization of many B cell surface marker proteins. Reexpression of CD20 restored the expression of the B cell surface proteins and the resting state of Ramos B cells. Similarly, treatment of Ramos or naive human B cells with the anti-CD20 antibody rituximab induced nanoscale receptor rearrangements and transient B cell activation in vitro and in vivo. A departure from the resting B cell state followed by the loss of B cell identity of CD20-deficient Ramos B cells was accompanied by a PAX5 to BLIMP-1 transcriptional switch, metabolic reprogramming toward oxidative phosphorylation, and a shift toward plasma cell development. Thus, anti-CD20 engagement or the loss of CD20 disrupts membrane organization, profoundly altering the fate of human B cells.

Humans reached the Mariana Islands in the western Pacific by ∼3,500 y ago, contemporaneous with or even earlier than the initial peopling of Polynesia. They crossed more than 2,000 km of open ocean to get there, whereas voyages of similar length did not occur anywhere else until more than 2,000 y later. Yet, the settlement of Polynesia has received far more attention than the settlement of the Marianas. There is uncertainty over both the origin of the first colonizers of the Marianas (with different lines of evidence suggesting variously the Philippines, Indonesia, New Guinea, or the Bismarck Archipelago) as well as what, if any, relationship they might have had with the first colonizers of Polynesia. To address these questions, we obtained ancient DNA data from two skeletons from the Ritidian Beach Cave Site in northern Guam, dating to ∼2,200 y ago. Analyses of complete mitochondrial DNA genome sequences and genome-wide SNP data strongly support ancestry from the Philippines, in agreement with some interpretations of the linguistic and archaeological evidence, but in contradiction to results based on computer simulations of sea voyaging. We also find a close link between the ancient Guam skeletons and early Lapita individuals from Vanuatu and Tonga, suggesting that the Marianas and Polynesia were colonized from the same source population, and raising the possibility that the Marianas played a role in the eventual settlement of Polynesia.

Steamboat Geyser in Yellowstone National Park’s Norris Geyser Basin began a prolific sequence of eruptions in March 2018 after 34 y of sporadic activity. We analyze a wide range of datasets to explore triggering mechanisms for Steamboat’s reactivation and controls on eruption intervals and height. Prior to Steamboat’s renewed activity, Norris Geyser Basin experienced uplift, a slight increase in radiant temperature, and increased regional seismicity, which may indicate that magmatic processes promoted reactivation. However, because the geothermal reservoir temperature did not change, no other dormant geysers became active, and previous periods with greater seismic moment release did not reawaken Steamboat, the reason for reactivation remains ambiguous. Eruption intervals since 2018 (3.16 to 35.45 d) modulate seasonally, with shorter intervals in the summer. Abnormally long intervals coincide with weakening of a shallow seismic source in the geyser basin’s hydrothermal system. We find no relation between interval and erupted volume, implying unsteady heat and mass discharge. Finally, using data from geysers worldwide, we find a correlation between eruption height and inferred depth to the shallow reservoir supplying water to eruptions. Steamboat is taller because water is stored deeper there than at other geysers, and, hence, more energy is available to power the eruptions.

The molecular basis for the severity and rapid spread of the COVID-19 disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely unknown. ORF8 is a rapidly evolving accessory protein that has been proposed to interfere with immune responses. The crystal structure of SARS-CoV-2 ORF8 was determined at 2.04-Å resolution by X-ray crystallography. The structure reveals a ∼60-residue core similar to SARS-CoV-2 ORF7a, with the addition of two dimerization interfaces unique to SARS-CoV-2 ORF8. A covalent disulfide-linked dimer is formed through an N-terminal sequence specific to SARS-CoV-2, while a separate noncovalent interface is formed by another SARS-CoV-2−specific sequence, ₇₃YIDI₇₆. Together, the presence of these interfaces shows how SARS-CoV-2 ORF8 can form unique large-scale assemblies not possible for SARS-CoV, potentially mediating unique immune suppression and evasion activities.

Mechanical tension along the length of axons, dendrites, and glial processes has been proposed as a major contributor to morphogenesis throughout the nervous system [D. C. Van Essen, Nature 385, 313–318 (1997)]. Tension-based morphogenesis (TBM) is a conceptually simple and general hypothesis based on physical forces that help shape all living things. Moreover, if each axon and dendrite strive to shorten while preserving connectivity, aggregate wiring length would remain low. TBM can explain key aspects of how the cerebral and cerebellar cortices remain thin, expand in surface area, and acquire their distinctive folds. This article reviews progress since 1997 relevant to TBM and other candidate morphogenetic mechanisms. At a cellular level, studies of diverse cell types in vitro and in vivo demonstrate that tension plays a major role in many developmental events. At a tissue level, I propose a differential expansion sandwich plus (DES+) revision to the original TBM model for cerebral cortical expansion and folding. It invokes tangential tension and “sulcal zipping” forces along the outer cortical margin as well as tension in the white matter core, together competing against radially biased tension in the cortical gray matter. Evidence for and against the DES+ model is discussed, and experiments are proposed to address key tenets of the DES+ model. For cerebellar cortex, a cerebellar multilayer sandwich (CMS) model is proposed that can account for many distinctive features, including its unique, accordion-like folding in the adult, and experiments are proposed to address its specific tenets.