The adaptation of the lungs to air breathing at birth requires the fine orchestration of different processes to control lung morphogenesis and progenitor cell differentiation. However, there is ...little understanding of the role that epigenetic modifiers play in the control of lung development. We found that the histone methyl transferase Ezh2 plays a critical role in lung lineage specification and survival at birth. We performed a genome-wide transcriptome study combined with a genome-wide analysis of the distribution of H3K27 tri-methylation marks to interrogate the role of Ezh2 in lung epithelial cells. Lung cells isolated from Ezh2-deficient and control mice at embryonic day E16.5 were sorted into epithelial and mesenchymal populations based on EpCAM expression. This enabled us to dissect the transcriptional and epigenetic changes induced by the loss of Ezh2 specifically in the lung epithelium. Here we provide a detailed description of the analysis of the RNA-seq and ChIP-seq data, including quality control, read mapping, differential expression and differential binding analyses, as well as visualisation methods used to present the data. These data can be accessed from the Gene Expression Omnibus database (super-series accession number GSE57393).
The collapse of a protostellar envelope results in the growth of a protostar and the development of a protoplanetary disk, playing a critical role during the early stages of star formation. ...Characterizing the gas infall in the envelope constrains the dynamical models of star formation. We present unambiguous signatures of infall, probed by optically thick molecular lines, toward an isolated embedded protostar, BHR 71 IRS1. The three-dimensional radiative transfer calculations indicate that a slowly rotating infalling envelope model following the "inside-out" collapse reproduces the observations of both HCO + J = 4 → 3 and CS J = 7 → 6 lines, as well as the low-velocity emission of the HCN J = 4 → 3 line. The envelope has a model-derived age of 12,000 3000 yr after the initial collapse. The envelope model underestimates the high-velocity emission at the HCN J = 4 → 3 and H13CN J = 4 → 3 lines, where outflows or a Keplerian disk may contribute. The ALMA observations serendipitously discover the emission of complex organic molecules (COMs) concentrated within a radius of 100 au, indicating that BHR 71 IRS1 harbors a hot corino. Eight species of COMs are identified, including CH3OH and CH3OCHO, along with H2CS, SO2 and HCN v2 = 1. The emission of methyl formate and 13C-methanol shows a clear velocity gradient within a radius of 50 au, hinting at an unresolved Keplerian rotating disk.
Dendritic cells (DCs) are can be broadly divided into conventional (cDC) and plasmacytoid (pDC) subsets. Despite the importance of this lineage diversity, its genetic basis is not fully understood. ...We found that conditional ablation of the Ets-family transcription factor PU.1 in DC-restricted progenitors led to increased pDC production at the expense of cDCs. PU.1 controlled many of the cardinal functions of DCs, such as antigen presentation by cDCs and type I interferon production by pDCs. Conditional ablation of PU.1 de-repressed the pDC transcriptional signature in cDCs. The combination of genome-wide mapping of PU.1 binding and gene expression analysis revealed a key role for PU.1 in maintaining cDC identity through the induction of the transcriptional regulator DC-SCRIPT. PU.1 activated DC-SCRIPT expression, which in turn promoted cDC formation, particularly of cDC1s, and repressed pDC development. Thus, cDC identity is regulated by a transcriptional node requiring PU.1 and DC-SCRIPT.
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•PU.1 is required for conventional dendritic cell (cDC) formation and function•PU.1 represses plasmacytoid DC differentiation•DC-SCRIPT (Zfp366) is a key transcriptional target of PU.1•DC-SCRIPT is specifically expressed in cDCs and promotes cDC1 differentiation
Dendritic cells can be divided into multiple functional subsets. Chopin et al. show that the transcription factor PU.1 promotes development of conventional dendritic cells while suppressing plasmacytoid dendritic cell formation. PU.1 functions by activating the expression of DC-SCRIPT, a key regulator of conventional dendritic cell differentiation.
Antibody-based therapeutics and vaccines are essential to combat COVID-19 morbidity and mortality after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Multiple mutations in ...SARS-CoV-2 that could impair antibody defenses propagated in human-to-human transmission and spillover or spillback events between humans and animals. To develop prevention and therapeutic strategies, we formed an international consortium to map the epitope landscape on the SARS-CoV-2 spike protein, defining and structurally illustrating seven receptor binding domain (RBD)–directed antibody communities with distinct footprints and competition profiles. Pseudovirion-based neutralization assays reveal spike mutations, individually and clustered together in variants, that affect antibody function among the communities. Key classes of RBD-targeted antibodies maintain neutralization activity against these emerging SARS-CoV-2 variants. These results provide a framework for selecting antibody treatment cocktails and understanding how viral variants might affect antibody therapeutic efficacy.
Next-generation T-cell therapies will likely continue to utilize T-cell receptors (TCRs) and chimeric antigen receptors (CARs) because each receptor type has advantages. TCRs often possess ...exceptional properties even when tested unmodified from patients' T cells. CARs are generally less sensitive, possibly because their ligand-binding domains are grafted from antibodies selected for binding affinity or avidity and not broadly optimized for a functional response. Because of the disconnect between binding and function among these receptor types, the ultimate potential of CARs optimized for sensitivity and selectivity is not clear. Here, we focus on a thoroughly studied immuno-oncology target, the HLA-A*02/HPV-E629-38 complex, and show that CARs can be optimized by a combination of high-throughput binding screens and low-throughput functional assays to have comparable activity to clinical TCRs in acute assays in vitro. These results provide a case study for the challenges and opportunities of optimizing high-performing CARs, especially in the context of targets utilized naturally by TCRs.
This work documents the first version of the U.S. Department of Energy (DOE) new Energy Exascale Earth System Model (E3SMv1). We focus on the standard resolution of the fully coupled physical model ...designed to address DOE mission‐relevant water cycle questions. Its components include atmosphere and land (110‐km grid spacing), ocean and sea ice (60 km in the midlatitudes and 30 km at the equator and poles), and river transport (55 km) models. This base configuration will also serve as a foundation for additional configurations exploring higher horizontal resolution as well as augmented capabilities in the form of biogeochemistry and cryosphere configurations. The performance of E3SMv1 is evaluated by means of a standard set of Coupled Model Intercomparison Project Phase 6 (CMIP6) Diagnosis, Evaluation, and Characterization of Klima simulations consisting of a long preindustrial control, historical simulations (ensembles of fully coupled and prescribed SSTs) as well as idealized CO2 forcing simulations. The model performs well overall with biases typical of other CMIP‐class models, although the simulated Atlantic Meridional Overturning Circulation is weaker than many CMIP‐class models. While the E3SMv1 historical ensemble captures the bulk of the observed warming between preindustrial (1850) and present day, the trajectory of the warming diverges from observations in the second half of the twentieth century with a period of delayed warming followed by an excessive warming trend. Using a two‐layer energy balance model, we attribute this divergence to the model's strong aerosol‐related effective radiative forcing (ERFari+aci = −1.65 W/m2) and high equilibrium climate sensitivity (ECS = 5.3 K).
Plain Language Summary
The U.S. Department of Energy funded the development of a new state‐of‐the‐art Earth system model for research and applications relevant to its mission. The Energy Exascale Earth System Model version 1 (E3SMv1) consists of five interacting components for the global atmosphere, land surface, ocean, sea ice, and rivers. Three of these components (ocean, sea ice, and river) are new and have not been coupled into an Earth system model previously. The atmosphere and land surface components were created by extending existing components part of the Community Earth System Model, Version 1. E3SMv1's capabilities are demonstrated by performing a set of standardized simulation experiments described by the Coupled Model Intercomparison Project Phase 6 (CMIP6) Diagnosis, Evaluation, and Characterization of Klima protocol at standard horizontal spatial resolution of approximately 1° latitude and longitude. The model reproduces global and regional climate features well compared to observations. Simulated warming between 1850 and 2015 matches observations, but the model is too cold by about 0.5 °C between 1960 and 1990 and later warms at a rate greater than observed. A thermodynamic analysis of the model's response to greenhouse gas and aerosol radiative affects may explain the reasons for the discrepancy.
Key Points
This work documents E3SMv1, the first version of the U.S. DOE Energy Exascale Earth System Model
The performance of E3SMv1 is documented with a set of standard CMIP6 DECK and historical simulations comprising nearly 3,000 years
E3SMv1 has a high equilibrium climate sensitivity (5.3 K) and strong aerosol‐related effective radiative forcing (‐1.65 W/m2)
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