The coronavirus disease 2019 (COVID-19) pandemic poses a current world-wide public health threat. However, little is known about its hallmarks compared to other infectious diseases. Here, we report ...the single-cell transcriptional landscape of longitudinally collected peripheral blood mononuclear cells (PBMCs) in both COVID-19- and influenza A virus (IAV)-infected patients. We observed increase of plasma cells in both COVID-19 and IAV patients and XIAP associated factor 1 (XAF1)-, tumor necrosis factor (TNF)-, and FAS-induced T cell apoptosis in COVID-19 patients. Further analyses revealed distinct signaling pathways activated in COVID-19 (STAT1 and IRF3) versus IAV (STAT3 and NFκB) patients and substantial differences in the expression of key factors. These factors include relatively increase of interleukin (IL)6R and IL6ST expression in COVID-19 patients but similarly increased IL-6 concentrations compared to IAV patients, supporting the clinical observations of increased proinflammatory cytokines in COVID-19 patients. Thus, we provide the landscape of PBMCs and unveil distinct immune response pathways in COVID-19 and IAV patients.
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•We generated a single-cell atlas of PBMCs in both COVID-19 and influenza patients•Plasma cells increase significantly in both COVID-19 and influenza patients•COVID-19 is featured with XAF1-, TNF-, and FAS-induced T cell apoptosis•COVID-19 activates distinct pathway (STAT1/IRF3) versus influenza (STAT3/NFκB)
COVID-19 and influenza are both respiratory infections with cytokine release syndrome. Zhu et al. use single-cell RNA sequencing of longitudinally collected PBMCs in both patients to reveal distinct immune response landscapes of the two diseases and identify virus-specific cell composition and immune response pathways.
Breakthrough infections by SARS-CoV-2 variants become the global challenge for pandemic control. Previously, we developed the protein subunit vaccine ZF2001 based on the dimeric receptor-binding ...domain (RBD) of prototype SARS-CoV-2. Here, we developed a chimeric RBD-dimer vaccine approach to adapt SARS-CoV-2 variants. A prototype-Beta chimeric RBD-dimer was first designed to adapt the resistant Beta variant. Compared with its homotypic forms, the chimeric vaccine elicited broader sera neutralization of variants and conferred better protection in mice. The protection of the chimeric vaccine was further verified in macaques. This approach was generalized to develop Delta-Omicron chimeric RBD-dimer to adapt the currently prevalent variants. Again, the chimeric vaccine elicited broader sera neutralization of SARS-CoV-2 variants and conferred better protection against challenge by either Delta or Omicron SARS-CoV-2 in mice. The chimeric approach is applicable for rapid updating of immunogens, and our data supported the use of variant-adapted multivalent vaccine against circulating and emerging variants.
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•A chimeric RBD-dimer immunogenic approach can be used to rapidly adapt SARS-CoV-2 variants•Chimeric RBD-dimers elicit broader responses to variants compared with homodimers•Prototype-Beta chimeric vaccine is protective in both mice and macaques•Delta-Omicron chimeric vaccine protects mice from either Delta or Omicron challenge
Vaccine immunogens designed as chimeras of the spike protein receptor-binding domain of two distinct SARS-CoV-2 variants elicit broad serum neutralization and protection from infection by the Beta, Delta, and Omicron variants in mice and macaques. The chimeric approach is applicable for rapid updating of immunogens against both circulating and emerging variants.
The transition from peri-implantation to gastrulation in mammals entails the specification and organization of the lineage progenitors into a body plan. Technical and ethical challenges have limited ...understanding of the cellular and molecular mechanisms that underlie this transition. We established a culture system that enabled the development of cynomolgus monkey embryos in vitro for up to 20 days. Cultured embryos underwent key primate developmental stages, including lineage segregation, bilaminar disc formation, amniotic and yolk sac cavitation, and primordial germ cell-like cell (PGCLC) differentiation. Single-cell RNA-sequencing analysis revealed development trajectories of primitive endoderm, trophectoderm, epiblast lineages, and PGCLCs. Analysis of single-cell chromatin accessibility identified transcription factors specifying each cell type. Our results reveal critical developmental events and complex molecular mechanisms underlying nonhuman primate embryogenesis in the early postimplantation period, with possible relevance to human development.
Integrative analysis of multi-omics layers at single cell level is critical for accurate dissection of cell-to-cell variation within certain cell populations. Here we report scCAT-seq, a technique ...for simultaneously assaying chromatin accessibility and the transcriptome within the same single cell. We show that the combined single cell signatures enable accurate construction of regulatory relationships between cis-regulatory elements and the target genes at single-cell resolution, providing a new dimension of features that helps direct discovery of regulatory patterns specific to distinct cell identities. Moreover, we generate the first single cell integrated map of chromatin accessibility and transcriptome in early embryos and demonstrate the robustness of scCAT-seq in the precise dissection of master transcription factors in cells of distinct states. The ability to obtain these two layers of omics data will help provide more accurate definitions of "single cell state" and enable the deconvolution of regulatory heterogeneity from complex cell populations.
Human pre-implantation embryonic development involves extensive changes in chromatin structure and transcriptional activity. Here, we report on LiCAT-seq, a technique that enables simultaneous ...profiling of chromatin accessibility and gene expression with ultra-low input of cells, and map the chromatin accessibility and transcriptome landscapes for human pre-implantation embryos. We observed global difference in chromatin accessibility between sperm and all stages of embryos, finding that the accessible regions in sperm tend to occur in gene-poor genomic regions. Integrative analyses between the two datasets reveals strong association between the establishment of accessible chromatin and embryonic genome activation (EGA), and uncovers transcription factors and endogenous retrovirus (ERVs) specific to EGA. In particular, a large proportion of the early activated genes and ERVs are bound by DUX4 and become accessible as early as the 2- to 4-cell stages. Our results thus offer mechanistic insights into the molecular events inherent to human pre-implantation development.
Vertical mixing is an important factor in determining the temperature, sharpness and depth of the equatorial Pacific thermocline, which are critical to the development of El Ninõ and Southern ...Oscillation (ENSO). Yet, properties, dynamical causes and large-scale impacts of vertical mixing in the thermocline are much less understood than that nearer the surface. Here, based on Argo float and the Tropical Ocean and Atmosphere (TAO) mooring measurements, we identify a large number of thermocline mixing events occurring down to the lower half of the thermocline and the lower flank of the Equatorial Undercurrent (EUC), in particular in summer to winter. The deep-reaching mixing events occur more often and much deeper during periods with tropical instability waves (TIWs) than those without and under La Niña than under El Niño conditions. We demonstrate that the mixing events are caused by lower Richardson numbers resulting from shear of both TIWs and the EUC.
Reconstructing the vertical structures of the ocean from sea surface information is of great importance for ocean and climate studies. In this study, an ensemble machine learning (Ens-ML) model is ...proposed to retrieve ocean subsurface thermal structure (OSTS) by using satellite-derived sea surface data and Argo data in the South China Sea (SCS). The input data include sea surface height (SSH), sea surface temperature (SST), sea surface salinity (SSS), sea surface wind (SSW), and geographic information (including longitude and latitude). We select three stable machine learning models, namely, extreme gradient boosting (XGBoost), RandomForest and light gradient boosting machine (LightGBM) as our benchmark models, and then use an artificial neural network (ANN) technique to combine outputs from the three individual models. The proposed Ens-ML model using sea surface data only by SSH, SST, SSS, and SSW performs less satisfactorily than that considering the contribution of geographical information, indicating that the geographical information is essential to estimate the OSTS accurately. The estimated OSTS from the Ens-ML model are compared with Argo data. The results show that the proposed Ens-ML model can accurately estimate the OSTS (upper 1000 m) in the SCS, which is relatively more accurate and precise than the individual models. The performance of the Ens-ML model also varies with season, and better estimation is obtained in winter, which is probably due to stronger mixing and weaker stratification. This study shows the great potential and advantage of the multi-model ensemble of machine learning algorithm for the ocean’s interior information retrieving, showing great potential in expanding the scope of ocean observations.
Nanoparticle vaccines displaying mosaic receptor-binding domains (RBDs) or spike (S) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or other sarbecoviruses are used in preparedness ...against potential zoonotic outbreaks. Here, we describe a self-assembling nanoparticle using lumazine synthase (LuS) as the scaffold to display RBDs from different sarbecoviruses. Mosaic nanoparticles induce sarbecovirus cross-neutralizing antibodies comparable to a nanoparticle cocktail. We find mosaic nanoparticles elicit a B cell receptor repertoire using an immunodominant germline gene pair of IGHV14-3:IGKV14-111. Most of the tested IGHV14-3:IGKV14-111 monoclonal antibodies (mAbs) are broadly cross-reactive to clade 1a, 1b, and 3 sarbecoviruses. Using mAb competition and cryo-electron microscopy, we determine that a representative IGHV14-3:IGKV14-111 mAb, M2-7, binds to a conserved epitope on the RBD, largely overlapping with the pan-sarbecovirus mAb S2H97. This suggests mosaic nanoparticles expand B cell recognition of the common epitopes shared by different clades of sarbecoviruses. These results provide immunological insights into the cross-reactive responses elicited by mosaic nanoparticles against sarbecoviruses.
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•Mosaic RBD nanoparticles elicit cross-reactive antibodies to sarbecoviruses•Mosaic nanoparticles induce BCR repertoire using an immunodominant IGHV14-3:IGKV14-111 pair•IGHV14-3:IGKV14-111 mAbs are cross-reactive to RBDs from clade 1a, 1b, and 3 sarbecoviruses•A representative IGHV14-3:IGKV14-111 mAb binds a conserved epitope across sarbecoviruses
Gao et al. dissect the BCR repertoires elicited by mosaic RBD nanoparticle vaccines across sarbecoviruses, revealing immunodominant IGHV14-3:IGKV14-111 germline usage. The IGHV14-3:IGKV14-111 mAbs are cross-reactive to RBDs from clade 1a, 1b, and 3 sarbecoviruses, targeting a conserved RBD-8 site. These findings provide immunological insights into pan-sarbecovirus mosaic nanoparticle vaccines.
Bottom circulation in the abyssal Caroline Sea is an important component of the global meridional overturning circulation. By use of a high-resolution regional ocean model, the influence of tidal ...mixing processes on bottom water and circulation in the Caroline Sea is investigated. Based on different configurations for diapycnal diffusivities of tidal mixing, three numerical experiments are performed: one completely without tidal mixing, one only with local tidal mixing due to the locally dissipated tidal energy, and one considering tidal mixing processes induced by the total dissipated tidal energy. The results show that tidal mixing processes in the abyssal Caroline Sea could sustain a relatively high horizontal density gradient and hence baroclinic pressure gradient not only across the two deep-water passages connecting to the open ocean, but also within the abyssal West Caroline Basin (WCB) and East Caroline Basin (ECB). Therefore, tidal mixing processes could maintain the large amounts of bottom water inflow, intensify the bottom basin/subbasin-scale horizontal circulation, and drive a more vigorous meridional overturning circulation in the abyssal WCB and ECB. Moreover, simulations of bottom water transport in the experiment with tidal mixing processes are more consistent with previous observations and estimates. These results suggest that tidal mixing processes play a crucial dynamic role in the bottom circulation, and is essential for ocean modelling.
In contrast to rodents, the mechanisms underlying human trophectoderm and early placenta specification are understudied due to ethical barriers and the scarcity of embryos. Recent reports have shown ...that human pluripotent stem cells (PSCs) can differentiate into trophectoderm (TE)-like cells (TELCs) and trophoblast stem cells (TSCs), offering a valuable in vitro model to study early placenta specification. Here, we demonstrate that the VGLL1 (vestigial-like family member 1), which is highly expressed during human and non-human primate TE specification in vivo but is negligibly expressed in mouse, is a critical regulator of cell fate determination and self-renewal in human TELCs and TSCs derived from naïve PSCs. Mechanistically, VGLL1 partners with the transcription factor TEAD4 (TEA domain transcription factor 4) to regulate chromatin accessibility at target gene loci through histone acetylation and acts in cooperation with GATA3 and TFAP2C. Our work is relevant to understand primate early embryogenesis and how it differs from other mammalian species.
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