Explore the vast range of titles available.

During early human pregnancy the uterine mucosa transforms into the decidua, into which the fetal placenta implants and where placental trophoblast cells intermingle and communicate with maternal cells. Trophoblast–decidual interactions underlie common diseases of pregnancy, including pre-eclampsia and stillbirth. Here we profile the transcriptomes of about 70,000 single cells from first-trimester placentas with matched maternal blood and decidual cells. The cellular composition of human decidua reveals subsets of perivascular and stromal cells that are located in distinct decidual layers. There are three major subsets of decidual natural killer cells that have distinctive immunomodulatory and chemokine profiles. We develop a repository of ligand–receptor complexes and a statistical tool to predict the cell-type specificity of cell–cell communication via these molecular interactions. Our data identify many regulatory interactions that prevent harmful innate or adaptive immune responses in this environment. Our single-cell atlas of the maternal–fetal interface reveals the cellular organization of the decidua and placenta, and the interactions that are critical for placentation and reproductive success. Transcriptomes of about 70,000 single cells from first-trimester deciduas and placentas reveal subsets of perivascular, stromal and natural killer cells in the decidua, with distinct immunomodulatory profiles that regulate the environment necessary for successful placentation.

Tumors subvert immune cell function to evade immune responses, yet the complex mechanisms driving immune evasion remain poorly understood. Here we show that tumors induce de novo steroidogenesis in T lymphocytes to evade anti-tumor immunity. Using a transgenic steroidogenesis-reporter mouse line we identify and characterize de novo steroidogenic immune cells, defining the global gene expression identity of these steroid-producing immune cells and gene regulatory networks by using single-cell transcriptomics. Genetic ablation of T cell steroidogenesis restricts primary tumor growth and metastatic dissemination in mouse models. Steroidogenic T cells dysregulate anti-tumor immunity, and inhibition of the steroidogenesis pathway is sufficient to restore anti-tumor immunity. This study demonstrates T cell de novo steroidogenesis as a mechanism of anti-tumor immunosuppression and a potential druggable target. Multiple mechanisms of immune evasion exploited by cancer cells have been described. Here, the authors show that genetic inactivation or pharmacological inhibition of tumor-induced Th2-mediated de novo steroidogenesis are sufficient to restore an efficient anti-tumor immune response and restrict tumor growth.

Gastrointestinal microbiota and immune cells interact closely and display regional specificity; however, little is known about how these communities differ with location. Here, we simultaneously assess microbiota and single immune cells across the healthy, adult human colon, with paired characterization of immune cells in the mesenteric lymph nodes, to delineate colonic immune niches at steady state. We describe distinct helper T cell activation and migration profiles along the colon and characterize the transcriptional adaptation trajectory of regulatory T cells between lymphoid tissue and colon. Finally, we show increasing B cell accumulation, clonal expansion and mutational frequency from the cecum to the sigmoid colon and link this to the increasing number of reactive bacterial species. The gut microbiota and their proximate immune cells engage in a dialog of reciprocal regulation. James and colleagues describe how immune cell and microbiotal populations vary along the length of the human colon.

Multimodal data is rapidly growing in many fields of science and engineering, including single-cell biology. We introduce MultiMAP, a novel algorithm for dimensionality reduction and integration. MultiMAP can integrate any number of datasets, leverages features not present in all datasets, is not restricted to a linear mapping, allows the user to specify the influence of each dataset, and is extremely scalable to large datasets. We apply MultiMAP to single-cell transcriptomics, chromatin accessibility, methylation, and spatial data and show that it outperforms current approaches. On a new thymus dataset, we use MultiMAP to integrate cells along a temporal trajectory. This enables quantitative comparison of transcription factor expression and binding site accessibility over the course of T cell differentiation, revealing patterns of expression versus binding site opening kinetics.

Human embryonic bone and joint formation is determined by coordinated differentiation of progenitors in the nascent skeleton. The cell states, epigenetic processes and key regulatory factors that underlie lineage commitment of these cells remain elusive. Here we applied paired transcriptional and epigenetic profiling of approximately 336,000 nucleus droplets and spatial transcriptomics to establish a multi-omic atlas of human embryonic joint and cranium development between 5 and 11 weeks after conception. Using combined modelling of transcriptional and epigenetic data, we characterized regionally distinct limb and cranial osteoprogenitor trajectories across the embryonic skeleton and further described regulatory networks that govern intramembranous and endochondral ossification. Spatial localization of cell clusters in our in situ sequencing data using a new tool, ISS-Patcher, revealed mechanisms of progenitor zonation during bone and joint formation. Through trajectory analysis, we predicted potential non-canonical cellular origins for human chondrocytes from Schwann cells. We also introduce SNP2Cell, a tool to link cell-type-specific regulatory networks to polygenic traits such as osteoarthritis. Using osteolineage trajectories characterized here, we simulated in silico perturbations of genes that cause monogenic craniosynostosis and implicate potential cell states and disease mechanisms. This work forms a detailed and dynamic regulatory atlas of bone and cartilage maturation and advances our fundamental understanding of cell-fate determination in human skeletal development. A multiomic atlas of human embryonic joint and cranium development enables detailed analysis of bone and cartilage maturation.

Predictive modeling of CO2 storage sites requires a detailed understanding of physico-chemical processes and scale-up challenges. Dramatic injectivity decline may occur due to salt precipitation pore clogging in high-salinity aquifers during subsurface CO2 injection. This study aims to elucidate the impact of CO2-induced salt crystallization in the porous medium on the geomechanical properties of reservoir sandstones. As the impact of salt precipitation cannot be isolated from the precursor interactions with CO2 and acidified brine, we present a comprehensive review and discuss CO2 chemo-mechanical interactions with sandstones. Laboratory geochemical CO2–brine–rock interactions at elevated pressures and temperatures were conducted on two sandstone sets with contrasting petrophysical qualities. Interaction paths comprised treatment with (a) CO2-acidified brine and (b) supercritical injection until brine dry-out, salt crystallization, and growth. Afterward, the core samples were tested in a triaxial apparatus at varying stresses and temperatures. The elastic moduli of intact, CO2-acidified brine treated, and salt-affected sandstones were juxtaposed to elucidate the geochemical–geomechanical-coupled impacts and identify the extent of crystallization damages. The salt-affected sandstones showed a maximum of 50% reduction in Young’s and shear moduli and twice an increase in Poisson’s ratio compared to intact condition. The deterioration was notably higher for the tighter reservoir sandstones, with higher initial stiffness and lower porosity–permeability. We propose two pore- and grain-scale mechanisms to explain how salt crystallization contributes to stress localization and mechanical damage. The results highlight the potential integrity risk imposed by salt crystallization in (hyper)saline aquifers besides injectivity, signaling mechanical failure exacerbated by pressure buildup.HighlightsGeochemically induced mechanical alterations in saline aquifer sandstones near CO2 injection wellbores are explored.The impacts of treatment with CO2-acidified brine and CO2-induced salt precipitation in pore space are juxtaposed experimentally.Salt crystallization damage profoundly and distinctly impacted the elastic parameters of two sandstone classes.Marked decline in Young’s modulus and rigidity signals elevated risk of mechanical failure in carbon storage reservoirs.Pore- and grain-level damage mechanisms are observed and conceptualized to describe stress localization imposed by salt crystallization.

Common genetic variants across individuals modulate the cellular response to pathogens and are implicated in diverse immune pathologies, yet how they dynamically alter the response upon infection is not well understood. Here, we triggered antiviral responses in human fibroblasts from 68 healthy donors, and profiled tens of thousands of cells using single-cell RNA-sequencing. We developed GASPACHO (GAuSsian Processes for Association mapping leveraging Cell HeterOgeneity), a statistical approach designed to identify nonlinear dynamic genetic effects across transcriptional trajectories of cells. This approach identified 1,275 expression quantitative trait loci (local false discovery rate 10%) that manifested during the responses, many of which were colocalized with susceptibility loci identified by genome-wide association studies of infectious and autoimmune diseases, including the OAS1 splicing quantitative trait locus in a COVID-19 susceptibility locus. In summary, our analytical approach provides a unique framework for delineation of the genetic variants that shape a wide spectrum of transcriptional responses at single-cell resolution. GASPACHO is a statistical method that identifies nonlinear dynamic genetic effects using single-cell RNA-seq data. Analysis of an antiviral response in human fibroblasts identifies 1,275 expression QTLs, many of which colocalize with risk loci for autoimmune and infectious diseases.

Formalin-fixed paraffin-embedded (FFPE) tissue specimens constitute a highly valuable source of clinical material for retrospective molecular studies. However, metabolomic assessment of such archival material remains still in its infancy. Hence, there is an urgent need for efficient methods enabling extraction and profiling of metabolites present in FFPE tissue specimens. Here we demonstrate the methodology for isolation of primary metabolites from archival tissues; either fresh-frozen, formalin-fixed or formalin-fixed and paraffin-embedded specimens of mouse kidney were analysed and compared in this work. We used gas chromatography followed by mass spectrometry (GC/MS approach) to identify about 80 metabolites (including amino acids, saccharides, carboxylic acids, fatty acids) present in such archive material. Importantly, about 75% of identified compounds were detected in all three types of specimens. Moreover, we observed that fixation with formalin itself (and their duration) did not affect markedly the presence of particular metabolites in tissue-extracted material, yet fixation for 24h could be recommended as a practical standard. Paraffin embedding influenced efficiency of extraction, which resulted in reduced quantities of several compounds. Nevertheless, we proved applicability of FFPE specimens for non-targeted GS/MS-based profiling of tissue metabolome, which is of great importance for feasibility of metabolomics studies using retrospective clinical material.

The ongoing energy transformation and growing share of renewable energy sources (RES) in electricity production force the search for large-scale energy storage facilities as a possibility for storing electricity from RES because its production is not correlated with the current demand in the power grid. This article discusses the use of salt caverns as large-scale energy storage facilities, proposing a combination of the possibilities of storing energy in natural gas and energy stored in compressed air. Based on the selected potential area where such a storage facility could operate in Poland, the optimal operating parameters of storage caverns were estimated. Several possible cavern exploitation scenarios were analyzed to estimate the impact of the convergence phenomenon in salt caverns on the active storage volume over the long term of exploitation. The obtained results showed that even a high frequency of cavern exploitation cycles does not significantly affect the loss of its capacity due to the convergence phenomenon. The results confirmed the possibility of the effective use of this type of installation for storing surpluses from RES.