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During pregnancy, the maternal uterus and fetus form a special microenvironment at the maternal-fetal interface to support fetal development. Extravillous trophoblasts (EVTs), differentiated from the fetus, invade into the decidua and interact with maternal cells. Human leukocyte antigen (HLA)-G is a non-classical MHC-I molecule that is expressed abundantly and specifically on EVTs in physiological conditions. Soluble HLA-G (sHLA-G) is also found in maternal blood, amniotic fluid, and cord blood. The abnormal expression and polymorphisms of HLA-G are related to adverse pregnancy outcomes such as preeclampsia (PE) and recurrent spontaneous abortion (RSA). Here we summarize current findings about three main roles of HLA-G during pregnancy, namely its promotion of spiral artery remodeling, immune tolerance, and fetal growth, all resulting from its interaction with immune cells. These findings are not only of great significance for the treatment of pregnancy-related diseases but also provide clues to tumor immunology research since HLA-G functions as a checkpoint in tumors.

Formation and segregation of cell lineages forming the heart have been studied extensively but the underlying gene regulatory networks and epigenetic changes driving cell fate transitions during early cardiogenesis are still only partially understood. Here, we comprehensively characterize mouse cardiac progenitor cells (CPCs) marked by Nkx2-5 and Isl1 expression from E7.5 to E9.5 using single-cell RNA sequencing and transposase-accessible chromatin profiling (ATAC-seq). By leveraging on cell-to-cell transcriptome and chromatin accessibility heterogeneity, we identify different previously unknown cardiac subpopulations. Reconstruction of developmental trajectories reveal that multipotent Isl1 + CPC pass through an attractor state before separating into different developmental branches, whereas extended expression of Nkx2-5 commits CPC to an unidirectional cardiomyocyte fate. Furthermore, we show that CPC fate transitions are associated with distinct open chromatin states critically depending on Isl1 and Nkx2-5 . Our data provide a model of transcriptional and epigenetic regulations during cardiac progenitor cell fate decisions at single-cell resolution. Cardiac progenitor cells (CPCs) form cardiomyocytes, pericytes, smooth muscle and endothelial cells during embryonic development. Here, the authors characterize mouse CPCs marked by Nkx2.5 and Isl1 from E7.5 to E9.5 by single cell RNA-seq and ATAC-seq, showing fate transitions involve distinct open chromatin state.

The temperature of the water wall in the furnace chamber is extremely important for the daily operation of a boiler. Considering the high temperature and dusty environment in the furnace, a temperature measurement device mainly composed of four parts (armored temperature sensor, in-furnace heat-collecting block, out-furnace fixing base, and protective cannula) was designed in this study, which could be used to directly obtain the temperature of the in-furnace water-wall. Numerical simulations of temperature measurement devices with different heat-collecting block structures were carried out using the computer fluid dynamics method. After comparing the measurement accuracy and considering the practical application scenarios, the optimized heat-collecting block structure with a specific expansion gap (0.5 mm wide and 4 mm deep) was selected for practical application. Such a temperature measurement device was then applied to a 1000 MW ultra-supercritical coal-fired boiler in China, and the tested in-furnace water-wall temperature data were in good agreement with relevant research. Compared with the conventional temperature measurement device arranged outside the furnace, the in-furnace water-wall temperature-measurement device adopted in this study has a more sensitive response characteristic and can directly reflect the temperature of the water wall inside the furnace. In addition, it can also reflect the local slag formation state of the water wall and has a long service life.

Background Activated microglia play a key role in initiating the inflammatory cascade following ischemic stroke and exert proinflammatory or anti-inflammatory effects, depending on whether they are polarized toward the M1 or M2 phenotype. The present study investigated the regulatory effect of icaritin (ICT) on microglial polarization in rats after cerebral ischemia/reperfusion injury (CI/RI) and explored the possible anti-inflammatory mechanisms of ICT. Methods A rat model of transient middle cerebral artery occlusion (tMCAO) was established. Following treatment with ICT, a G protein-coupled estrogen receptor (GPER) inhibitor or an extracellular signal-regulated kinase (ERK) inhibitor, the Garcia scale and rotarod test were used to assess neurological and locomotor function. 2,3,5-Triphenyltetrazolium chloride (TTC) and Fluoro-Jade C (FJC) staining were used to evaluate the infarct volume and neuronal death. The levels of inflammatory factors in the ischemic penumbra were evaluated using enzyme-linked immunosorbent assays (ELISAs). In addition, western blotting, immunofluorescence staining and quantitative PCR (qPCR) were performed to measure the expression levels of markers of different microglial phenotypes and proteins related to the GPER–ERK–nuclear factor kappa B (NF-κB) signaling pathway. Results ICT treatment significantly decreased the cerebral infarct volume, brain water content and fluorescence intensity of FJC; improved the Garcia score; increased the latency to fall and rotation speed in the rotarod test; decreased the levels of interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), Iba1, CD40, CD68 and p-P65-NF-κB; and increased the levels of CD206 and p-ERK. U0126 (an inhibitor of ERK) and G15 (a selective antagonist of GPER) antagonized these effects. Conclusions These findings indicate that ICT plays roles in inhibiting the inflammatory response and achieving neuroprotection by regulating GPER–ERK–NF-κB signaling and then inhibiting microglial activation and M1 polarization while promoting M2 polarization, which provides a new therapeutic for against cerebral ischemic stroke. Graphical Abstract

The increasing sodium salts (NaCl, NaHCO3, NaSO4 etc.) in agricultural soil is a serious global concern for sustainable agricultural production and food security. Soybean is an important food crop, and their cultivation is severely challenged by high salt concentration in soils. Classical transgenic and innovative breeding technologies are immediately needed to engineer salt tolerant soybean plants. Additionally, unfolding the molecular switches and the key components of the soybean salt tolerance network are crucial for soybean salt tolerance improvement. Here we review our understandings of the core salt stress response mechanism in soybean. Recent findings described that salt stress sensing, signalling, ionic homeostasis (Na + /K + ) and osmotic stress adjustment might be important in regulating the soybean salinity stress response. We also evaluated the importance of antiporters and transporters such as Arabidopsis K + Transporter 1 ( AKT1 ) potassium channel and the impact of epigenetic modification on soybean salt tolerance. We also review key phytohormones, and osmo-protectants and their role in salt tolerance in soybean. In addition, we discuss the progress of omics technologies for identifying salt stress responsive molecular switches and their targeted engineering for salt tolerance in soybean. This review summarizes recent progress in soybean salt stress functional genomics and way forward for molecular breeding for developing salt-tolerant soybean plant.

Conformation capture technologies (e.g., Hi-C) chart physical interactions between chromatin regions on a genome-wide scale. However, the structural variability of the genome between cells poses a great challenge to interpreting ensemble-averaged Hi-C data, particularly for long-range and interchromosomal interactions. Here, we present a probabilistic approach for deconvoluting Hi-C data into a model population of distinct diploid 3D genome structures, which facilitates the detection of chromatin interactions likely to co-occur in individual cells. Our approach incorporates the stochastic nature of chromosome conformations and allows a detailed analysis of alternative chromatin structure states. For example, we predict and experimentally confirm the presence of large centromere clusters with distinct chromosome compositions varying between individual cells. The stability of these clusters varies greatly with their chromosome identities. We show that these chromosome-specific clusters can play a key role in the overall chromosome positioning in the nucleus and stabilizing specific chromatin interactions. By explicitly considering genome structural variability, our population-based method provides an important tool for revealing novel insights into the key factors shaping the spatial genome organization.

Respiratory viral infections during pregnancy threaten maternal pulmonary health and fetal development, however the mechanisms linking lung infection to distant uterine immune disruption remain unclear. Here, we demonstrate that respiratory viral infection attenuates uterine immune activation, impairing vascular remodeling and trophoblast invasion, which compromises embryonic growth. Treatment with the dipeptidylpeptidase 4 (DPP4) inhibitor sitagliptin restores immune homeostasis in both the lung and uterus, markedly reducing pregnancy complications. Mechanistically, while pulmonary infection expands interleukin-1 receptor type 2–expressing (IL1R2⁺) CD11b⁺ myeloid cells in the lung, this expansion is attenuated by DPP4 inhibition. These cells migrate to the decidua and disrupt pregnancy-maintaining immune signaling. Single-cell RNA sequencing confirms accumulation of IL1R2⁺ regulatory macrophages at both sites. Genetic Il1r2 ablation similarly reduces uterine IL1R2⁺ cells and restores gestation. This study reveals a lung-uterus immune axis and identifies DPP4 inhibition as a dual-organ therapeutic strategy against viral-induced pregnancy pathology. The mechanism of respiratory viral infection impacting distant immune responses in the uterus remains to be explored. The authors here identify pulmonary infection induces IL1R2⁺ myeloid cells migration to decidua, disrupting gestational immunity. Dipeptidyl peptidase 4 (DPP4) inhibitor treatment curbs this cell accumulation and alleviates immune dysregulation.

Background Cancer cachexia is a deadly wasting syndrome that accompanies various diseases (including ~ 50% of cancers). Clinical studies have established that cachexia is not a nutritional deficiency and is linked to expression of certain proteins ( e.g. , interleukin-6 and C-reactive protein), but much remains unknown about this often fatal syndrome. Methods First, cachexia was created in experimental mouse models of lung cancer. Samples of human lung cancer were used to identify the association between the serum lipocalin 2 (LCN2) level and cachexia progression. Then, mouse models with LCN2 blockade or LCN2 overexpression were used to ascertain the role of LCN2 upon ferroptosis and cachexia. Furthermore, antibody depletion of tissue-infiltrating neutrophils (TI-Neu), as well as myeloid-specific-knockout of Lcn2 , were undertaken to reveal if LCN2 secreted by TI-Neu caused cachexia. Finally, chemical inhibition of ferroptosis was conducted to illustrate the effect of ferroptosis upon tissue wasting. Results Protein expression of LCN2 was higher in the wasting adipose tissue and muscle tissues of experimental mouse models of lung cancer cachexia. Moreover, evaluation of lung cancer patients revealed an association between the serum LCN2 level and cachexia progression. Inhibition of LCN2 expression reduced cachexia symptoms significantly and inhibited tissue wasting in vivo. Strikingly, we discovered a significant increase in the number of TI-Neu in wasting tissues, and that these innate immune cells secreted high levels of LCN2. Antibody depletion of TI-Neu, as well as myeloid-specific-knockout of Lcn2 , prevented ferroptosis and tissue wasting in experimental models of lung cancer cachexia. Chemical inhibition of ferroptosis alleviated tissue wasting significantly and also prolonged the survival of cachectic mice. Conclusions Our study provides new insights into how LCN2-induced ferroptosis functionally impacts tissue wasting. We identified LCN2 as a potential target in the treatment of cancer cachexia.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, whose initiation and development are driven by alterations in driver genes. In this study, we identified four driver genes (TP53, PTEN, CTNNB1, and KRAS) that show a high frequency of somatic mutations or copy number variations (CNVs) in patients with HCC. Four different spontaneous HCC mouse models were constructed to screen for changes in various kinase signaling pathways. The sgTrp53 + sgPten tumor upregulated mTOR and noncanonical nuclear factor‐κB signaling, which was shown to be strongly inhibited by rapamycin (an mTOR inhibitor) in vitro and in vivo. The JAK‐signal transducer and activator of transcription (STAT) signaling was activated in Ctnnb1mut + sgPten tumor, the proliferation of which was strongly inhibited by napabucasin (a STAT3 inhibitor). Additionally, mTOR, cytoskeleton, and AMPK signaling were upregulated while rapamycin and ezrin inhibitors exerted potent antiproliferative effects in sgPten + KrasG12D tumor. We found that JAK‐STAT, MAPK, and cytoskeleton signaling were activated in sgTrp53 + KrasG12D tumor and the combination of sorafenib and napabucasin led to the complete inhibition of tumor growth in vivo. In patients with HCC who had the same molecular classification as our mouse models, the downstream signaling pathway landscapes associated with genomic alterations were identical. Our research provides novel targeted therapeutic options for the clinical treatment of HCC, based on the presence of specific genetic alterations within the tumor. Hepatocellular carcinoma (HCC) is one of the most lethal and fastest growing malignancies worldwide. The authors aimed to investigate the differences between patients with HCC based on tumor molecular classification and provide targeted therapeutic options for them. The authors elucidated the cooperation between certain driver genes that leads to different transcriptomic and proteomic profiles, reflecting the intertumor complexity observed in HCC patients and screened out targeted inhibitors of sorafenib‐resistant tumors with different molecular classifications.

Early cancer detection by cell-free DNA faces multiple challenges: low fraction of tumor cell-free DNA, molecular heterogeneity of cancer, and sample sizes that are not sufficient to reflect diverse patient populations. Here, we develop a cancer detection approach to address these challenges. It consists of an assay, cfMethyl-Seq, for cost-effective sequencing of the cell-free DNA methylome (with > 12-fold enrichment over whole genome bisulfite sequencing in CpG islands), and a computational method to extract methylation information and diagnose patients. Applying our approach to 408 colon, liver, lung, and stomach cancer patients and controls, at 97.9% specificity we achieve 80.7% and 74.5% sensitivity in detecting all-stage and early-stage cancer, and 89.1% and 85.0% accuracy for locating tissue-of-origin of all-stage and early-stage cancer, respectively. Our approach cost-effectively retains methylome profiles of cancer abnormalities, allowing us to learn new features and expand to other cancer types as training cohorts grow. Early cancer detection by cell-free DNA (cfDNA) is challenged by the low amount of tumour DNA in cfDNA, tumour heterogeneity and the small patient cohorts. Here, the authors develop a method, cfMethyl-Seq, for cost-effective methylome profiling of cfDNA and for detecting and locating cancer.