Human complex mixture analysis by "FD Multi-SNP Mixture Kit".

Introduction: Multiple linked single nucleotide polymorphisms (SNPs) have shown potential in personal identification and mixture detection. However, the limited number of marker and sequencing errors have obstructed accurate DNA typing. Methods: To develop more candidate loci, the diversity value (D-value) was introduced as a new parameter for screening the novel polymorphic multiple linked-SNP markers, referred to as multi-SNP. In this study, a "FD Multi-SNP Mixture Kit" comprising 567 multi-SNPs was developed for mixture detection. Additionally, a new computational error correction method was applied as a quality control approach for sequencing data. Results: The results demonstrated higher typing success rates than the conventional CE typing method. For single-source DNA, approximately 70-80 loci were detected with a DNA input of 0.009765625 ng. More than 65% of the minor alleles were distinguishable at 1 ng DNA with a frequency of 0.5% in 2- to 4-person mixtures. Conclusion: This study offers a polymorphic and high-resolution detection method for DNA genotyping and complex mixture detection, providing an alternative strategy for addressing challenging mixed DNA traces.

A new pressure-densified orthogonal hard superconducting phase of RhB4.

A new hard superconducting phase of RhB4 with the space group Cmca is predicted, and the phase transition and mechanical and superconducting properties of RhB4 under 300 GPa are studied using first principles. We predict a new high-pressure phase of RhB4 by substituting the most stable Cmca structure of OsB4, known for its excellent mechanical properties. The calculated enthalpy shows that above 112.6 GPa, Cmca is superior to Pmmn as was previously predicted by particle swarm optimization. The stability of the predicted phase is checked using formation enthalpy, elastic constant and phonon dispersion. Additionally, the convex hull of the Rh-B system confirms that the phase is expected to be synthesized experimentally. The Cmca phase is an incompressible hard material with a hardness of 23.75 GPa at 300 GPa attributed to strong intralayer covalent B-B bonds. Furthermore, the phase is a relatively pressure-insensitive superconductor, with a Tc of 8.6 K at 112.6 GPa and a pressure-dependent coefficient of -0.03 K GPa-1. The finding reveals a superconducting hard material that is well-suited for extreme high-pressure environments.

Koliella bifissiva sp. nov (Chlorellaceae, Chlorophyta) and Analysis of Its Organelle Genomes.

Chlorellacean members are common in aquatic or subaerial habitats, and many of them have significant economic value. Taxonomic reports and organelle genome data for the Nannochloris clade, an important subgroup within this family, are limited, hindering the understanding and exploitation of this clade. In this study, a fusiform-celled strain, FACHB-3607, was isolated from a pond in China. Through examination of morphological characteristics and phylogenetic analyses of rbcL, 18S rDNA, and ITS, it was identified as a new species within the Nannochloris clade, named Koliella bifissiva sp. nov. In addition, this study provided a first insight into the organellar genomes of the genus Koliella. The K. bifissiva chloroplast had a 99.8 kb genome, and the mitochondrion had a 40.8 kb genome, which are moderate sizes within the Nannochloris clade. Phylogenomic analysis showed that K. bifissiva is most closely related to Nannochloris sp. "desiccata", followed by Marvania. In contrast, Picochlorum was the most distantly related species. The organelle genomes of the Nannochloris clade display dynamic evolution, reflected in variations in genome size, gene content and order, and selection pressure. This research enhances our knowledge of species diversity and evolutionary history in the Nannochloris clade.

Investigation of Toxoplasma gondii Infection in Yunnan Semi-fine Wool Sheep (Ovis aries) and wild Rodents in Yunnan, China.

BACKGROUND: Toxoplasma gondii, a globally distributed zoonotic obligate intracellular parasite, infects a wide array of mammals, including humans, sheep, and birds. As a unique sheep breed in southwestern China, Yunnan semi-fine wool sheep occupies an important position in animal husbandry in Zhaotong due to its strong adaptability, high reproductive rate, and excellent wool quality. Lambs infected with T. gondii are prone to neurological symptoms and growth retardation, while T. gondii infection in ewes can cause abortions, stillbirths, and deformities, thus affecting sheep reproduction and sheep product quality. Meanwhile, mutton and dairy products contaminated with T. gondii can become potential sources of human infection, potentially threatening public health and safety. METHOD: To understand the T. gondii infection in semi-fine wool sheep in Zhaotong, Yunnan Province, 586 blood samples were collected and subjected to indirect hemagglutination assay (IHA) for T. gondii antibodies, and the infection-related factors were analyzed through cross-sectional analysis. In the meantime, nested PCR was conducted on a total of 217 samples collected from 31 rodents caught in and around the sheep breeding ground to test the T. gondii B1 gene in rodent tissues. RESULTS: A total of 94 sera tested positive for T. gondii antibodies, with a total positive rate of 16.04% (94/586) (95% CI: 14.77-20.89). Cross-sectional statistical analysis on factors related to semi-fine wool sheep infection rate, including sampling season, sex, age, and weight, suggested that age (< 6 months: 23.81%; 6-12 months: 11.74%; > 12 months: 15.83%) was a significant factor explaining the infection rate differences (P = 0.003 < 0.05, χ2 = 11.62, df = 2). Thus, age was considered a key risk factor for T. gondii infection in this study (odds ratio, OR = 2.35, 95% CI: 1.42-3.87). Nested PCR analysis on 217 (heart, liver, spleen, lung, kidney, brain, and muscle) tissues from the 31 rodents indicated that 11 tested positive. The total infection rate of rodents in and around the breeding ground was 35.48% (11/31), and 14 samples tested positive, with a positive infection rate of 6.45% (14/217). CONCLUSION: The T. gondii infection rates of semi-fine wool sheep and rodents from their breeding environment in Zhaotong, Yunnan Province, were high, necessitating enhanced prevention, control, and treatment measures to ensure the healthy breeding of semi-fine wool sheep and veterinary public health and safety.

Predictive value of CXCL1+_FAP+ phenotype in CAFs for distant metastasis and its correlation with PD-L1 expression in locoregionally advanced nasopharyngeal carcinoma patients.

OBJECTIVE: There is a lack of effective biomarkers for predicting the distant metastasis in nasopharyngeal carcinoma (NPC). We aimed to explore the expression of FAP+Cancer-associated fibroblasts (CAFs) derived CXCL1 in NPC and its predictive values for distant metastasis and correlation with PD-L1 expression. MATERIALS AND METHODS: A total of 345 patients with locoregionally advanced NPC were retrospectively enrolled (the training cohort: the validation cohort = 160:185). Co-expression of CXCL1 and FAP and the expression of PD-L1 were detected by multi-immunofluorescence staining and immunohistochemistry, respectively. The primary end-point was distant metastasis-free survival (DMFS). The Kaplan-Meier method was used to calculate the survival. The Cox proportional hazards model was used to assess prognostic risk factors. RESULTS: A novel CXCL1+_FAP+ phenotype in CAFs was identified in NPC and then used to divide patients into low and high risk groups. Both in the training cohort and validation cohort, patients in the high risk group had poorer DMFS, overall survival (OS), progression-free survival (PFS) and locoregional relapse-free survival (LRFS) than patients in the low risk group. Multivariate analysis revealed CXCL1+_FAP+ phenotype was an independent prognostic factor for DMFS, OS, PFS and LRFS. Further results showed patients in the high risk group had higher PD-L1 expression than those in the low risk group. CONCLUSION: Our study showed CXCL1+_FAP+ phenotype in CAFs could effectively classified locoregionally advanced NPC patients into different risk groups for distant metastasis and might be a potential biomarker for anti-PD-1/PD-L1 immunotherapy.

Stereochemical insights into enantioselective antiplasmodial lignanamides from the twigs and leaves of Solanum erianthum.

Stereochemical investigations on the twigs and leaves of Solanum erianthum afforded five pairs of lignanamide enantiomers and a previously undescribed phenolic amide (3). Particularly, two pairs of previously undescribed lignanamide racemates (1a/1b-2a/2b) represent the first case of natural products that feature an unreported 5/5-fused N/O-biheterocyclic core. Their structures, including the absolute configurations, were determined unambiguously by using spectroscopic analyses and electronic circular dichroism calculations. A speculative biogenetic pathway for 1-3 was proposed. Interestingly, these lignanamides exhibited enantioselective antiplasmodial activities against drug-sensitive Plasmodium falciparum 3D7 strain and chloroquine-resistant Plasmodium falciparum Dd2 strain, pointing out that chirality plays an important role in drug development.

Ripretinib inhibits HIV-1 transcription through modulation of PI3K-AKT-mTOR.

Despite the effectiveness of antiretroviral therapy (ART) in prolonging the lifespan of individuals infected with HIV-1, it does not offer a cure for acquired immunodeficiency syndrome (AIDS). The "block and lock" approach aims to maintain the provirus in a state of extended transcriptional arrest. By employing the "block and lock" strategy, researchers endeavor to impede disease progression by preventing viral rebound for an extended duration following patient stops receiving ART. The crux of this strategy lies in the utilization of latency-promoting agents (LPAs) that are suitable for impeding HIV-1 provirus transcription. However, previously documented LPAs exhibited limited efficacy in primary cells or samples obtained from patients, underscoring the significance of identifying novel LPAs that yield substantial outcomes. In this study, we performed high-throughput screening of FDA-approved compound library in the J-Lat A2 cell line to discover more efficacious LPAs. We discovered ripretinib being an LPA candidate, which was validated and observed to hinder proviral activation in cell models harboring latent infections, as well as CD4+ T cells derived from infected patients. We demonstrated that ripretinib effectively impeded proviral activation through inhibition of the PI3K-AKT-mTOR signaling pathway in the HIV-1 latent cells, thereby suppressing the opening states of cellular chromatin. The results of this research offer a promising drug candidate for the implementation of the "block and lock" strategy in the pursuit of an HIV-1 cure.

Genome assembly of autotetraploid Actinidia arguta highlights adaptive evolution and enables dissection of important economic traits.

Actinidia arguta, the most widely distributed Actinidia species and the second cultivated species in the genus, can be distinguished from the currently cultivated Actinidia chinensis on the basis of its small and smooth fruit, rapid softening, and excellent cold tolerance. Adaptive evolution of tetraploid Actinidia species and the genetic basis of their important agronomic traits are still unclear. Here, we generated a chromosome-scale genome assembly of an autotetraploid male A. arguta accession. The genome assembly was 2.77 Gb in length with a contig N50 of 9.97 Mb and was anchored onto 116 pseudo-chromosomes. Resequencing and clustering of 101 geographically representative accessions showed that they could be divided into two geographic groups, Southern and Northern, which first diverged 12.9 million years ago. A. arguta underwent two prominent expansions and one demographic bottleneck from the mid-Pleistocene climate transition to the late Pleistocene. Population genomics studies using paleoclimate data enabled us to discern the evolution of the species' adaptation to different historical environments. Three genes (AaCEL1, AaPME1, and AaDOF1) related to flesh softening were identified by multi-omics analysis, and their ability to accelerate flesh softening was verified through transient expression assays. A set of genes that characteristically regulate sexual dimorphism located on the sex chromosome (Chr3) or autosomal chromosomes showed biased expression during stamen or carpel development. This chromosome-level assembly of the autotetraploid A. arguta genome and the genes related to important agronomic traits will facilitate future functional genomics research and improvement of A. arguta.

Comprehensive review of amino acid transporters as therapeutic targets.

The solute carrier (SLC) family, with more than 400 membrane-bound proteins, facilitates the transport of a wide array of substrates such as nutrients, ions, metabolites, and drugs across biological membranes. Amino acid transporters (AATs) are membrane transport proteins that mediate transfer of amino acids into and out of cells or cellular organelles. AATs participate in many important physiological functions including nutrient supply, metabolic transformation, energy homeostasis, redox regulation, and neurological regulation. Several AATs have been found to significantly impact the progression of human malignancies, and dysregulation of AATs results in metabolic reprogramming affecting tumor growth and progression. However, current clinical therapies that directly target AATs have not been developed. The purpose of this review is to highlight the structural and functional diversity of AATs, the molecular mechanisms in human diseases such as tumors, kidney diseases, and emerging therapeutic strategies for targeting AATs.

Inter-arm blood pressure difference in post-stroke patients with hemiparesis.

The aim of this study was to investigate that inter-arm blood pressure (BP) difference (IAD) and reference arm in 420 post-stroke patients with hemiparesis. Synchronous bilateral-arm BP was measured with two automatic BP devices, and the systolic BP difference of ≥10 mm Hg was recorded as increased sIAD. The arm with higher systolic BP (SBP) was assigned as the reference arm. Our results showed that the prevalence of sIAD was 18.1% in the total group. The paretic arms had similar mean SBP levels (133.6±18.4 vs. 133.8±18.4 mm Hg, NS) and DBP (77.8±11.5 vs. 77.2±10.9 mm Hg, NS) as compared with the unaffected arms. The detection rate of hypertension or uncontrolled hypertension on the SBP values of the reference arm was higher than that on the unaffected arm (41.8% vs. 36.3%). It is concluded that in the post-stroke patients with hemiparesis in the rehabilitation period, the prevalence of sIAD ≥10 mmHg was relatively higher, and using the unaffected arm, rather than the unaffected arm, for BP measurement could induce correctly detection of hypertension.

Genome-wide identification of heat shock protein gene family and their responses to pathogen challenge in Trachinotus ovatus.

Heat Shock Proteins (HSPs) are a widely distributed family of proteins produced in response to heat and other stresses. To develop a deeper understanding of the mechanisms governing expression of HSPs in the bony fish Trachinotus ovatus, we carried out a whole genome analysis and identified 43 HSP genes. Based on their phylogenetic relationships with Danio rerio, Seriola dumerili, and Seriola lalandi, they were divided into four subfamilies: HSP20, HSP60, HSP70, and HSP90. We performed an analysis of the predicted physicochemical properties and subcellular localization of proteins encoded by these genes. The chromosomal localization results showed that the HSP genes are distributed across 20 chromosomes of T. ovatus.These genes were found to be expressed in different tissues, and they showed differential expression in the immune response against Streptococcus agalactiae. However, there was no significant differential expression in the different skin tissue locations of T. ovatus after infection by Cryptocaryon irritans Brown. This study provides basic information for further research on the evolution and structure and function of HSPs in teleosts.

Intestinal epithelial dopamine receptor signaling drives sex-specific disease exacerbation in a mouse model of multiple sclerosis.

Although the gut microbiota can influence central nervous system (CNS) autoimmune diseases, the contribution of the intestinal epithelium to CNS autoimmunity is less clear. Here, we showed that intestinal epithelial dopamine D2 receptors (IEC DRD2) promoted sex-specific disease progression in an animal model of multiple sclerosis. Female mice lacking Drd2 selectively in intestinal epithelial cells showed a blunted inflammatory response in the CNS and reduced disease progression. In contrast, overexpression or activation of IEC DRD2 by phenylethylamine administration exacerbated disease severity. This was accompanied by altered lysozyme expression and gut microbiota composition, including reduced abundance of Lactobacillus species. Furthermore, treatment with N2-acetyl-L-lysine, a metabolite derived from Lactobacillus, suppressed microglial activation and neurodegeneration. Taken together, our study indicates that IEC DRD2 hyperactivity impacts gut microbial abundances and increases susceptibility to CNS autoimmune diseases in a female-biased manner, opening up future avenues for sex-specific interventions of CNS autoimmune diseases.

ESIPT-based fluorescent enhanced probes prompted by methylated ß-cyclodextrin for the detection of thiophenols.

Thiophenol and its derivatives are compounds with high toxicity to organisms and environmental pollution, so it is necessary to detect the level of thiophenols in the environment and biological samples. The probes 1a-b were obtained by introducing the 2,4-dinitrophenyl ether group into diethylcoumarin-salicylaldehyde based compounds. And they can form host-guest compounds with methylated ß-cyclodextrin (M-ß-CD), the association constants of inclusion complexes are 49.2 M-1, 125 M-1 respectively. The fluorescence intensities of probes 1a-b at 600 nm (1a) and 670 nm (1b) increased significantly in thiophenols detection. Meanwhile, with the addition of M-ß-CD, the hydrophobic cavity of M-ß-CD significantly increased the fluorescence intensity of probes 1a-b, thus the detection limits of probes 1a-b to thiophenols were reduced from 410 nM, 365 nM to 62 nM, 33 nM respectively. Whereas, the good selectivity and short response time of probes 1a-b towards thiophenols was not affected in the presence of M-ß-CD. Moreover, probes 1a-b were used for further water sample detection and HeLa cell imaging experiments due to their good response to thiophenols and the results suggested that probes 1a-b had the potential to detect the content of thiophenols in water samples and living cells.

Higher ETCOc predicts longer phototherapy treatment in neonatal hyperbilirubinemia.

Objective: This study aimed to evaluate the predictive performance of end-tidal carbon monoxide corrected to ambient carbon monoxide (ETCOc) values phototherapy in neonates with significant hyperbilirubinemia. Methods: A prospective study was conducted on neonates with significant hyperbilirubinemia who received phototherapy between 3 and 7 days of life. The breath ETCOc and serum total bilirubin of the recruited infants were measured on admission. Results: The mean ETCOc at admission in 103 neonates with significant hyperbilirubinemia was 1.70 ppm. The neonates were categorized into two groups: phototherapy duration ≤72 h (n = 87) and >72 h (n = 16) groups. Infants who received phototherapy for >72 h had significantly higher ETCOc (2.45 vs. 1.60, P = 0.001). The cutoff value of ETCOc on admission for predicting longer phototherapy duration was 2.4 ppm, with a sensitivity of 62.5% and specificity of 88.5%, yielding a 50% positive predictive value and a 92.7% negative predictive value. Conclusion: ETCOc on admission can help predict the duration of phototherapy in neonates with hyperbilirubinemia, facilitate clinicians to judge disease severity, and make clinical communication easier and more efficient.

Carryover Contamination-Controlled Amplicon Sequencing Workflow for Accurate Qualitative and Quantitative Detection of Pathogens: a Case Study on SARS-CoV-2.

Carryover contamination during amplicon sequencing workflow (AMP-Seq) put the accuracy of the high-throughput detection for pathogens at risk. The purpose of this study is to develop a carryover contaminations-controlled AMP-Seq (ccAMP-Seq) workflow to enable accurate qualitative and quantitative detection for pathogens. By using the AMP-Seq workflow to detect SARS-CoV-2, Aerosols, reagents and pipettes were identified as potential sources of contaminations and ccAMP-Seq was then developed. ccAMP-Seq used filter tips and physically isolation of experimental steps to avoid cross contamination, synthetic DNA spike-ins to compete with contaminations and quantify SARS-CoV-2, dUTP/uracil DNA glycosylase system to digest the carryover contaminations, and a new data analysis procedure to remove the sequencing reads from contaminations. Compared to AMP-Seq, the contamination level of ccAMP-Seq was at least 22-folds lower and the detection limit was also about an order of magnitude lower-as low as one copy/reaction. By testing the dilution series of SARS-CoV-2 nucleic acid standard, ccAMP-Seq showed 100% sensitivity and specificity. The high sensitivity of ccAMP-Seq was further confirmed by the detection of SARS-CoV-2 from 62 clinical samples. The consistency between qPCR and ccAMP-Seq was 100% for all the 53 qPCR-positive clinical samples. Seven qPCR-negative clinical samples were found to be positive by ccAMP-Seq, which was confirmed by extra qPCR tests on subsequent samples from the same patients. This study presents a carryover contamination-controlled, accurate qualitative and quantitative amplicon sequencing workflow that addresses the critical problem of pathogen detection for infectious diseases. IMPORTANCE Accuracy, a key indicator of pathogen detection technology, is compromised by carryover contamination in the amplicon sequencing workflow. Taking the detection of SARS-CoV-2 as case, this study presents a new carryover contamination-controlled amplicon sequencing workflow. The new workflow significantly reduces the degree of contamination in the workflow, thereby significantly improving the accuracy and sensitivity of the SARS-CoV-2 detection and empowering the ability of quantitative detection. More importantly, the use of the new workflow is simple and economical. Therefore, the results of this study can be easily applied to other microorganism, which has great significance for improving the detection level of microorganism.

Tiotropium in Patients with Bronchiectasis: A Prospective Cohort Study.

PURPOSE: There are limited studies on the use of bronchodilators for the treatment of bronchiectasis. This study investigated the efficacy of tiotropium in patients with bronchiectasis and airflow limitation. METHODS: This study was a prospective cohort study, including 169 patients with bronchiectasis and airflow limitation from 2015 to 2019. The clinical outcomes observed in our study were the effect of tiotropium on the frequency of moderate exacerbations, the time to the first severe exacerbation, and the annual decline in FEV1. RESULTS: After 12 months, the annual decline in the FEV1 after bronchodilator use was 27.08 ml or 42.9 ml per year in the group with or without tiotropium, respectively. Treatment with tiotropium was associated with a decreased risk of moderate exacerbation of bronchiectasis (Adjusted RR 0.618 95% CI 0.493-0.774; P < 0.005). The time to the first severe acute exacerbation of bronchiectasis in the tiotropium group was longer than the non-tiotropium group (Adjusted HR 0.333 95% CI 0.219-0.506; P < 0.001). CONCLUSION: In conclusion, prospective cohort study showed that tiotropium effectively ameliorated the annual decline in the FEV1, with a lower-risk rate of moderate exacerbations and prolonging the time to the first-time severe exacerbation in patients with bronchiectasis and airflow limitation.

Biphasic alcoholysis coupled with high-speed countercurrent chromatography for high performance on separating phorbol from Croton tiglium Linn extracts.

Phorbol is a tetracyclic diterpenoid found in Euphorbia tirucalli, Croton tiglium, and Rehmannia glutinosa, and is nuclear of various phorbol esters. The rapid obtaining of phorbol with high purity highly contributes to its application, such as synthesizing phorbol esters with designable side chains and particular therapeutic efficacy. This study introduced a biphasic alcoholysis method for obtaining phorbol from croton oil by using polarity imparity organic solvents in both phases and established a high-speed countercurrent chromatography method for simultaneous separation and purification of phorbol. The optimized operation conditions of biphasic alcoholysis were a reaction time of 91 min, a temperature of 14°C, and a croton oil-methanol ratio of 1:30 (g:ml). The phorbol during the biphasic alcoholysis was 3.2-fold higher in content than that obtained in conventional monophasic alcoholysis. The optimized high-speed countercurrent chromatography method was using the ethyl acetate/n-butyl alcohol/water at 4.7:0.3:5 (v:v:v) with Na2 SO4 at 0.36 g/10 ml as the solvent system, using the mobile phase flow rate of 2 ml/min, the revolution of 800 r/min, under which the retention of the stationary phase was achieved at 72.83%. The crystallized phorbol following high-speed countercurrent chromatography was obtained as high purity of 94%.

The Structure and Function of Glial Networks: Beyond the Neuronal Connections.

Glial cells, consisting of astrocytes, oligodendrocyte lineage cells, and microglia, account for >50% of the total number of cells in the mammalian brain. They play key roles in the modulation of various brain activities under physiological and pathological conditions. Although the typical morphological features and characteristic functions of these cells are well described, the organization of interconnections of the different glial cell populations and their impact on the healthy and diseased brain is not completely understood. Understanding these processes remains a profound challenge. Accumulating evidence suggests that glial cells can form highly complex interconnections with each other. The astroglial network has been well described. Oligodendrocytes and microglia may also contribute to the formation of glial networks under various circumstances. In this review, we discuss the structure and function of glial networks and their pathological relevance to central nervous system diseases. We also highlight opportunities for future research on the glial connectome.

Methylated Chromenoquinoline as a Novel Nucleus Fluorescent Probe for Nucleic Acid Imaging.

Two chromenoquinoline-based fluorescent probes 1a-b have been synthesized and investigated. Photofading behaviors of compounds 1a-b showed that at least 89% absorption remained after 6 h irradiating, meanwhile, many of ions and amino acids had negligible impacts on their fluorescence intensity, which meant they had excellent photostability and selectivity. Probes 1a-b exhibited strong absorption and emission in organic solvents with large fluorescence quantum yields, even in water probe 1a still had a relatively large fluorescence quantum yield (20%). Combined with DFT calculation, the influence of alkylation on optical properties of 1b was elucidated. In addition, the fluorescence intensity of probe 1b with red emission enhanced by 5.4-fold and 5.3-fold after DNA and RNA added, and the fluorescence quantum yield increased from 3% to 17% and 14%, respectively, but the neutral molecule 1a had no response to nucleic acid. Furthermore, confocal microscopy imaging of probes 1a-b showed that 1a targeted lipid droplets while the methylated probe 1b to nucleus in living HeLa cells. The results indicated that the subcellular targeting zone could be changed by alkylation of nitrogen atom on chromenoquinoline-based conveniently, which provided a new idea for designing and synthesizing new subcellular labeled probes.

An active glutamine/α-ketoglutarate/HIF-1α axis prevents pregnancy loss by triggering decidual IGF1+GDF15+NK cell differentiation.

Deficiency of decidual NK (dNK) cell number and function has been widely regarded as an important cause of spontaneous abortion. However, the metabolic mechanism underlying the crosstalk between dNK cells and embryonic trophoblasts during early pregnancy remains largely unknown. Here, we observed that enriched glutamine and activated glutaminolysis in dNK cells contribute to trophoblast invasion and embryo growth by insulin-like growth factor-1 (IGF-1) and growth differentiation factor-15 (GDF-15) secretion. Mechanistically, these processes are dependent on the downregulation of EGLN1-HIF-1α mediated by α-ketoglutarate (α-KG). Blocking glutaminolysis with the GLS inhibitor BPTES or the glutamate dehydrogenase inhibitor EGCG leads to early embryo implantation failure, spontaneous abortion and/or fetal growth restriction in pregnant mice with impaired trophoblast invasion. Additionally, α-KG supplementation significantly alleviated pregnancy loss mediated by defective glutaminolysis in vivo, suggesting that inactivated glutamine/α-ketoglutarate metabolism in dNK cells impaired trophoblast invasion and induced pregnancy loss.