Extensive reforms to improve funding efficiency: an interview with President Xiankang Dou of National Natural Science Foundation of China.

Dr. Xiankang Dou () was appointed the President of the National Natural Science Foundation of China (NSFC) in April 2023. As a distinguished researcher specializing in studying the middle and upper atmosphere of earth, Dr. Dou had served as the President of Wuhan University during 2016 to 2022 and was elected an academician of the Chinese Academy of Sciences (CAS) in 2017. At his new post in NSFC, Dr. Dou's first priorities include curtailing personal favors in the review process (often known as 'say hello' with an intent to lobby), reforming the scoring and renewing mechanisms for the National Science Fund for Distinguished Young Scholars (DYS), opening the channel for DYS applications to researchers from Hong Kong and Macau, extending the age limit of female scientists for applying for DYS, and initiating funding programs for outstanding doctoral and undergraduate students. Recently, National Science Review (NSR) had an interview with Dr. Dou. He believes only through reform and experimentation can NSFC make steady progress in its efforts to support research of basic science and applied basic science in China and to cultivate promising scholars.

Development and Validation of an Explainable Deep Learning Model to Predict In-Hospital Mortality for Patients With Acute Myocardial Infarction: Algorithm Development and Validation Study.

BACKGROUND: Acute myocardial infarction (AMI) is one of the most severe cardiovascular diseases and is associated with a high risk of in-hospital mortality. However, the current deep learning models for in-hospital mortality prediction lack interpretability. OBJECTIVE: This study aims to establish an explainable deep learning model to provide individualized in-hospital mortality prediction and risk factor assessment for patients with AMI. METHODS: In this retrospective multicenter study, we used data for consecutive patients hospitalized with AMI from the Chongqing University Central Hospital between July 2016 and December 2022 and the Electronic Intensive Care Unit Collaborative Research Database. These patients were randomly divided into training (7668/10,955, 70%) and internal test (3287/10,955, 30%) data sets. In addition, data of patients with AMI from the Medical Information Mart for Intensive Care database were used for external validation. Deep learning models were used to predict in-hospital mortality in patients with AMI, and they were compared with linear and tree-based models. The Shapley Additive Explanations method was used to explain the model with the highest area under the receiver operating characteristic curve in both the internal test and external validation data sets to quantify and visualize the features that drive predictions. RESULTS: A total of 10,955 patients with AMI who were admitted to Chongqing University Central Hospital or included in the Electronic Intensive Care Unit Collaborative Research Database were randomly divided into a training data set of 7668 (70%) patients and an internal test data set of 3287 (30%) patients. A total of 9355 patients from the Medical Information Mart for Intensive Care database were included for independent external validation. In-hospital mortality occurred in 8.74% (670/7668), 8.73% (287/3287), and 9.12% (853/9355) of the patients in the training, internal test, and external validation cohorts, respectively. The Self-Attention and Intersample Attention Transformer model performed best in both the internal test data set and the external validation data set among the 9 prediction models, with the highest area under the receiver operating characteristic curve of 0.86 (95% CI 0.84-0.88) and 0.85 (95% CI 0.84-0.87), respectively. Older age, high heart rate, and low body temperature were the 3 most important predictors of increased mortality, according to the explanations of the Self-Attention and Intersample Attention Transformer model. CONCLUSIONS: The explainable deep learning model that we developed could provide estimates of mortality and visual contribution of the features to the prediction for a patient with AMI. The explanations suggested that older age, unstable vital signs, and metabolic disorders may increase the risk of mortality in patients with AMI.

PRDM14 extinction enables the initiation of trophoblast stem cell formation.

Trophoblast stem cells (TSCs) can be chemically converted from embryonic stem cells (ESCs) in vitro. Although several transcription factors (TFs) have been recognized as essential for TSC formation, it remains unclear how differentiation cues link elimination of stemness with the establishment of TSC identity. Here, we show that PRDM14, a critical pluripotent circuitry component, is reduced during the formation of TSCs. The reduction is further shown to be due to the activation of Wnt/ß-catenin signaling. The extinction of PRDM14 results in the erasure of H3K27me3 marks and chromatin opening in the gene loci of TSC TFs, including GATA3 and TFAP2C, which enables their expression and thus the initiation of the TSC formation process. Accordingly, PRDM14 reduction is proposed here as a critical event that couples elimination of stemness with the initiation of TSC formation. The present study provides novel insights into how induction signals initiate TSC formation.

Spatiotemporal Controllable Sono-Nanovaccines Driven by Free-Field Based Whole-Body Ultrasound for Personalized Cancer Therapy.

Therapeutic cancer vaccines fail to produce satisfactory outcomes against solid tumors since vaccine-induced anti-tumor immunity is significantly hampered by immunosuppression. Generating an in situ cancer vaccine targeting immunological cold tumor microenvironment (TME) appears attractive. Here, a type of free-field based whole-body ultrasound (US)-driven nanovaccines are constructed, named G5-CHC-R, by conjugating the sonosensitizer, Chenghai chlorin (CHC) and the immunomodulator, resiquimod (R848) on top of a super small-sized dendrimeric nanoscaffold. Once entering tumors, R848 can be cleaved from a hypoxia-sensitive linker, thus modifying the TME via converting macrophage phenotypes. The animals bearing orthotopic pancreatic cancer with intestinal metastasis and breast cancer with lung metastasis are treated with G5-CHC-R under a free-field based whole-body US system. Benefit from the deep penetration capacity and highly spatiotemporal selectiveness, G5-CHC-R triggered by US represented a superior alternative for noninvasive irradiation of deep-seated tumors and magnification of local immune responses via driving mass release of tumor antigens and "cold-warm-hot" three-state transformation of TME. In addition to irradiating primary tumors, a robust adaptive anti-tumor immunity is potentiated, leading to successful induction of systemic tumor suppression. The sono-nanovaccines with good biocompatibility posed wide applicability to a broad spectrum of tumors, revealing immeasurable potential for translational research in oncology.

TNF-α promotes osteocyte necroptosis by upregulating TLR4 in postmenopausal osteoporosis.

Postmenopausal osteoporosis (PMOP) is a common kind of osteoporosis that is associated with excessive osteocyte death and bone loss. Previous studies have shown that TNF-α-induced osteocyte necroptosis might exert a stronger effect on PMOP than apoptosis, and TLR4 can also induce cell necroptosis, as confirmed by recent studies. However, little is known about the relationship between TNF-α-induced osteocyte necroptosis and TLR4. In the present study, we showed that TNF-α increased the expression of TLR4, which promoted osteocyte necroptosis in PMOP. In patients with PMOP, TLR4 was highly expressed at skeletal sites where exists osteocyte necroptosis, and high TLR4 expression is correlated with enhanced TNF-α expression. Osteocytes exhibited robust TLR4 expression upon exposure to necroptotic osteocytes in vivo and in vitro. Western blotting and immunofluorescence analyses demonstrated that TNF-α upregulated TLR4 expression in vitro, which might further promote osteocyte necroptosis. Furthermore, inhibition of TLR4 by TAK-242 in vitro effectively blocked osteocyte necroptosis induced by TNF-α. Collectively, these results suggest a novel TLR4-mediated process of osteocyte necroptosis, which might increase osteocyte death and bone loss in the process of PMOP.

A Galectin-9-Driven CD11chigh Decidual Macrophage Subset Suppresses Uterine Vascular Remodeling in Preeclampsia.

BACKGROUND: Preeclampsia is a serious disease of pregnancy that lacks early diagnosis methods or effective treatment, except delivery. Dysregulated uterine immune cells and spiral arteries are implicated in preeclampsia, but the mechanistic link remains unclear. METHODS: Single-cell RNA sequencing and spatial transcriptomics were used to identify immune cell subsets associated with preeclampsia. Cell-based studies and animal models including conditional knockout mice and a new preeclampsia mouse model induced by recombinant mouse galectin-9 were applied to validate the pathogenic role of a CD11chigh subpopulation of decidual macrophages (dMφ) and to determine its underlying regulatory mechanisms in preeclampsia. A retrospective preeclampsia cohort study was performed to determine the value of circulating galectin-9 in predicting preeclampsia. RESULTS: We discovered a distinct CD11chigh dMφ subset that inhibits spiral artery remodeling in preeclampsia. The proinflammatory CD11chigh dMφ exhibits perivascular enrichment in the decidua from patients with preeclampsia. We also showed that trophoblast-derived galectin-9 activates CD11chigh dMφ by means of CD44 binding to suppress spiral artery remodeling. In 3 independent preeclampsia mouse models, placental and plasma galectin-9 levels were elevated. Galectin-9 administration in mice induces preeclampsia-like phenotypes with increased CD11chigh dMφ and defective spiral arteries, whereas galectin-9 blockade or macrophage-specific CD44 deletion prevents such phenotypes. In pregnant women, increased circulating galectin-9 levels in the first trimester and at 16 to 20 gestational weeks can predict subsequent preeclampsia onset. CONCLUSIONS: These findings highlight a key role of a distinct perivascular inflammatory CD11chigh dMφ subpopulation in the pathogenesis of preeclampsia. CD11chigh dMφ activated by increased galectin-9 from trophoblasts suppresses uterine spiral artery remodeling, contributing to preeclampsia. Increased circulating galectin-9 may be a biomarker for preeclampsia prediction and intervention.

Hyperinsulinemia impairs decidualization via AKT-NR4A1 signaling: new insight into polycystic ovary syndrome (PCOS)-related infertility.

BACKGROUND: Investigating the underlying molecular mechanisms responsible for endometrial dysfunction in women with PCOS is essential, particularly focusing on the role of hyperinsulinemia. METHODS: We explored the role of insulin in the decidualization process using a synthetic decidualization assay. To dissect the effects of PI3K/AKT-NR4A signaling, we employed small interfering RNAs (siRNAs) targeting the NR4A genes and inhibitors of the PI3K/AKT pathway. We also investigated the disruption of AKT-NR4A1 signaling in the endometrium of PCOS female rats induced with dehydroepiandrosterone (DHEA). Quantitative real-time PCR (qRT-PCR) and Western blot (WB) analyses were utilized to evaluate gene expression regulation. RESULTS: Insulin was found to suppress the expression of decidualization markers in human endometrial stromal cells (hESC) in a dose-dependent manner, concurrently triggering an inappropriate activation of the PI3K/AKT pathway. Members of the NR4A family, as downstream effectors in the PI3K/AKT pathway, were implicated in the insulin-induced disruptions during the decidualization process. Moreover, the endometrium of PCOS models showed significantly elevated levels of phosphorylated (Ser473) AKT, with a corresponding reduction in Nr4a1 protein. CONCLUSIONS: Our research demonstrates that insulin negatively regulates decidualization in hESC via the PI3K/AKT-NR4A pathway. In vivo analysis revealed a significant dysregulation of the AKT-NR4A1 pathway in the endometrium of PCOS rats. These findings offer novel insights into the pathogenesis of infertility and endometrial disorders associated with hyperinsulinemia in PCOS.

Meeting the challenges of invasive alien species.

Here we report the Assessment Report on Invasive Alien Species and their Control released by IPBES, and the status of IAS in China.

Photoaged Tire Wear Particles Leading to the Oxidative Damage on Earthworms (Eisenia fetida) by Disrupting the Antioxidant Defense System: The Definitive Role of Environmental Free Radicals.

Tire wear particles (TWPs) have caused increasing concerns due to their detrimental effects on the soil ecosystem. However, the role of weathering in altering the toxicity of TWP to soil organisms is poorly understood. In this study, the toxicity of original and photoaged TWP was compared using earthworms (Eisenia fetida) as soil model organisms. The obtained results indicated that photoaging of TWP resulted in an increase of environmentally persistent free radicals (EPFRs) from 3.69 × 1017 to 5.20 × 1017 spin/g. Meanwhile, photoaged TWP induced the changes of toxic endpoint in E. fetide, i.e., the increase of the weight loss and death ratio from 0.0425 to 0.0756 g/worm and 23.3 to 50% compared to original TWP under a 10% concentration, respectively. Analyses of transcriptomics, antioxidant enzyme activity, and histopathology demonstrated that the enhanced toxicity was mainly due to oxidative damage, which was induced by disruption in the antioxidant defense system. Free-radical quenching and correlation analysis further suggested that the excessive production of ex vivo reactive oxygen species, induced by EPFRs, led to the exhaustion of the antioxidant defense system. Overall, this work provides new insights into the potential hazard of the weathered TWP in a soil environment and has significant implications for the recycling and proper disposal of spent tire particles.

Effects of IFN-γ on the immunological microenvironment and TAM polarity in stage IA non-small cell lung cancer and its mechanisms.

OBJECTIVE: To investigate the effect of interferon-γ (IFN-γ) on the immune microenvironment and the polarity of tumor-associated macrophages (TAMs) in stage IA non-small cell lung cancer (NSCLC) and its mechanisms. METHODS: Human non-small cell lung cancer A549 cells were treated with a series of IFN-γ concentrations (0, 50, 100, 150, 200, 250, and 300 ng/mL). Tumor tissues from patients with stage IA NSCLC were cultured using the air-liquid interface culture technique to establish a tumor microenvironment (TME) organ model. The NSCLC model was constructed by subcutaneously embedding small tumor pieces into the back of nonobese diabetic severe combined immune deficiency (NOD SCID) mice. The size and weight of the tumors were recorded, and the tumor volume was calculated. CCK-8 assays were used to investigate cell proliferation, flow cytometry and TUNEL staining were used to evaluate cell apoptosis, colony formation was investigated by cloning experiments, and cell invasion and migration were evaluated by Transwell assays and scratch tests. The expression of apoptosis-related proteins (Bax, Bcl-2 and C-caspase 3), M2 polarization-related markers (CD163, CD206 and IDO1), and marker proteins of cytotoxic T cells and helper T cells (CD8 and CD4) was detected by Western blot. The expression of Ki-67 and IDO1 was detected by immunohistochemistry, and the levels of IL-6, IL-10, IL-13 and TNF-α were measured by ELISA. The expression of CD68 was measured by RT‒qPCR, and the phagocytosis of TAMs was evaluated by a Cell Trace CFSE kit and cell probe staining. RESULTS: The proliferation activity of A549 cells increased with increasing IFN-γ concentration and peaked when the concentration reached 200 ng/mL, and the proliferation activity of A549 cells was suppressed thereafter. After treatment with 200 ng/mL IFN-γ, the apoptosis rate of cells decreased, the number of cell colonies increased, the invasion and migration of cells were promoted, the expression of Bax and C-caspase 3 was downregulated, and the expression of Bcl-2 was upregulated in cells and the TME model. In the TME model, CD163, CD206, IDO1 and Ki-67 were upregulated, CD8 and CD4 were downregulated, apoptosis was reduced, the levels of IL-6 and TNF-α were decreased, and the levels of IL-10 and IL-13 were increased. IL-4 induced TAMs to express CD163 and CD206, reduced the levels of IL-6 and TNF-α, increased the levels of IL-10 and IL-13, and weakened the phagocytic function of TAMs. IFN-γ treatment further enhanced the effect of IL-4 and enhanced the viability of A549 cells. IDO1 decreased the viability of T cells and NK cells, while suppressing the effect of IFN-γ. In mice, compared with NSCLC mice, the tumor volume and weight of the IFN-γ group were increased, the expression of CD163, CD206, IDO1, Ki-67 and Bcl-2 in tumor tissue was upregulated, the expression of Bax and C-caspase 3 was downregulated, and apoptosis was reduced. The levels of IL-6 and TNF-α were decreased, and the levels of IL-10 and IL-13 were increased in the serum of mice. CONCLUSION: In stage IA NSCLC, a low concentration of IFN-γ promotes the polarization of TAMs to the M2 phenotype in the TME model by upregulating the expression of IDO1, promoting the viability of cancer cells, inhibiting the viability of T cells and NK cells, and thus establishing an immune microenvironment conducive to tumor progression.

Ling-Ling Chen: RNA has its own features; don't study it as a protein.

Non-coding RNA (ncRNA) has been a very active research area over the past 30 years. From small ncRNA - the discovery of RNA interference won the lead researchers the Nobel Prize, to long ncRNA (lncRNA), which has attracted much attention in recent years, various ncRNAs participate in all kinds of biological processes and show a variety of biomedical application prospects. Recently, National Science Review (NSR) interviewed Ling-Ling Chen, a professor at the Center for Excellence in Molecular Cell Science (CEMCS) of the Chinese Academy of Sciences (CAS), deputy director of the State Key Laboratory of Molecular Biology and director of the CAS Key Laboratory of RNA Science and Engineering, to talk about the magic world of RNA. Ling-Ling Chen and her team have been studying ncRNA for more than 10 years, and have witnessed and promoted the development of this field. They discovered unconventional lncRNAs without polyadenylated (polyA) tails or N7-methylguanosine (m7G) caps, including sno-lncRNAs (small nucleolar lncRNAs), SPAs (5' snoRNA capped and 3' polyadenylated RNAs) and circRNAs (circular RNAs), and have made remarkable progress clarifying the biogenetic mechanisms and functions of these RNAs and exploring their biomedical application. Chen said: 'I am 45 years old. I hope I will not stagnate here, but make new discoveries.'

In Situ Forming of Nitric Oxide and Electric Stimulus for Nerve Therapy by Wireless Chargeable Gold Yarn-Dynamos.

Endogenous signals, namely nitric oxide (NO) and electrons, play a crucial role in regulating cell fate as well as the vascular and neuronal systems. Unfortunately, utilizing NO and electrical stimulation in clinical settings can be challenging due to NO's short half-life and the invasive electrodes required for electrical stimulation. Additionally, there is a lack of tools to spatiotemporally control gas release and electrical stimulation. To address these issues, an "electromagnetic messenger" approach that employs on-demand high-frequency magnetic field (HFMF) to trigger NO release and electrical stimulation for restoring brain function in cases of traumatic brain injury is introduced. The system comprises a NO donor (poly(S-nitrosoglutathione), pGSNO)-conjugated on a gold yarn-dynamos (GY) and embedded in an implantable silk in a microneedle. When subjected to HFMF, conductive GY induces eddy currents that stimulate the release of NO from pGSNO. This process significantly enhances neural stem cell (NSC) synapses' differentiation and growth. The combined strategy of using NO and electrical stimulation to inhibit inflammation, angiogenesis, and neuronal interrogation in traumatic brain injury is demonstrated in vivo.

How to encourage students in learning chemistry?

Chemistry is a basis for almost all science and engineering disciplines, and needs to be well mastered by both researchers and students. But in the eyes of many Chinese students and their parents, chemistry is not an initial choice because first, it seems to be less important than mathematics and physics, and second, chemistry-majored students usually cannot get high salaries after graduation, and may encounter safety risks when conducting chemical experiments. How can we encourage students in learning chemistry? How can we improve higher chemistry education so that students can truly grasp the basic chemical principles, increase their chemical skills and apply the learnt knowledge in their future careers? Here in this panel discussion, six experts in higher chemistry education try to give their observations and opinions on these issues. Yadong Li President at Anhui Normal University; inorganic chemist. Yan Li Professor at College of Chemistry and Molecular Engineering, Peking University. Jian Pei Professor at College of Chemistry and Molecular Engineering, Peking University. Zhenfeng Xi Professor at College of Chemistry and Molecular Engineering, Peking University. Song Gao (Chair) President at Sun Yat-sen University; inorganic chemist. Lan-Sun Zheng (Chair) Professor at College of Chemistry and Chemical Engineering, Xiamen University.

Causal relationship in gut microbiota and upper urinary urolithiasis using Mendelian randomization.

Background: Several reports in recent years have found an association between gut microbiota and upper urinary urolithiasis. However, the causal relationship between them remains to be clarified. Methods: Genetic variation is used as a tool in Mendelian randomization for inference of whether exposure factors have a causal effect on disease outcomes. We selected summary statistics from a large genome-wide association study of the gut microbiome published by the MiBioGen consortium with a sample size of 18,340 as an exposure factor and upper urinary urolithiasis data from FinnGen GWAS with 4,969 calculi cases and 213,445 controls as a disease outcome. Then, a two-sample Mendelian randomization analysis was performed by applying inverse variance-weighted, MR-Egger, maximum likelihood, and weighted median. In addition, heterogeneity and horizontal pleiotropy were excluded by sensitivity analysis. Results: IVW results confirmed that class Deltaproteobacteria (OR = 0.814, 95% CI: 0.666-0.995, P = 0.045), order NB1n (OR = 0.833, 95% CI: 0.737-0.940, P = 3.15 × 10-3), family Clostridiaceae1 (OR = 0.729, 95% CI: 0.581-0.916, P = 6.61 × 10-3), genus Barnesiella (OR = 0.695, 95% CI: 0.551-0.877, P = 2.20 × 10-3), genus Clostridium sensu_stricto_1 (OR = 0.777, 95% CI: 0.612-0.986, P = 0.0380), genus Flavonifractor (OR = 0.711, 95% CI: 0.536-0.944, P = 0.0181), genus Hungatella (OR = 0.829, 95% CI: 0.690-0.995, P = 0.0444), and genus Oscillospira (OR = 0.758, 95% CI: 0.577-0.996, P = 0.0464) had a protective effect on upper urinary urolithiasis, while Eubacterium xylanophilum (OR =1.26, 95% CI: 1.010-1.566, P = 0.0423) had the opposite effect. Sensitivity analysis did not find outlier SNPs. Conclusion: In summary, a causal relationship was found between several genera and upper urinary urolithiasis. However, we still need further randomized controlled trials to validate.

The unique expression pattern of human leukocyte antigen in trophoblasts potentially explains the key mechanism of maternal-fetal tolerance and successful pregnancy.

The success of pregnancy mainly depends on immune tolerance of the mother for the semi-allogeneic fetus. The placenta carrying paternal antigens develops in the maternal uterus without suffering immune attack, making the underlying mechanism of maternal tolerance an enduring mystery. As we all know, human leukocyte antigen (HLA) plays an important role in antigen processing and presentation, thus inducing specific immune responses. Therefore, it is reasonable to speculate that the absence of classical HLA class-I（HLA-I) and HLA class-II (HLA-II) molecules in trophoblasts may account for the maternal-fetal tolerance. Here, we review the HLA-involved interactions between trophoblast cells and decidual immune cells, which contribute to the immunotolerance in the development of normal pregnancy. We also compare the similarity between the maternal-fetal interface and tumor-immune microenvironment because the important role of HLA molecules in tumor immune invasion can provide some references to studies of maternal-fetal immune tolerance. Besides, the abnormal HLA expression is likely to be associated with unexplained miscarriage, making HLA molecules potential therapeutic targets. The advances reported by these studies may exert profound influences on other research areas, including tumor immunity, organ transplantation and autoimmune disease in the future.

Proline hydroxylase 2 (PHD2) promotes brown adipose thermogenesis by enhancing the hydroxylation of UCP1.

OBJECTIVE: Brown adipose tissue (BAT) plays a crucial role in regulating non-shivering thermogenesis under cold exposure. Proline hydroxylases (PHDs) were found to be involved in adipocyte differentiation and lipid deposition. However, the effects of PHDs on regulatory mechanisms of BAT thermogenesis are not fully understood. METHODS: We detected the expression of PHDs in different adipose tissues by using immunoblotting and real-time PCR. Further, immunoblotting, real-time PCR, and immunostaining were performed to determine the correlation between proline hydroxylase 2 (PHD2) and UCP1 expression. Inhibitor of PHDs and PHD2-sgRNA viruses were used to construct the PHD2-deficiency model in vivo and in vitro to investigate the impacts of PHD2 on BAT thermogenesis. Afterward, the interaction between UCP1 and PHD2 and the hydroxylation modification level of UCP1 were verified by Co-IP assays and immunoblotting. Finally, the effect of specific proline hydroxylation on the expression/activity of UCP1 was further confirmed by site-directed mutation of UCP1 and mass spectrometry analysis. RESULTS: PHD2, but not PHD1 and PHD3, was highly enriched in BAT, colocalized, and positively correlated with UCP1. Inhibition or knockdown of PHD2 significantly suppressed BAT thermogenesis under cold exposure and aggravated obesity of mice fed HFD. Mechanistically, mitochondrial PHD2 bound to UCP1 and regulated the hydroxylation level of UCP1, which was enhanced by thermogenic activation and attenuated by PHD2 knockdown. Furthermore, PHD2-dependent hydroxylation of UCP1 promoted the expression and stability of UCP1 protein. Mutation of the specific prolines (Pro-33, 133, and 232) in UCP1 significantly mitigated the PHD2-elevated UCP1 hydroxylation level and reversed the PHD2-increased UCP1 stability. CONCLUSIONS: This study suggested an important role for PHD2 in BAT thermogenesis regulation by enhancing the hydroxylation of UCP1.

SHP2 participates in decidualization by activating ERK to maintain normal nuclear localization of progesterone receptor.

In brief: The establishment and maintenance of embryo implantation and pregnancy require decidualization of endometrial stromal cells. This paper reveals that SHP2 ensures the correct subcellular localization of progesterone receptor, thereby safeguarding the process of decidualization. Abstract: Decidualization is the process of conversion of endometrial stromal cells into decidual stromal cells, which is caused by progesterone production that begins during the luteal phase of the menstrual cycle and then increases throughout pregnancy dedicated to support embryonic development. Decidualization deficiency is closely associated with various pregnancy complications, such as recurrent miscarriage (RM). Here, we reported that Src-homology-2-containing phospho-tyrosine phosphatase (SHP2), a key regulator in the signal transduction process downstream of various receptors, plays an indispensable role in decidualization. SHP2 expression was upregulated during decidualization. SHP2 inhibitor RMC-4550 and shRNA-mediated SHP2 reduction resulted in a decreased level of phosphorylation of ERK and aberrant cytoplasmic localization of progesterone receptor (PR), coinciding with reduced expression of IGFBP1 and various other target genes of decidualization. Solely inhibiting ERK activity recapitulated these observations. Administration of RMC-4550 led to decidualization deficiency and embryo absorption in mice. Moreover, reduced expression of SHP2 was detected in the decidua of RM patients. Our results revealed that SHP2 is key to PR's nuclear localization, thereby indispensable for decidualization and that reduced expression of SHP2 might be engaged in the pathogenesis of RM.

cAMP/PKA signaling promotes AKT deactivation by reducing CIP2A expression, thereby facilitating decidualization.

cAMP signaling is widely known to be indispensable for decidualization, but the details are not fully understood. Here, we show that cAMP signaling promotes AKT deactivation in endometrial stromal cells, which favors their decidualization. The deactivation of AKT is found to be a consequence of the reduced expression of several inhibitors of PP2A, the major phosphatase of AKT, with CIP2A being the most prominent. CIP2A reduction is obligatory for decidualization, as persistent CIP2A expression impairs chromatin remodeling and the expression of several decidualization markers (IGFBP1, PRL, MAOA, and IL-15). Furthermore, analyses of the responsiveness of the CIP2A promoter to cAMP signaling suggest the ETS family to be a bridge between cAMP signaling and CIP2A reduction. Our results provide novel insights into the role of cAMP signaling in decidualization and might benefit the development of novel therapies for decidualization deficiency, AKT-driven tumors, and the reverse, insulin resistance.