Nanoarchitectonics of S-Scheme Heterojunction Photocatalysts: A Nanohouse Design Improves Photocatalytic Nitrate Reduction to Ammonia Performance.

Photocatalytic nitrate reduction reaction (NitRR) is a promising route for environment remediation and sustainable ammonia synthesis. To design efficient photocatalysts, the recently emerged nanoarchitectonics approach holds great promise. Here, we report a nanohouse-like S-scheme heterjunction photocatalyst with high photocatalytic NitRR performance. The nano-house has a floor of plate-like metal organic framework-based photocatalyst (NH2-MIL-125), on which another photocatalyst Co(OH)2 nanosheet is grown while ZIF-8 hollow cages are also constructed as the surrounding wall/roof. Experimental and simulation results indicate that the positively charged, highly porous and hydrophobic ZIF-8 wall can modulate the environment in the nanohouse by (i) NO3- enrichment / NH4+ discharge and (ii) suppression of the competitive hydrogen evolution reaction. In combination with the enhanced electron-hole separation and strong redox capability in the NH2-MIL-125@Co(OH)2 S-scheme heterjunction confined in the nano-house, the designed photocatalyst delivers an ammonia yield of 2454.9 µmol g-1 h-1 and an apparent quantum yield of 8.02% at 400 nm in pure water. Our work provides new insights into the design principles of advanced photocatalytic NitRR photocatalyst.

Inhibition of USP10 induces myeloma cell apoptosis by promoting cyclin D3 degradation.

The cell cycle regulator cyclin D3 (CCND3) is highly expressed in multiple myeloma (MM) and it promotes MM cell proliferation. After a certain phase of cell cycle, CCND3 is rapidly degraded, which is essential for the strict control of MM cell cycle progress and proliferation. In the present study, we investigated the molecular mechanisms regulating CCND3 degradation in MM cells. By utilizing affinity purification-coupled tandem mass spectrometry, we identified the deubiquitinase USP10 interacting with CCND3 in human MM OPM2 and KMS11 cell lines. Furthermore, USP10 specifically prevented CCND3 from K48-linked polyubiquitination and proteasomal degradation, therefore enhancing its activity. We demonstrated that the N-terminal domain (aa. 1-205) of USP10 was dispensable for binding to and deubiquitinating CCND3. Although Thr283 was important for CCND3 activity, it was dispensable for CCND3 ubiquitination and stability modulated by USP10. By stabilizing CCND3, USP10 activated the CCND3/CDK4/6 signaling pathway, phosphorylated Rb, and upregulated CDK4, CDK6 and E2F-1 in OPM2 and KMS11 cells. Consistent with these findings, inhibition of USP10 by Spautin-1 resulted in accumulation of CCND3 with K48-linked polyubiquitination and degradation that synergized with Palbociclib, a CDK4/6 inhibitor, to induce MM cell apoptosis. In nude mice bearing myeloma xenografts with OPM2 and KMS11 cells, combined administration of Spautin-l and Palbociclib almost suppressed tumor growth within 30 days. This study thus identifies USP10 as the first deubiquitinase of CCND3 and also finds that targeting the USP10/CCND3/CDK4/6 axis may be a novel modality for the treatment of myeloma.

HOXA10 improves endometrial receptivity by upregulating E-cadherin†.

In the endometrium of women with recurrent implantation failure and unexplained recurrent miscarriage, the expression levels of homeobox A10 and E-cadherin were positively correlated. To explore whether homeobox A10 regulates E-cadherin during endometrial receptivity establishment, Ishikawa and RL95-2 cells were transfected with target-specific small interfering RNA (siRNA) and overexpression plasmid of homeobox A10. The expression levels of homeobox A10 and E-cadherin were measured by western blot and quantitative Real-time Polymerase Chain Reaction (qRT-PCR). Attachment assay of JEG-3 spheroids to endometrial cells were conducted to explore the adhesive functions after homeobox A10 interfered. Chromatin immunoprecipitation assays and dual luciferase reporter were used to investigate the regulatory mechanism of homeobox A10. The CD1 mice were transfected with si-homeobox A10 to confirm these results in vivo. In Ishikawa and RL95-2 cells, the expression of E-cadherin was positively correlated with homeobox A10 when it was silenced/overexpressed. Consistently, the adhesion of endometrial epithelium cells and trophoblast cells was inhibited after homeobox A10 was silenced, and exogenous restoration of E-cadherin expression reversed this effect to some extent. Homeobox A10 regulates the expression of E-cadherin by directly binding to a conserved motif (TGTACTAAAAA) located in the E-cadherin promoter region. In addition, after knockdown of homeobox A10 in CD1 mice, both the implantation and live birth rates were decreased. In conclusion, homeobox A10 can bind to the E-cadherin promoter region and directly regulate its expression, thereby improving endometrial receptivity and subsequently increasing the embryo adhesion and implantation.

The probability and possible influence factors of intermittent ovarian function recovery in patients with premature ovarian insufficiency.

RESEARCH QUESTION: What are the probability and underlying influence factors of intermittent ovarian function recovery in patients with idiopathic premature ovarian insufficiency (POI)? DESIGN: This was a retrospective cohort study conducted in tertiary hospitals recruiting 162 patients diagnosed with POI based on European Society of Human Reproduction and Embryology criteria from June 2015 to March 2022. The incidence of intermittent ovarian function recovery was evaluated, and the possible influence factors were investigated by univariate and multivariate analysis. RESULTS: Among 162 POI patients, 48 (29.63%) presented intermittent ovarian function recovery, and 11 (6.79%) were natural pregnancies; 114 (70.37%) patients failed to show ovarian function recovery. No association was found between initial clinical features and intermittent ovarian function recovery. In contrast, the variables of FSH, LH, oestradiol, anti-Müllerian hormone (AMH), ovarian volume, passive smoking and weekly exercise time after diagnosis were correlated with intermittent ovarian function recovery in patients with POI and further analysis indicated that FSH concentration at diagnosis (odds ratio [OR] 0.964, 95% confidence interval [CI] 0.934-0.995, P = 0.023), passive smoking (OR 0.369, 95% CI 0.141-0.963, P = 0.042) and weekly exercise time after diagnosis (OR 5.592, 95% CI 1.83-17.088, P = 0.003) were influence factors of intermittent ovarian function recovery in POI patients. CONCLUSIONS: The incidence of intermittent ovarian function recovery in patients with idiopathic POI was 29.63%, and the natural pregnancy rate was 6.79%. Lower FSH concentration at diagnosis, no passive smoking and a weekly exercise time ≥1.5 h after the diagnosis may be beneficial for intermittent ovarian function recovery in POI patients.

TRIM25 activates AKT/mTOR by inhibiting PTEN via K63-linked polyubiquitination in non-small cell lung cancer.

The PTEN/AKT/mTOR signaling pathway is frequently dysregulated in non-small cell lung cancer (NSCLC), but the mechanisms are not well-understood. The present study found that the ubiquitin ligase TRIM25 is highly expressed in NSCLC tissues and promotes NSCLC cell survival and tumor growth. Mechanistic studies revealed that TRIM25 binds to PTEN and mediates its K63-linked ubiquitination at K266. This modification prevents the plasma membrane translocation of PTEN and reduces its phosphatase activity therefore accumulating PI(3,4,5)P3. TRIM25 thus activates the AKT/mTOR signaling. Moreover, we found that the antibacterial nitroxoline can activate PTEN by reducing its K63-linked polyubiquitination and sensitizes NSCLC to cisplatin-induced apoptosis. This study thus identified a novel modulation on the PTEN signaling pathway by TRIM25 and provides a potential target for NSCLC treatment.

The function of metformin in endometrial receptivity (ER) of patients with polycyclic ovary syndrome (PCOS): a systematic review and meta-analysis.

BACKGROUND: This meta-analysis summarizes evidence from studies using metformin (Met) to improve endometrial receptivity (ER) in women with PCOS. METHODS: Following the PRISMA protocol, we conducted a comprehensive search of academic literature from various databases, including PubMed, EMbase and Cochrane libraries. Studies published in English before Jan 27, 2021, were recruited for primary screening. Data on endometrial thickness (EMT), endometrial artery resistance index (RI), clinical pregnancy rate (CPR) and miscarriage rate (MR) were extracted and analyzed. RESULTS: Sixty-two eligible studies that included 6571 patients were evaluated in this meta-analysis. Primary indicators are EMT and endometrial aetery RI; secondary indicators include the clinical pregnancy rate and miscarriage rate. Metformin significantly increased EMT (SMD = 2.04, 95% CI (0.96,3.12),P = 0.0002) and reduced endometrial artery RI compared to the non-Met group (SMD = - 2.83, 95% CI: (- 5.06, - 0.59), P = 0.01). As expected, metformin also improved CPR and reduced MR in PCOS patients as a result, clinical pregnancy rate (risk ratio [RR] = 1.26, 95% CI: 1.11-1.43, P = 0.0003), and miscarriage rate (RR = 0.73, 95% CI:0.58-0.91, P = 0.006). CONCLUSION: Metformin may improve endometrial receptivity (ER) in PCOS patients by increasing EMT and reducing endometrial artery RI. However, the level of most original studies was low, with small sample sizes. More large-scale, long-term RCTs with rigorous methodologies are needed.

Suppression of the USP10/CCND1 axis induces glioblastoma cell apoptosis.

Recent studies show that the expression of CCND1, a key factor in cell cycle control, is increased following the progress and deteriotation of glioma and predicts poor outcomes. On the other hand, dysregulated deubiquitinase USP10 also predicts poor prognosis for patients with glioblastoma (GBM). In the present study, we investigated the interplay between CCND1 protein and USP10 in GBM cells. We showed that the expression of CCND1 was significantly higher in both GBM tissues and GBM-derived stem cells. USP10 interacted with CCND1 and prevented its K48- but not K63-linked polyubiquitination in GBM U251 and HS683 cells, which led to increased CCND1 stability. Consistent with the action of USP10 on CCND1, knockdown of USP10 by single-guided RNA downregulated CCND1 and caused GBM cell cycle arrest at the G1 phase and induced GBM cell apoptosis. To implement this finding in the treatment of GBMs, we screened a natural product library and found that acevaltrate (AVT), an active component derived from the herbal plant Valeriana jatamansi Jones was strikingly potent to induce GBM cell apoptosis, which was confirmed by the Annexin V staining and activation of the apoptotic signals. Furthermore, we revealed that AVT concentration-dependently suppressed USP10-mediated deubiquitination on CCND1 therefore inducing CCND1 protein degradation. Collectively, the present study demonstrates that the USP10/CCND1 axis could be a promising therapeutic target for patients with GBMs.

m6A demethylase ALKBH5 inhibits pancreatic cancer tumorigenesis by decreasing WIF-1 RNA methylation and mediating Wnt signaling.

BACKGROUND: Pancreatic cancer is one of the most lethal types of cancer with extremely poor diagnosis and prognosis, and chemo-resistance remains a major challenge. The dynamic and reversible N6-methyladenosine (m6A) RNA modification has emerged as a new layer of epigenetic gene regulation. METHODS: qRT-PCR and IHC were applied to examine ALKBH5 levels in normal and pancreatic cancer tissues. Cancer cell proliferation and chemo-resistance were evaluated by clonogenic formation, chemosensitivity detection, and Western blotting assays. m6A-seq was performed to identify target genes. We evaluated the inhibitory effect of ALKBH5 in both in vivo and in vitro models. RESULTS: Here, we show that m6A demethylase ALKBH5 is downregulated in gemcitabine-treated patient-derived xenograft (PDX) model and its overexpression sensitized pancreatic ductal adenocarcinoma (PDAC) cells to chemotherapy. Decreased ALKBH5 levels predicts poor clinical outcome in PDAC and multiple other cancers. Furthermore, silencing ALKBH5 remarkably increases PDAC cell proliferation, migration, and invasion both in vitro and in vivo, whereas its overexpression causes the opposite effects. Global m6A profile revealed altered expression of certain ALKBH5 target genes, including Wnt inhibitory factor 1 (WIF-1), which is correlated with WIF-1 transactivation and mediation of the Wnt pathway. CONCLUSIONS: Our work uncovers the tumor suppressive and chemo-sensitizing function for ALKBH5, which provides insight into critical roles of m6A methylation in PDAC.

RNF6 promotes myeloma cell proliferation and survival by inducing glucocorticoid receptor polyubiquitination.

RNF6, a RING-type ubiquitin ligase, has been identified as an oncogene in various cancers but its role in multiple myeloma (MM) remains elusive. In the present study we first showed that the expression levels of RNF6 in MM were significantly elevated compared with the bone marrow cells of healthy donors. Overexpression of RNF6 in LP1 and PRMI-8266 MM cell lines promoted cell proliferation, whereas knockdown of RNF6 led to apoptosis of MM cells. Furthermore, we revealed that RNF6, as a ubiquitin ligase, interacted with glucocorticoid receptor (GR) and induced its K63-linked polyubiquitination. Different from current knowledge, RNF6 increased GR stability at both endogenous and exogenous contexts. Such an action greatly promoted GR transcriptional activity, which was confirmed by luciferase assays and by the increased expression levels of prosurvival genes including Bcl-xL and Mcl-1, two typical downstream genes of the GR pathway. Consistent with these findings, ectopic expression of RNF6 in MM cells conferred resistance to dexamethasone, a typical anti-myeloma agent. In conclusion, we demonstrate that RNF6 promotes MM cell proliferation and survival by inducing atypical polyubiquitination to GR, and RNF6 could be a promising therapeutic target for the treatment of MM.

G-CSF-mobilized peripheral blood mononuclear cells combined with platelet-rich plasma accelerate restoration of ovarian function in cyclophosphamide-induced POI rats†.

Peripheral blood mononuclear cells (PBMCs) are rich in hematopoietic cells and mesenchymal stem cells. Platelet-rich plasma (PRP) is rich in various growth factors. PBMCs and PRP have been suggested, individually, to restore ovarian function by improving the local microenvironment. The current study investigated the effect of granulocyte colony-stimulating factor (G-CSF)-mobilized PBMCs combined with PRP on restoring ovarian function in rats with primary ovarian insufficiency (POI). Thirty adult female rats were randomly subdivided into five groups: normal control (control), cyclophosphamide (CTX) plus subsequent PBS (POI + PBS), CTX plus subsequent PRP (POI + PRP), CTX plus subsequent G-CSF-mobilized PBMCs (POI + PBMCs), and CTX plus subsequent G-CSF-mobilized PBMCs combined with PRP (POI + PBMCs + PRP). CTX exposure induced the typical POI phenotype with increased diestrus; shortened estrus; follicle arrest at all stages; decreased serum levels of estradiol-17ß (E2) and anti-Mullerian hormone (AMH); and increased levels of follicle-stimulating hormone (FSH). Transplantation of mobilized PBMCs with PRP resulted in a much earlier restoration of the estrous cycle, sex hormone levels, and preantral follicle growth in POI rats. Expression of the male-specific Sry gene in the ovarian tissues of POI + PBMCs + PRP female recipient rats was evident at 5, 10, and 20 days posttransplantation along with significant increases in the expression of angiogenesis markers CD34+ and VEGF and folliculogenesis markers AMH and FSHR. Additionally, PBMCs in combination with PRP mitigated granulosa cell apoptosis by downregulating BAX and upregulating BCL-2. These results demonstrate that G-CSF-mobilized PBMCs combined with PRP accelerate the restoration of ovarian function in POI rats by increasing ovarian neovascularization, reducing granulosa cell apoptosis, and promoting folliculogenesis.

Mebendazole elicits potent antimyeloma activity by inhibiting the USP5/c-Maf axis.

c-Maf is a critical oncogenic transcription factor that contributes to myelomagenesis. Our previous studies demonstrated that the deubiquitinase USP5 stabilizes c-Maf and promotes myeloma cell proliferation and survival; therefore, the USP5/c-Maf axis could be a potential target for myeloma therapy. As a concept of principle, the present study established a USP5/c-Maf-based luciferase system that was used to screen an FDA-approved drug library. It was found that mebendazole, a typical anthelmintic drug, preferentially induced apoptosis in c-Maf-expressing myeloma cells. Moreover, oral administration of mebendazole delayed the growth of human myeloma xenografts in nude mice but did not show overt toxicity. Further studies showed that the selective antimyeloma activity of mebendazole was associated with the inhibition of the USP5/c-Maf axis. Mebendazole downregulated USP5 expression and disrupted the interaction between USP5 and c-Maf, thus leading to increased levels of c-Maf ubiquitination and subsequent c-Maf degradation. Mebendazole inhibited c-Maf transcriptional activity, as confirmed by both luciferase assays and expression measurements of c-Maf downstream genes. In summary, this study identified mebendazole as a USP5/c-Maf inhibitor that could be developed as a novel antimyeloma agent.

A novel STAT3 inhibitor negatively modulates platelet activation and aggregation.

The signal transducer and activator of transcription 3 (STAT3) plays a critical role in platelet functions. This study sought to understand the effects of the STAT3 inhibitor SC99 on platelet activation and aggregation. Immunoblotting assays were applied to measure the effects of SC99 on the STAT3 signaling pathway. A ChronoLog aggregometer was used to evaluate platelet aggregation. A flow cytometer was used to evaluate P-selectin expression in the presence of SC99. AlamarBlue and Annexin-V staining were used to evaluate platelet viability and apoptosis, respectively. A fluorescence microscope was applied to analyze platelet spreading. SC99 inhibited the phosphorylation of JAK2 and STAT3 in human platelets but had no effects on the phosphorylation of AKT, p65 or Src, all of which are involved in platelet activation. Further studies revealed that SC99 inhibited human platelet aggregation induced by collagen and thrombin in a dose-dependent manner. SC99 inhibited thrombin-induced P-selectin expression and fibrinogen binding to single platelets. Moreover, SC99 inhibited platelet spreading on fibrinogen and clot retraction mediated by outside-in signaling. SC99 inhibited platelet aggregation in mice but it did not significantly prolong the bleeding time. Taken together, the present study revealed that SC99 inhibited platelet activation and aggregation as a STAT3 inhibitor. This agent can be developed as a promising treatment for thrombotic disorders.

[Efficacy of volume-targeted ventilation for the treatment of neonatal respiratory distress syndrome].

OBJECTIVE: To investigate the efficacy of volume-targeted ventilation (VTV) for the treatment of neonatal respiratory distress syndrome (NRDS). METHODS: Fifty-two neonates with NRDS between August 2013 and August 2015 were randomly divided into two groups: VTV and pressure-controlled ventilation (PCV) (n=26 each ). A/C+Vc+ ventilation model was applied in the VTV group, and A/C+PCV ventilation model was applied in the PCV group. Arterial blood gas analysis was performed at 6, 24, and 48 hours after ventilation. The following parameters were observed: time of invasive ventilation, duration of oxygen therapy, mortality, and the incidence rates of hypocapnia, pneumothorax, ventilator-associated pneumonia (VAP), grade III-IV periventricular-intraventricular hemorrhage (PVH-IVH), periventricular leukomalacia (PVL), bronchopulmonary dysplasia (BPD), and retinopathy of prematurity (ROP). RESULTS: Compared with the PCV group, the VTV group had a significantly shorter time of invasive ventilation (P<0.05) and significantly lower incidence rates of hypocapnia, VAP, and PVL (P<0.05); however, there were no significant differences in the duration of oxygen therapy, mortality, and incidence rates of pneumothorax, grade III-IV PVH-IVH, BPD, and ROP. CONCLUSIONS: VTV has a better efficacy than PCV in the treatment of NRDS, and is worthy of clinical promotion and application.

Bioinformatics-based analysis of the dialog between COVID-19 and RSA.

Pregnant women infected with SARS-CoV-2 in early pregnancy may face an increased risk of miscarriage due to immune imbalance at the maternal-fetal interface. However, the molecular mechanisms underlying the crosstalk between COVID-19 infection and recurrent spontaneous abortion (RSA) remain poorly understood. This study aimed to elucidate the transcriptomic molecular dialog between COVID-19 and RSA. Based on bioinformatics analysis, 307 common differentially expressed genes were found between COVID-19 (GSE171110) and RSA (GSE165004). Common DEGs were mainly enriched in ribosome-related and cell cycle-related signaling pathways. Using degree algorithm, the top 10 hub genes (RPS27A, RPL5, RPS8, RPL4, RPS2, RPL30, RPL23A, RPL31, RPL26, RPL37A) were selected from the common DEGs based on their scores. The results of the qPCR were in general agreement with the results of the raw letter analysis. The top 10 candidate drugs were also selected based on P-values. In this study, we provide molecular markers, signaling pathways, and small molecule compounds that may associate COVID-19. These findings may increase the accurate diagnosis and treatment of COVID-19 patients.

[Effects of endogenous dopamine on two-state voltage oscillations of striatum medium spiny neurons].

OBJECTIVE: To explore the effects of endogenous dopamine (DA) on striatum medium spiny neurons (MSNs) in acute brain slices by the means of electrophysiology and elucidate the impact of nigrostriatal circuit loop on the functional status of MSNs. METHODS: Various structural combinations of striatum and cortex or/and substantia nigra were used to explore the conditions with appearance of spontaneous two-state voltage oscillations. And the blockage of dopaminergic or glutamic acid receptor was employed to examine how amino glutaminic acid from cortex and dopamine from substantia nigra influenced two-state voltage oscillations. RESULTS: It was found that 65.2% (30/46) MSNs recorded in corticostriatonigral slices displayed spontaneous and two-state voltage oscillations.92.3% (24/26) of MSNs in dorsal striatum close to cortex. And the percentage was only 30% (6/20) in ventral striatum. The amplitude of depolarized plateau potential (up state) decreased through a blockage of dopamine receptor (P < 0.05). The potential level of up state decreased through a blockage of D1 receptor (P < 0.05) and action potentials were stopped. The results of blocking D2 receptors were the increased potentials level of two states (P < 0.05). The membrane potential of MSNs showed a stable resting level in corticostriatonigral (-67 ± 3 mV, n = 10), corticostriatal (-70 ± 3 mV, n = 10), striatal (-73 ± 3 mV, n = 10) and nigrostriatal (-71 ± 3 mV, n = 10) slices. There was no significant difference (P > 0.05) . CONCLUSION: Endogenous dopamine from substantia nigra may regulate the instantaneous integration and coding of information from cortex by tonic effect on short-term plasticity of paired and short pulses in corticostriatal synapses.

G-CSF-mobilized peripheral blood mononuclear cells combined with platelet-rich plasma restored the ovarian function of aged rats.

BACKGROUND: Regenerative medicine with peripheral blood mononuclear cell (PBMC) transplantation sheds light on the issue of premature ovarian insufficiency (POI). However, the efficiency of PBMC treatment in natural ovarian aging (NOA) remains unclear. METHODS: Thirteen-month-old female Sprague-Dawley (SD) rats were used to verify the NOA model. Seventy-two NOA rats were randomly divided into three groups: the NOA control group, PBMC group, and PBMC+platelet-rich plasma (PRP) group. PBMCs and PRP were transplanted by intraovarian injection. The effects on ovarian function and fertility were measured after transplantation. RESULTS: Transplantation of PBMCs could restore the normal estrous cycle, consistent with the recovery of serum sex hormone levels, increased follicle numbers at all stages, and restoration of fertility by facilitating pregnancy and live birth. Moreover, when combined with PRP injection, these effects were more significant. The male-specific SRY gene was detected in the ovary at all four time points, suggesting that PBMCs continuously survived and functioned in NOA rats. In addition, after PBMC treatment, the expression of angiogenesis-related and glycolysis-related markers in the ovaries was upregulated, which indicated that these effects were associated with angiogenesis and glycolysis. CONCLUSIONS: PBMC transplantation restores the ovarian functions and fertility of NOA rats, and PRP could enhance the efficiency. Increased ovarian vascularization, follicle production, and glycolysis are likely the major mechanisms.

Influence of maternal obesity on embryonic vitrification injury and subsequent pregnancy outcomes: A retrospective cohort study.

Background: We previously reported that obese mice had significantly high lipid content in embryos, and excessive lipids are detrimental to embryonic development. However, whether maternal obesity has an effect on embryonic vitrification injury and subsequent pregnancy outcomes is still controversial. This study was conducted to clarify the influence of maternal obesity on embryonic vitrification injury and subsequent pregnancy outcomes by in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). Methods: We retrospectively collected medical record of IVF/ICSI patients from reproductive medicine centers in two tertiary hospitals. The patients were classified into a low-weight group (<18.5 kg/m2), normal-weight group (18.5-23.9 kg/m2), overweight group (24.0-27.9 kg/m2) and obese group (≥28.0 kg/m2) according to their body mass index (BMI). Multivariable logistic regression analysis was performed to compare pregnancy outcomes in fresh and frozen embryo transfer among different BMI groups to define the correlation between BMI and embryonic vitrification injury. Results: A total of 44 773 women among 20-40 years old were recruited in this study, of which 27 797 underwent their first fresh embryo transfer and 16 976 underwent their first frozen embryo transfer. For fresh embryo transfer, there was no significant difference in the clinical pregnancy rate, live birth rate, and miscarriage rate of 4 BMI groups. For frozen-thawed embryo transfer, there was a significant increase in the clinical pregnancy rate of the overweight group (AOR = 1.14, 95% CI: 1.05-1.25) and the obese group (AOR = 1.24, 95% CI: 1.03-1.50), while the miscarriage rate (AOR = 1.42, 95% CI: 1.05-1.92) also showed a significant increase in the obese group compared to the normal-weight group. Conclusion: This study provided a new understanding of the effect of maternal obesity on embryonic vitrification injury. Maternal obesity does not worsen the outcome of IVF/ICSI, particularly in the frozen-thawed group.

Serotonin accumulation in transgenic rice by over-expressing tryptophan decarboxylase results in a dark brown phenotype and stunted growth.

A mutant M47286 with a stunted growth, low fertility and dark-brown phenotype was identified from a T-DNA-tagged rice mutant library. This mutant contained a copy of the T-DNA tag inserted at the location where the expression of two putative tryptophan decarboxylase genes, TDC-1 and TDC-3, were activated. Enzymatic assays of both recombinant proteins showed tryptophan decarboxylase activities that converted tryptophan to tryptamine, which could be converted to serotonin by a constitutively expressed tryptamine 5' hydroxylase (T5H) in rice plants. Over-expression of TDC-1 and TDC-3 in transgenic rice recapitulated the stunted growth, darkbrown phenotype and resulted in a low fertility similar to M47286. The degree of stunted growth and dark-brown color was proportional to the expression levels of TDC-1 and TDC-3. The levels of tryptamine and serotonin accumulation in these transgenic rice lines were also directly correlated with the expression levels of TDC-1 and TDC-3. A mass spectrometry assay demonstrated that the darkbrown leaves and hulls in the TDC-overexpressing transgenic rice were caused by the accumulation of serotonin dimer and that the stunted growth and low fertility were also caused by the accumulation of serotonin and serotonin dimer, but not tryptamine. These results represent the first evidence that over-expression of TDC results in stunted growth, low fertility and the accumulation of serotonin, which when converted to serotonin dimer, leads to a dark brown plant color.

Identification and validation of a signature based on macrophage cell marker genes to predict recurrent miscarriage by integrated analysis of single-cell and bulk RNA-sequencing.

Recurrent miscarriage (RM) is a chronic, heterogeneous autoimmune disease that has serious social and personal consequences. No valid and reliable diagnostic markers or therapeutic targets for RM have been identified. Macrophages impact the innate immune system and can be used as diagnostic and prognostic markers for many diseases. We first collected 16 decidua and villi tissue samples from 5 normal patients and 3 RM patients for single-cell RNA sequencing data analysis and identified 1293 macrophage marker genes. We then screened a recurrent miscarriage cohort (GSE165004) for 186 macrophage-associated marker genes that were significantly differentially expressed between RM patients and the normal pregnancy endometrial tissues, and performed a functional enrichment analysis of differentially expressed genes. We then identified seven core genes (ACTR2, CD2AP, MBNL2, NCSTN, PUM1, RPN2, and TBC1D12) from the above differentially expressed gene group that are closely related to RM using the LASSO, Random Forest and SVM-RFE algorithms. We also used GSE26787 and our own collection of clinical specimens to further evaluate the diagnostic value of the target genes. A nomogram was constructed of the expression levels of these seven target genes to predict RM, and the ROC and calibration curves showed that our nomogram had a high diagnostic value for RM. These results suggest that ACTR2 and NCSTN may be potential targets for preventative RM treatments.