N6-methyladenosine-mediated feedback regulation of abscisic acid perception via phase-separated ECT8 condensates in Arabidopsis.

N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic mRNAs, yet how plants recognize this chemical modification to swiftly adjust developmental plasticity under environmental stresses remains unclear. Here we show that m6A mRNA modification and its reader protein EVOLUTIONARILY CONSERVED C-TERMINAL REGION 8 (ECT8) act together as a key checkpoint for negative feedback regulation of abscisic acid (ABA) signalling by sequestering the m6A-modified ABA receptor gene PYRABACTIN RESISTANCE 1-LIKE 7 (PYL7) via phase-separated ECT8 condensates in stress granules in response to ABA. This partially depletes PYL7 mRNA from its translation in the cytoplasm, thus reducing PYL7 protein levels and compromising ABA perception. The loss of ECT8 results in defective sequestration of m6A-modified PYL7 in stress granules and permits more PYL7 transcripts for translation. This causes overactivation of ABA-responsive genes and the consequent ABA-hypersensitive phenotypes, including drought tolerance. Overall, our findings reveal that m6A-mediated sequestration of PYL7 by ECT8 in stress granules negatively regulates ABA perception, thereby enabling prompt feedback regulation of ABA signalling to prevent plant cell overreaction to environmental stresses.

Structural optimization of siRNA conjugates for albumin binding achieves effective MCL1-directed cancer therapy.

The high potential of siRNAs to silence oncogenic drivers remains largely untapped due to the challenges of tumor cell delivery. Here, divalent lipid-conjugated siRNAs are optimized for in situ binding to albumin to improve pharmacokinetics and tumor delivery. Systematic variation of the siRNA conjugate structure reveals that the location of the linker branching site dictates tendency toward albumin association versus self-assembly, while the lipid hydrophobicity and reversibility of albumin binding also contribute to siRNA intracellular delivery. The lead structure increases tumor siRNA accumulation 12-fold in orthotopic triple negative breast cancer (TNBC) tumors over the parent siRNA. This structure achieves approximately 80% silencing of the anti-apoptotic oncogene MCL1 and yields better survival outcomes in three TNBC models than an MCL-1 small molecule inhibitor. These studies provide new structure-function insights on siRNA-lipid conjugate structures that are intravenously injected, associate in situ with serum albumin, and improve pharmacokinetics and tumor treatment efficacy.

Association between prenatal perfluorinated compounds exposure and risk of pregnancy complications: A meta-analysis.

BACKGROUND AND OBJECTIVE: Per- and polyfluoroalkyl substances (PFASs) have been shown to be persistent and bioaccumulative. An elevated danger of pregnancy complications perhaps connected with exposure to PFASs, but the potential effects remain elusive. The objective of this study is to investigate the possible association between PFASs exposure and pregnancy complications, drawing upon existing evidence. METHODS: Electronic databases of PubMed, Qvid Medline, Embase, and Web of Science were searched thoroughly to identify eligible research published prior to November 28, 2023, examining the relationship between PFASs and pregnancy-related complications. To evaluate the quality of observational studies incorporated into the article, the Strengthening Reporting of Observational Studies in Epidemiology (STROBE) tool was utilized. The main outcomes assessed in this study included gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), gestational hypertension (GH), and preeclampsia (PE). RESULTS: Twenty-five relevant studies involving 30079 participants were finally selected from four databases. The combined estimates indicate that prenatal exposure to perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorobutane sulfonic acid (PFBS), and perfluoroenanthic acid (PFHpA) is associated with gestational diabetes mellitus (GDM) (PFOA: OR = 1.45, 95%CI: 1.07-1.94, P = 0.015; PFHxS: OR = 1.16, 95%CI: 1.00-1.36, P = 0.055; PFBS: OR = 1.44, 95%CI: 1.16-1.79, P = 0.001; PFHpA: OR = 1.41, 95%CI: 1.10-1.82, P = 0.008). The exposure to PFBS is positively associated with HDP (OR = 1.27, 95%CI: 1.14-1.41, P < 0.001), while both PFOA and PFHpA demonstrate statistically significant positive correlations with GH (PFOA: OR = 1.09, 95%CI: 1.00-1.19, P = 0.049; PFHpA: OR = 1.43, 95%CI: 1.15-1.78, P = 0.001). Negative correlations were observed for prenatal perfluorododecanoic acid (PFDoA) exposure and GH (OR = 0.71, 95%CI: 0.57-0.87, P = 0.001). However, no compelling evidence was identified to link PFASs exposure with the risk of PE. CONCLUSION: According to the meta-analysis findings, exposure to PFASs may be linked to GDM, HDP, and GH, but it does not significantly raise the risk of PE alone. Further research with larger sample size is required to verify this potential association and explore the biological mechanisms.

Polypeptide N-Acetylgalactosaminyltransferase 14 (GALNT14) as a Chemosensitivity-Related Biomarker for Osteosarcoma.

Purpose: Osteosarcoma is the most common primary bone tumor. Polypeptide N-acetylgalactosaminyltransferase 14 (GALNT14), a member of the N-acetylgalactosaminyltransferase family, has been considered to be associated with various cancers. However, its role in osteosarcoma remains unknown. Here, we aimed to explore the expression and potential mechanism of GALNT14 in osteosarcoma through bioinformatics analysis and in vitro experiments. Methods: We investigated GALNT14 expression in osteosarcoma using GEO, the TIMER database, and clinical samples. Protein-protein interaction (PPI) network analysis on GALNT14 was performed by STRING. TARGET was used to identify differentially expressed genes (DEGs) between high and low GALNT14 expression. The correlation between GALNT14 and cuproptosis-related genes in osteosarcoma was analyzed by R language. The prognostic significance of GALNT14 was examined by Kaplan-Meier survival analysis. Additionally, we inhibited GALNT14 function in an osteosarcoma cell line by transfecting siRNA and subsequently explored the effect on drug sensitivity by CCK-8, clonogenic assay, and flow cytometry. Results: GALNT14 was significantly elevated in osteosarcoma tissue, osteosarcoma cell lines, and metastatic osteosarcoma. PPI analysis revealed that GALNT14 was associated with MUC7, MUC13, MUC5AC, C1GALT1, MUC15, MUC16, MUC1, MUC4, MUC21, and MUC17. In the high GALNT14 expression group, we discovered 81 upregulated DEGs and 73 downregulated DEGs. Functional enrichment analysis of DEGs showed significant enrichment in the Wnt, TGF-ß, Hippo, PI3K signaling pathways and cell adhesion molecules. Expression of cuproptosis-related genes was closely related in osteosarcoma, and GALNT14 expression was significantly positively correlated with FDX1, a key regulator of cuproptosis. Kaplan-Meier survival showed that GALNT14 was linked to poor overall survival and disease-free survival in osteosarcoma. In vitro experiments suggested that GALNT14 was associated with chemotherapy resistance in osteosarcoma. Conclusion: We identified a GALNT family gene, GALNT14, that was highly expressed in osteosarcoma. This gene was closely associated with metastasis, progression, cuproptosis-related genes, and chemosensitivity of osteosarcoma, and showed correlation with poor overall survival and disease-free survival in osteosarcoma.

Serum levels of polychlorinated biphenyls and polybrominated diphenyl ethers in early pregnancy and their associations with gestational diabetes mellitus.

Polychlorinated Biphenyls (PCBs) and Polybrominated Diphenyl Ethers (PBDEs) are extensively present in humans and may disturb glucose metabolism during pregnancy. However, previous reports on the associations between PCBs/PBDEs levels and gestational diabetes mellitus (GDM) have been inconsistent. We performed a nested case-control study to measure the serum levels of 6 PCB and 7 PBDE congeners in early pregnancy, and to assess their associations with GDM risk and blood glucose levels. Totally, 208 serum samples (104 GDM cases and 104 controls) were included based on a prospective cohort which was carried out in Jiangsu province, China, from 2020 to 2022. The results showed that PCB-153 was the major PCB congener, whereas PBDE-47 was the predominant PBDE congener. The continuous concentrations of PCB-153, PBDE-28, and total PCB were significantly related to an increased risk of GDM, with adjusted ORs (95%CI) of 1.25 (1.04-1.50), 1.19 (1.02-1.39), and 1.37 (1.05-1.79), respectively. Potential dose-response relationships were also observed between serum levels of PCB-153 (P = 0.011), PBDE-28 (P = 0.028), total PCB (P = 0.048), and total PCB/PBDE (P = 0.010) and GDM risk. Moreover, PCB-153, PBDE-28 and total PCB levels were positively related to 1-h OGTT blood glucose (adjusted ßPCB-153: 0.14, 95%CI: 0.00-0.28; adjusted ßPBDE-28: 0.20, 95%CI: 0.08-0.32; adjusted ßtotal PCB: 0.30, 95%CI: 0.09-0.50), whereas none of the PCBs/PBDEs were statistically related to fasting blood glucose and 2-h OGTT blood glucose (all P > 0.05). Further meta-analysis also supported the association of PCBs exposure with GDM risk. Our study provides further evidence that PCBs/PBDEs exposure may increase GDM risk during pregnancy.

The landscape of mitophagy in sepsis reveals PHB1 as an NLRP3 inflammasome inhibitor.

Mitophagy is a selective autophagy targeting damaged and potential cytotoxic mitochondria, which can effectively prevent excessive cytotoxic production from damaged mitochondria and alleviate the inflammatory response. However, the potential role of mitophagy in sepsis remains poorly explored. Here, we studied the role of mitophagy in sepsis and its immune heterogeneity. By performing mitophagy-related typing on 348 sepsis samples, three clusters (A, B, and C) were obtained. Cluster A had the highest degree of mitophagy accompanied by lowest disease severity, while cluster C had the lowest degree of mitophagy with the highest disease severity. The three clusters had unique immune characteristics. We further revealed that the expression of PHB1 in these three clusters was significantly different and negatively correlated with the severity of sepsis, suggesting that PHB1 was involved in the development of sepsis. It has been reported that impaired mitophagy leads to the over-activation of inflammasomes, which promotes sepsis development. Further analysis showed that the expressions of NLRP3 inflammasomes core genes in cluster C were significantly up-regulated and negatively correlated with PHB1. Next, we verified whether PHB1 downregulation caused the activation of inflammasomes and found that the PHB1 knockdown increased the levels of mtDNA in the cytoplasm and enhanced the activation of NLRP3 inflammasomes. In addition, mitophagy inhibitor treatment abolished PHB1 knockdown-mediated activation of NLRP3 inflammasomes, suggesting that PHB1 inhibited the activation of inflammasomes through mitophagy. In conclusion, this study reveals that a high degree of mitophagy may predict a good outcome of sepsis, and PHB1 is a key NLRP3 inflammasome regulator via mitophagy in inflammatory diseases such as sepsis.

Reversal of H2O2-induced cell death by knockdown of HOTAIR in HTR-8/SVneo cells by mediation of miR-106b-5p/ACSL4 axis.

Preeclampsia is a serious threat to the health of pregnant women. Injury of trophoblasts could contribute to the progression of preeclampsia, and H2O2 was able to induce apoptosis in trophoblasts. LncRNAs have been reported to be involved in the progression of preeclampsia. Additionally, lncRNA HOTAIR is upregulated in patients with preeclampsia. However, the function of HOTAIR in H2O2-treated trophoblasts remains unclear. To explore the function of HOTAIR in preeclampsia, HTR-8/SVneo cells were stimulated with H2O2. RT-qPCR was performed to measure HOTAIR expression in HTR-8/SVneo cells. The apoptosis of HTR-8/SVneo cells was measured using TUNEL staining. The mitochondrial membrane potential was measured using JC-1 staining. Western blotting was performed to detect the expression of ACSL4, GPX4, and FTH1 in HTR-8/SVneo cells. The level of HOTAIR in HTR-8/SVneo cells was upregulated by H2O2. In addition, H2O2 notably inhibited the proliferation of HTR-8/SVneo cells, whereas knockdown of HOTAIR reversed this phenomenon. The mitochondrial membrane potential in HTR-8/SVneo cells was significantly inhibited by H2O2 and partially abolished by HOTAIR silencing. Moreover, HOTAIR could bind to miR-106b-5p; ACSL4 was identified as the downstream target of miR-106b-5p. Furthermore, HOTAIR knockdown reversed H2O2-induced ferroptosis in HTR-8/SVneo cells by regulating miR-106b-5p/ACSL4. Collectively, the knockdown of HOTAIR reversed H2O2-induced ferroptosis in HTR-8/SVneo cells by mediating miR-106b-5p/ACSL4. Thus, HOTAIR may serve as a new therapeutic target against preeclampsia.

Study on the Role of an Erythrocyte Membrane-Coated Nanotheranostic System in Targeted Immune Regulation of Alzheimer's Disease.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases in the elderly population. Despite significant advances in studies of the pathobiology on AD, there is still no effective treatment. Here, an erythrocyte membrane-camouflaged nanodrug delivery system (TR-ZRA) modified with transferrin receptor aptamers that can be targeted across the blood-brain barrier to ameliorate AD immune environment is established. Based on metal-organic framework (Zn-CA), TR-ZRA is loaded with CD22shRNA plasmid to silence the abnormally high expression molecule CD22 in aging microglia. Most importantly, TR-ZRA can enhance the ability of microglia to phagocytose Aß and alleviate complement activation, which can promote neuronal activity and decrease inflammation level in the AD brain. Moreover, TR-ZRA is also loaded with Aß aptamers, which allow rapid and low-cost monitoring of Aß plaques in vitro. After treatment with TR-ZRA, learning, and memory abilities are enhanced in AD mice. In conclusion, the biomimetic delivery nanosystem TR-ZRA in this study provides a promising strategy and novel immune targets for AD therapy.

Recent advances in the plant epitranscriptome.

Chemical modifications of RNAs, known as the epitranscriptome, are emerging as widespread regulatory mechanisms underlying gene regulation. The field of epitranscriptomics advances recently due to improved transcriptome-wide sequencing strategies for mapping RNA modifications and intensive characterization of writers, erasers, and readers that deposit, remove, and recognize RNA modifications, respectively. Herein, we review recent advances in characterizing plant epitranscriptome and its regulatory mechanisms in post-transcriptional gene regulation and diverse physiological processes, with main emphasis on N6-methyladenosine (m6A) and 5-methylcytosine (m5C). We also discuss the potential and challenges for utilization of epitranscriptome editing in crop improvement.

Structural Optimization of siRNA Conjugates for Albumin Binding Achieves Effective MCL1-Targeted Cancer Therapy.

The high potential for therapeutic application of siRNAs to silence traditionally undruggable oncogenic drivers remains largely untapped due to the challenges of tumor cell delivery. Here, siRNAs were optimized for in situ binding to albumin through C18 lipid modifications to improve pharmacokinetics and tumor delivery. Systematic variation of siRNA conjugates revealed a lead structure with divalent C18 lipids each linked through three repeats of hexaethylene glycol connected by phosphorothioate bonds. Importantly, we discovered that locating the branch site of the divalent lipid structure proximally (adjacent to the RNA) rather than at a more distal site (after the linker segment) promotes association with albumin, while minimizing self-assembly and lipoprotein association. Comparison to higher albumin affinity (diacid) lipid variants and siRNA directly conjugated to albumin underscored the importance of conjugate hydrophobicity and reversibility of albumin binding for siRNA delivery and bioactivity in tumors. The lead conjugate increased tumor siRNA accumulation 12-fold in orthotopic mouse models of triple negative breast cancer over the parent siRNA. When applied for silencing of the anti-apoptotic oncogene MCL-1, this structure achieved approximately 80% MCL1 silencing in orthotopic breast tumors. Furthermore, application of the lead conjugate structure to target MCL1 yielded better survival outcomes in three independent, orthotopic, triple negative breast cancer models than an MCL1 small molecule inhibitor. These studies provide new structure-function insights on optimally leveraging siRNA-lipid conjugate structures that associate in situ with plasma albumin for molecular-targeted cancer therapy.

Degradation of 1-alkyl-3-methylimidazolium tetrafluoroborate in an ultrasonic zero-valent zinc and activated carbon micro-electrolysis system.

Increased attention has been given to the removal of ionic liquids (ILs) from natural water environments. In this work, 5 kinds of 1-alkyl-3-methylimidazoliumtetrafluoroborate ([Cnmim][BF4] (n = 2, 4, 6, 8, 10)) ILs were degraded in an ultrasonic zero-valent zinc (ZVZ) and activated carbon (AC) micro-electrolysis system. Optimization of degradation conditions and the degradation levels were studied by high performance liquid chromatography, the surface morphology of the ZVZ and AC changed before and after the reaction were observed by scanning electron microscope. The degradation intermediates were detected by gas chromatography- mass spectrometry and ion chromatography, and inferred the degradation pathway. The degradation effect of [C4mim][BF4] was best with ultrasonic assistance, pH 3 and an AC/ZVZ ratio of 1:1. The degradation of [Cnmim][BF4] in aqueous solution exceeded 91.7% in 120 min, and the mineralization level exceeded 88.9%. The surface of smooth and dense ZVZ particles became loose flocculent and the porous surface of AC became larger and rougher after reaction. The degradation pathway suggested that the imidazolium ring was sulfurized or oxidized, and then the ring was opened to form N-alkyl formamide and N-methyl formamide. ZVZ/AC micro-electrolysis combined with ultrasonic irradiation is an effective method to remove ILs, which provides new insight into IL degradation.

Risk factors for brain injury in premature infants with twin-to-twin transfusion syndrome: a retrospective cohort study.

Background: Brain injury (BI) is prevalent in premature infants with twin-to-twin transfusion syndrome (TTTS), while risk factors of BI in these patients remains unknown. Our study aims to discern potential risk factors that contribute to BI in premature infants with TTTS. Methods: We conducted a retrospective cohort and analyzed clinical data of premature infants diagnosed with TTTS at the Northwest Women's and Children's Hospital between January 1, 2015 and January 1, 2020. Data included the infants' perinatal information, key postnatal examinations, laboratory tests, and treatments. Results: Of the 84 patients enrolled in the study, 22 (26.2%) were categorized in the BI group and 62 (73.8%) in the non-BI group, based on cranial imaging. No significant differences were found at baseline between the groups in relation to the proportion of males (40.9% vs. 35.5%, P=0.845), median gestational age (weeks) [31.9 (31.5, 33.4) vs. 34.2 (31.6, 35.4), P=0.061], average weight (g) (1,676.4±567.5 vs. 1,845.2±511.7, P=0.200), maternal age (years) [29.5 (26.0, 31.0) vs. 28.5 (27.8, 31.0), P=0.656], the proportion of in-vitro fertilization (9.1% vs. 16.1%, P=0.648), cesarean sections (86.4% vs. 93.5%, P=0.549) or TTTS donor infants (50.0% vs. 51.6%, P=0.897). Multivariate logistic regression analysis indicated that invasive mechanical ventilation [invasive mechanical ventilation (IMV); odds ratio (OR) =4.365; 95% confidence interval (CI): 1.066-17.870; P=0.040], [necrotizing enterocolitis (NEC); OR =8.632; 95% CI: 1.542-48.318; P=0.014], [single intrauterine fetal demise (sIUFD); OR =14.067; 95% CI: 1.298-224.421; P=0.031], and a 5-minute Apgar score <9 (OR =4.663; 95% CI: 1.015-21.419; P=0.048) were strongly associated with BI in TTTS premature infants. Conclusions: Our study identifies IMV, NEC, sIUFD, and a 5-minute Apgar score <9 as independent risk factors for BI in premature infants with TTTS.

Five critically ill pregnant women/parturients treated with extracorporeal membrane oxygenation.

BACKGROUND: Maternal mortality has always been a major medical concern. Recently, the successful application of extracorporeal membrane oxygenation (ECMO) technology in the rescue of near-death patients has been reported. CASE PRESENTATION: This study retrospectively analyzed 5 cases of critically ill pregnant women/parturients treated with ECMO for respiratory and circulatory failure in the Wuxi People's Hospital from 2018 to 2020. The mean age of the 5 cases was 30.2 years. Among them, Cases 1 and 5 were treated with Venoarterial (VA) ECMO. Case 1 was diagnosed with congenital heart disease, atrial septal defect, and severe pulmonary hypertension. VA ECMO was applied before cesarean section and was successfully removed after double lung transplantation, but the patient died 10 months after delivery from lung infection. While Case 5 was diagnosed with systemic lupus erythematosus, lupus nephritis, thrombotic vascular disease, HELLP syndrome, and cerebral hemorrhage. VA ECMO was applied 39 days after cesarean section, and the patient died 40 days after delivery due to multiple organ failure. Cases 3 and 4 were treated with Venovenous (VV) ECMO. Case 3 was diagnosed with refractory postpartum hemorrhage, and Case 4 was diagnosed with postpartum hypoglycemic coma, aspiration pneumonia, and shock. They were treated with VV ECMO after delivery, and all survived after successful evacuation. Another Case (Case 2) was diagnosed with postpartum pelvic infection, sepsis and septic shock, and was treated with VA ECMO at 15 days after delivery. The patient changed to VV ECMO at 30 days after delivery due to significant improvement in heart function and poor lung function, but eventually died of multiple organ failure. For the 5 cases, the mean duration of ECMO was 8.7 days, the mean duration of intensive care was 22.0 days, and the mean length of hospital stay was 57.6 days. As a result, 3 patients gradually returned to normal with significant improvement in ventilation and oxygenation after ECMO treatment. CONCLUSIONS: ECMO technology can be used to treat some of the critical obstetric patients with respiratory and circulatory failure that is ineffective to conventional treatment, but it has no therapeutic effect on the primary disease.

Study on the Effect of Early Comprehensive Intervention of Skin Contact Combined with Breastfeeding on Improving Blood Glucose in Early Birth of Newborns with Gestational Diabetes Mellitus.

Objective: To explore the value of early comprehensive intervention of skin contact combined with breastfeeding on improving early blood glucose in newborns with gestational diabetes mellitus (GDM). Methods: A total of 300 newborns from pregnant women with gestational diabetes who were hospitalized in Wuxi People's Hospital from January 2021 to December 2021 were randomly assigned into the observation group (n = 150) and the control group (n = 150). The former group received early comprehensive intervention of skin contact combined with breastfeeding, and the latter group received postnatal naked contact, physical examination after late navel severing, and routine nursing intervention such as early contact and early sucking in 30 min. The peripheral blood microglucose value at 1 and 2 hours after birth, neonatal hospitalization rate, ear temperature of 30 min, 60 min, 90 min, and 120 min after birth, neonatal crying, incidence of postpartum hemorrhage, uterine contraction/wound pain index, lactation before delivery, immediately after delivery, early sucking 15 min, and 2 hours postpartum were observed. Results: Compared to the control group, the values of trace blood glucose at 1 hour and 2 hours after birth in the observation group were higher, and the difference between groups was statistically significant (P < 0.05), the neonatal hospitalization rate in the observation group was lower, and the difference between groups was statistically significant (P < 0.05); the ear temperature of 30 min, 60 min, 90 min and 120 min after birth in the observation group was higher, and the difference between groups was statistically significant (P < 0.05). The crying frequency of newborns in the observation group was lower, and the difference between groups was statistically significant (P < 0.05). The incidence of postpartum hemorrhage in the observation group was lower, and the difference between groups was statistically significant (P < 0.05). The rate of uterine contraction/wound pain index grade 1 in the observation group was higher, and the difference between groups was statistically significant (P < 0.05). The rates of uterine contraction/wound pain index grade 2 and grade 3 in the observation group were lower, and the difference between groups was statistically significant (P < 0.05). The rate of lactation at 2 hours postpartum in the observation group was higher, and the difference between groups was statistically significant (P < 0.05). Conclusion: Early comprehensive intervention of skin contact combined with breastfeeding can significantly increase the early blood glucose of newborns with GDM, effectively promote the occurrence of early hypoglycemia of GDM newborns, avoid a series of serious complications caused by excessive fluctuation of blood sugar, promote the stability of vital signs of newborns, reduce the hospitalization rate of newborns, improve the success rate of breastfeeding, reduce uterine contraction/wound pain, and reduce the incidence of postpartum hemorrhage. My clinical registration number is chictr220059454.

Study of tRNA-Derived Fragment tRF-20-S998LO9D in Pan-Cancer.

Objective: The purpose is to study the effect of tRNA-derived fragments (tRFs) on pan-cancer through bioinformatics. Methods: The expression information of tRF-20-S998LO9D, a type of tRF-5, was retrieved through MINTbase in pan-cancer and verified by qPCR. We preliminarily explored the effect of tRF-20-S998LO9D on cell proliferation in breast cancer and lung cancer cell lines. Then an online KM-plotter provided by OncotRF was used to discover the prognostic significance. GO/KEGG analyses were executed to predict the potential mechanism of tRF-20-S998LO9D in cancer. Results: We found that tRF-20-S998LO9D was highly expressed in a variety of cancers like breast invasive carcinoma, head and neck squamous cell carcinoma, kidney renal clear cell carcinoma, lung squamous cell carcinoma, pheochromocytoma and paraganglioma, and uterine corpus endometrial carcinoma. Inhibition of tRF-20-S998LO9D led to reduced cell proliferation in breast cancer (MCF-7) and lung squamous cell carcinoma (SK-MES-1) cells. Elevated tRF-20-S998LO9D indicated poor prognosis in a variety of cancers. tRF-20-S998LO9D might be involved in multiple cancer-related pathways. Conclusion: We concluded that tRF-20-S998LO9D was upregulated and negatively correlated with prognosis of a variety of cancers. It may be a potential cancer-promoting marker in pan-cancer.

BRD7 Stabilizes P53 via Dephosphorylation of MDM2 to Inhibit Tumor Growth in Breast Cancer Harboring Wild-type P53.

Bromodomain-containing protein 7 (BRD7) was found to be down-expressed in nasopharyngeal carcinoma as well as breast cancer and to function as a potential tumor suppressor. BRD7 interacts with p53 and is required for p53-dependent oncogene-induced senescence. However, the mechanism how BRD7 functions as tumor suppressor roles in breast cancer remains unclear. MTT, colony formation assay, cell cycle, cell apoptosis, and tumorigenicity assays were performed to evaluate the biological functions of BRD7 in breast cancer cells in vitro and in vivo. Real-time PCR, western blot, luciferase reporter gene assays, and co-immunoprecipitation were used to examine the gene expression, transcription activation and protein-protein interaction. We reported that BRD7 effectively suppressed cell proliferation and tumor growth in vitro and in vivo. In addition, BRD7 increased p53 protein stability through ubiquitin-dependent proteasome pathway and regulated the expression of p53 downstream target genes by activating its transcriptional activity in breast cancers harboring wild-type p53. Mechanistically, BRD7 decreased phosphorylation and activation of MDM2 via inactivating its upstream kinase AKT depending on the bromodomain of BRD7, therefore BRD7 significantly reduced the amounts of phosphorylated MDM2 binding with p53 eventually decreasing ubiquitination level of p53. Furthermore, silencing the expression of p53 at least partly reversed the inhibition effect of BRD7 on cell proliferation and tumor growth in vitro and in vivo. Our studies identify that BRD7 stabilizes p53 by inhibiting the phosphorylation of MDM2 via AKT pathway dependent on its bromodomain to function as a tumor suppressor in breast cancer harboring wild-type p53.

Exosomal mRNA and lncRNA profiles in cord blood of preeclampsia patients.

BACKGROUND: Exosomes are endosome-derived membrane vesicles that contain numerous RNAs and allow intercellular communication. The roles of mRNAs and lncRNAs from umbilical cord blood exosomes in the development of preeclampsia (PE) remain unclear. METHODS: In the study, microarray technology was used to construct the differential mRNA and lncRNA expression profiles in umbilical cord blood exosomes between PE patients and normal controls. RESULTS: Totally, 120 differentially expressed mRNAs and 248 differentially expressed lncRNAs were identified. Pathway analysis showed that the differentially expressed mRNAs were related to glycolysis/gluconeogenesis, PI3K-Akt signaling pathway and JAK-STAT signaling pathway, which are critical in PE development. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted for the differential lncRNA-associated mRNAs. We found several significantly enriched pathways were closely associated with metabolic process, cell proliferation, differentiation, and apoptosis. Moreover, the constructed pathway network revealed key pathways in PE, including apoptosis and TGF-beta signaling pathway. Further analysis of lncRNA/miRNA interactions showed that most of the lncRNAs had miRNA binding sites, and some of them were associated with PE. CONCLUSIONS: The study highlights the importance of exosomal mRNAs and lncRNAs in umbilical cord blood, and provides new insight into the development of PE.

Circular RNA expression profiles in umbilical cord blood exosomes from normal and gestational diabetes mellitus patients.

Circular RNA (circRNA) is a novel member of endogenous noncoding RNAs with widespread distribution and diverse cellular functions. Recently, circRNAs have been identified for their enrichment and stability in exosomes. However, the roles of circRNAs from umbilical cord blood exosomes in gestational diabetes mellitus (GDM) occurrence and fetus growth remains poorly understood. In the present study, we used microarray technology to construct a comparative circRNA profiling of umbilical cord blood exosomes between GDM patients and controls. We found the exosome particle size was larger, and the exosome concentration was higher in the GDM patients. A total of 88,371 circRNAs in umbilical cord blood exosomes from two groups were evaluated. Of these, 229 circRNAs were significantly up-regulated and 278 circRNAs were significantly down-regulated in the GDM patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathway analyses demonstrated that circRNA parental genes involved in the regulation of metabolic process, growth and development were significantly enriched, which are important in GDM development and fetus growth. Further circRNA/miRNA interactions analysis showed that most of the exosomal circRNAs harbored miRNA binding sites, and some miRNAs were associated with GDM. Collectively, these results lay a foundation for extensive studies on the role of exosomal circRNAs in GDM development and fetus growth.

Differential mRNA and Long Noncoding RNA Expression Profiles in Umbilical Cord Blood Exosomes from Gestational Diabetes Mellitus Patients.

Background and Aims: Exosomes contain numerous RNAs and transfer them between cells or organs, thereby establishing intercellular or interorgan communication. The roles of mRNAs and long noncoding RNAs (lncRNAs) from umbilical cord blood exosomes in gestational diabetes mellitus (GDM) occurrence and fetus growth remain poorly understood. We aimed to establish the differential mRNA and lncRNA expression profiles in umbilical cord blood exosomes from GDM patients compared with normal controls. Results: Using microarray technology, we identified 84 mRNAs and 256 lncRNAs as differentially expressed in umbilical cord blood exosomes of GDM patients compared with controls. The protein-protein interaction network revealed that the differentially expressed mRNAs were associated with glucagon signaling pathway, an important GDM-related pathway. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathway analyses were performed for mRNAs associated with differentially expressed lncRNAs. The results indicated that metabolic process, growth, and development were significantly enriched, which are important in GDM development and fetus growth. Moreover, pathway network was constructed to reveal the key pathways in GDM, such as metabolic pathways and insulin signaling pathway. Further lncRNA/miRNA interaction analysis showed that most of the exosomal lncRNAs harbored miRNA binding sites, and some were associated with GDM. Conclusion: These results showed that exosomal mRNAs and lncRNAs are aberrantly expressed in the umbilical cord blood of GDM patients and play potential roles in GDM development and fetus growth.

Genome-wide identification and expression profiling of the carotenoid cleavage dioxygenase (CCD) gene family in Brassica napus L.

Carotenoid cleavage dioxygenase (CCD), a key enzyme in carotenoid metabolism, cleaves carotenoids to form apo-carotenoids, which play a major role in plant growth and stress responses. CCD genes had not previously been systematically characterized in Brassica napus (rapeseed), an important oil crop worldwide. In this study, we identified 30 BnCCD genes and classified them into nine subgroups based on a phylogenetic analysis. We identified the chromosomal locations, gene structures, and cis-promoter elements of each of these genes and performed a selection pressure analysis to identify residues under selection. Furthermore, we determined the subcellular localization, physicochemical properties, and conserved protein motifs of the encoded proteins. All the CCD proteins contained a retinal pigment epithelial membrane protein (RPE65) domain. qRT-PCR analysis of expression of 20 representative BnCCD genes in 16 tissues of the B. napus cultivar Zhong Shuang 11 ('ZS11') revealed that members of the BnCCD gene family possess a broad range of expression patterns. This work lays the foundation for functional studies of the BnCCD gene family.