YBX2 modulates mRNA stability via interaction with YTHDF2 in endometrial cancer cells.

RNA-binding proteins (RBPs) fine-tune gene expression by modulating RNA stability, translation, and degradation. RBPs are involved in the development of endometrial cancer. In particular, Y-box-binding protein 2 (YBX2), a germ cell-specific member of the YBX family, has been reported to maintain cancer stem cell-like phenotypes in endometrial cancer. However, the mechanism by which YBX2 modulates mRNA stability in endometrial cancer cells remains unknown. In this study, we examined the effects of the ectopic expression of YBX2 in endometrial adenocarcinoma-derived Ishikawa cells. We found that elevated levels of YBX2 delayed cell proliferation, without increasing cell apoptosis. Transcriptomic analysis revealed disturbances in gene expression caused by YBX2. Interestingly, heat shock protein family A (Hsp70) member 6 (HSPA6) levels were downregulated due to the reduced mRNA stability after YBX2 binding. YBX2 facilitated the formation of relatively stable cytoplasmic granules in tumor cells via its mRNA binding domain. Moreover, N6-methyladenosine (m6A) reader proteins are recruited by YBX2 granules via the cold-shock domain. Notably, knockdown of YTH N6-methyladenosine RNA-binding protein F2 (YTHDF2), an m6A reader, ameliorated the reduction in HSPA6 mRNA levels induced by YBX2, indicating the synergistic effects of YBX2 and YTHDF2 on mRNA stability. Therefore, YBX2 regulates RNA stability by interacting with the m6A reader proteins.

APOE ε4 allele modifies the associations of toxic metals and their mixture with cognitive impairment among older adults.

BACKGROUND: The evidence of interactive effect of the toxic metal (TM) mixture and apolipoprotein E (APOE) ε4 gene on cognitive impairment in older adults is scarce. We aimed to explore whether the associations of single TMs and their mixture with cognitive impairment depend on APOE ε4 in Chinese community-dwelling older people. METHODS: A total of 1148 older adults from a subset of the baseline survey of a cohort study were included. Blood arsenic (As), cadmium (Cd), lead (Pb), strontium (Sr), and vanadium (V) were detected by inductively coupled plasma mass spectrometry. APOE gene (rs429358, rs7412) polymorphisms were analyzed by the Polymerase Chain Reaction instrument. Mixed effects logistic regression was applied to estimate the relationships of single TMs and APOE genotype with cognitive impairment. Weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) models were performed to examine joint impacts of the TM mixture, as well as the interaction of the TM mixture with APOE ε4 genotype on cognitive impairment. RESULTS: Pb displayed a significant linear association with an increased odds of cognitive impairment after adjustment for covariates (Ptrend = 0.045). While APOE genotype did not show a significant correlation with cognitive impairment. WQS showed that the TM mixture was associated with an increased risk of cognitive impairment by 31.0% (OR=1.31, 95% CI: 0.92, 1.87) while no significance was found. BKMR exhibited a significant linear association between the TM mixture and cognitive impairment. Moreover, both WQS and BKMR indicated that Pb contributed the most to cognitive impairment within the mixture. Significant interactions of Pb or the TM mixture and APOE genotype on cognitive impairment were observed, contributing to 38.1% and 38.2% of total effects, respectively. CONCLUSIONS: APOE ε4 allele amplifies the associations of single Pb or the TM mixture with cognitive impairment. These findings may help to develop precision prevention.

Validation of hyperthermia as an enhancer of chemotherapeutic efficacy: insights from a bladder cancer organoid model.

OBJECTIVE: This study aimed to evaluate the combined efficacy of hyperthermia and chemotherapy using a bladder cancer organoid model and to explore hyperthermia-related molecular pathways. METHOD: Tumor organoids were generated by embedding RT4 bladder cancer cells into Matrigel. The resulting organoids were treated with pirarubicin or gemcitabine at 37 °C or 42 °C. Proliferation was determined by Ki67 immunofluorescence staining, and apoptosis was assessed using a TdT-mediated dUTP nick end labeling (TUNEL) assay. RNA sequencing was used to identify the differentially expressed genes. RESULTS: Bladder cancer organoids were successfully established and exhibited robust proliferative abilities. Treatment with gemcitabine or pirarubicin under hyperthermic conditions caused pronounced structural damage to the organoids and increased cell death compared to that in the normothermically treated group. Furthermore, Ki67 labeling and TUNEL assays showed that the hyperthermia chemotherapy group showed a significantly reduced proliferation rate and high level of apoptosis. Finally, RNA sequencing revealed the IFN-γ signaling pathway to be associated with hyperthermia. CONCLUSION: Overall, hyperthermia combined with chemotherapy exerted better therapeutic effects than those of normothermic chemotherapy in grade 1-2 non-muscle-invasive bladder cancer, potentially through activation of the IFN-γ-JAK-STAT pathway.

Short-term associations between ambient PM1, PM2.5, and PM10 and hospital admissions, length of hospital stays, and hospital expenses for patients with cardiovascular diseases in rural areas of Fuyang, East China.

Evidence on the impacts of PM1, PM2.5, and PM10 on the hospital admissions, length of hospital stays (LOS), and hospital expenses among patients with cardiovascular disease (CVD) is still limited in China, especially in rural areas. This study was performed in eight counties of Fuyang from 1 January 2015 to 30 June 2017. We use a three-stage time-series analysis to explore the effects of short-term exposure to PM1, PM2.5, and PM10 on hospital admissions, LOS, and hospital expenses for CVDs. An increment of 10 ug/m3 in PM1, PM2.5, and PM10 corresponded to an increment of 1.82% (95% CI: 1.34, 2.30), 0.96% (95% CI: 0.44, 1.48), and 0.79% (95% CI: 0.63%, 0.95%) in CVD hospital admissions, respectively. We observed that daily concentrations of PMs were associated with an increase in hospital admissions, LOS, and expenses for CVDs. Sustained endeavors are required to reduce air pollution so as to attenuate disease burdens from CVDs.

Associations of toxic metals and their mixture with hyperuricemia in Chinese rural older adults.

Previous studies have related single toxic metals (TMs) to hyperuricemia (HUA) among the general population, however, the association of the TM mixture with HUA, especially in older adults, remains poorly understood. We aimed to examine the relationships between individual TMs and their mixture and HUA in Chinese rural older adults. This study consisted of 2075 rural older adults aged 60 years or over. Blood concentrations of aluminum (Al), arsenic (As), barium (Ba), cadmium (Cd), cesium (Cs), gallium (Ga), mercury (Hg), lead (Pb), thallium (Tl), and uranium (U) were detected using inductively coupled plasma mass spectrometry. The associations of single TMs with HUA were assessed using logistic regression and restricted cubic spline (RCS) models, and the association of TM mixture with HUA was explored using the elastic net with environmental risk score (ENET-ERS), quantile g-computation (QGC), and Bayesian kernel machine regression (BKMR) models, respectively. Adjusted logistic regression model showed that Cs (OR = 1.65, 95% CI 1.37-1.99) and Pb (OR = 1.46, 95% CI 1.28-1.67) were positively related to HUA, and RCS model exhibited a positive linear association of Cs and Pb with HUA. ENET-ERS and QGC models quantified a positive correlation between the TM mixture and the odds of HUA, with estimated ORs of 1.15 (95% CI 1.11-1.19) and 1.84 (95% CI 1.37-2.47), respectively, and Cs and Pb had the most weight. BKMR model demonstrated a significant linear association between the TM mixture and increased odds of HUA, with the posterior inclusion probabilities (PIPs) of both Cs and Pb being 1.00. Moreover, we observed a positive interaction between Cs and Pb on HUA. The TM mixture is associated with increased odds of HUA in rural older adults, which may mainly be driven by Cs and Pb. Subsequent studies are warranted to confirm these findings and clarify the mechanisms linking multiple TMs with HUA.

hsa-miR-320a-3p and hsa-miR-483-5p levels in human granulosa cells: promising bio-markers of live birth after IVF/ICSI.

BACKGROUND: MicroRNAs (miRNAs) are considered potential biomarkers for various diseases. This study investigated whether hsa-miR-320a-3p and hsa-miR-483-5p levels in human ovarian granulosa cells derived from follicular fluids are associated with embryo developmental competence. METHODS: We collected 195 granulosa cells samples and analyzed the treatment outcomes in patients undergoing in vitro fertilization (n = 147) or intracytoplasmic sperm injection (n = 48) cycles. The hsa-miR-320a-3p and hsa-miR-483-5p levels in granulosa cells were measured using quantitative reverse transcription-polymerase chain reaction. RESULTS: Patients were subdivided into four groups according to the granulosa cells hsa-miR-320a-3p and hsa-miR-483-5p levels quartiles (Q1-Q4). Embryo developmental competence was compared using the chi-square test. Patients in Q3 were less likely to achieve a normal fertilization rate for in vitro fertilization and blastocyst formation than those in Q1 as they expressed high levels of hsa-miR-320a-3p and hsa-miR-483-5p (P < 0.05). Patients in Q3 and Q4 were less likely to achieve a good-quality embryo as they expressed high levels of hsa-miR-483-5p and hsa-miR-320a-3p (P < 0.05). The hsa-miR-320a-3p and hsa-miR-483-5p levels were not associated with clinical pregnancy. However, multiple regression analysis indicated that in Q3 and Q4 intervals had experienced a decreased chance of live birth due to high expression levels of hsa-miR-320a-3p and hsa-miR-483-5p levels. The relative hsa-miR-320a-3p expression levels in granulosa cells were weakly and positively correlated with the patient age (P = 0.0033). Moreover, both the basal follicle stimulating hormone (P = 0.0003) and ovarian stimulation protocols (P = 0.006 and P = 0.004) significantly and positively affected hsa-miR-320a-3p levels. The days of stimulation was negatively correlated with the relative hsa-miR-320a-3p expression level (P = 0.047). CONCLUSIONS: The hsa-miR-320a-3p and hsa-miR-483-5p levels in human granulosa cells negatively correlated with the good-quality embryo rate and live birth, indicating that hsa-miR-320a-3p and hsa-miR-483-5p can be used as potential negative indicators to predict good-quality embryos and live births.

The association between essential trace element mixture and cognitive function in Chinese community-dwelling older adults.

BACKGROUND: The evidence about the effect of essential trace element (ETE) mixture on cognitive function amongst older adults is limited. This study aims to evaluate the associations of single ETEs and ETE mixture with cognitive function using a representative sample of community-dwelling older adults in China. METHODS: A total of 3814 older adults were included in the study. Urinary concentrations of selenium (Se), vanadium (V), cobalt (Co), strontium (Sr), and molybdenum (Mo) were detected by inductively coupled plasma mass spectrometry. Cognitive function in older adults was assessed using the Chinese version of the Mini-Mental State Examination (MMSE). Linear regression and Bayesian kernel machine regression (BKMR) were performed to explore the associations of single ETEs and ETE mixture with cognitive function, respectively. RESULTS: Linear regression showed that urinary levels of Se and V were positively associated with MMSE scores in the adjusted single-element models. BKMR also showed marginally positive associations of Se and V with MMSE scores. Moreover, higher urinary levels of ETE mixture were significantly associated with increased MMSE scores in a dose-response pattern, and Se was the most important contributor within the mixture. Both Se and V demonstrated positive additive effects on the associations of other ETEs with MMSE scores, whereas Co had a negative additive effect. CONCLUSIONS: V and Se are positively associated with cognitive function, individually and as a mixture. ETE mixture exhibits a linear dose-response association with improved cognitive function, with Se being the most important component within the mixture. Mixture analyses rather than single ETE analyses may provide a real-world perspective on the relationship between ETE mixture and cognitive function. Further cohort studies are needed to clarify the association of multiple ETEs with cognitive function.

C-Type Natriuretic Peptide (CNP) Could Improve Sperm Motility and Reproductive Function of Asthenozoospermia.

This study is to analyze the effect of C-type natriuretic peptide (CNP) on sperm motility of asthenozoospermia and explore the influence mechanism of CNP on the reproductive system and sperm motility. Our results showed that the concentration of CNP in asthenospermia patients' semen was lower than in normal people's. The motility of sperm could be improved markedly by CNP and 8-Br-cGMP, while the effect of CNP was inhibited by NPR-B antagonist and KT5823. In the asthenozoospermia mouse model induced by CTX, CNP injection could improve sperm motility in the epididymis, alleviate tissue damage in the testes and epididymis, and increase testosterone levels. The asthenospermia mouse model showed high activity of MDA and proinflammatory factors (TNF-α, IL-6), as well as low expression of antioxidants (SOD, GSH-Px, CAT) in the testis and epididymis, but this situation could be significantly ameliorated after being treated with CNP. Those studies indicated that the concentration of CNP in the semen of asthenospermia patients is lower than in normal people and could significantly promote sperm motility through the NPR-B/cGMP pathway. In the asthenospermia mouse model induced by CTX, CNP can alleviate the damage of cyclophosphamide to the reproductive system and sperm motility. The mechanism may involve increasing testosterone and reducing ROS and proinflammatory factors to damage the tissue and sperm.

The association of marital status with cognitive function and the role of gender in Chinese community-dwelling older adults: a cross-sectional study.

BACKGROUND: Evidence of the association between marital status and cognitive function in Chinese older adults is limited. AIMS: To examine the relationship between marital status and cognitive function and to explore the role of gender amongst older adults from three Chinese communities. METHODS: A total of 1376 participants aged 60 years or over were included in this cross-sectional study. Cognitive function was assessed using the Chinese version of the mini-mental state examination (MMSE). Marital status and other variables were collected using a standardized questionnaire. Multiple linear regression models were used to examine associations between marital statuses and cognitive function amongst the target population. The moderating role of gender in these potential associations has also been explored. RESULTS: In univariate linear regression models, compared to being married, both being widowed (ß [95% CI]: -1.46[-2.78 to - 0.13]) and being single (ß [95% CI]: - 4.88[-6.43 to - 3.38]) were associated with lower MMSE scores. After adjustment for confounding factors, the significant association of being widowed with MMSE scores disappeared (ß [95% CI: - 0.08[- 1.04 to 0.86]), but the association of being single with MMSE scores still existed (ß [95% CI]: - 1.87[- 3.17 to - 0.58]). Furthermore, the association of being single with MMSE scores was statistically significant in men (ß [95% CI]: - 5.25[- 7.17 to - 3.33]) but not in women (ß [95% CI: 0.88[- 0.87 to 2.64]). DISCUSSION AND CONCLUSIONS: Being single was associated with poorer cognitive function compared with their married counterparts in older Chinese men but not in women. More preventive measurements should be implemented for single men to reduce or delay cognitive decline. This is particularly important in the context of an aging population in China.

The associations between urinary metals and metal mixtures and kidney function in Chinese community-dwelling older adults with diabetes mellitus.

BACKGROUND: Previous studies have found associations between single toxic metals, such as arsenic and cadmium, and kidney function in adults with diabetes. However, studies with regards to other metals and metal mixtures are still limited. OBJECTIVE: Our study aimed to investigate the associations between urinary concentrations of 5 selected metals and metal mixtures and kidney function using a sample of older adults with diabetes mellitus in Chinese communities. METHODS: In a sample of older adults (n = 5186), 592 eligible subjects were included in this study. Urinary concentrations of 5 metals, i.e., arsenic (As), cadmium (Cd), vanadium (V), cobalt (Co), and thallium (Tl), were measured by inductively coupled plasma mass spectrometer (ICP-MS). Estimated glomerular filtration rate (eGFR) was calculated and dichotomized into indicator of chronic kidney disease (CKD). Logistic analysis and Bayesian kernel machine regression (BKMR) were used to explore the associations between single metals and metal mixtures and CKD, respectively. RESULTS: Urinary levels of As and V were positively correlated with CKD (OR=2.37, 95% CI: 1.31-4.30 for As; OR=2.24, 95% CI: 1.25-4.03 for V), when compared the 4th quartile with the 1st quartile. After adjustment for potential confounders, the significant association between As and CKD still existed (OR=2.73, 95% CI: 1.23-6.07). BKMR analyses showed strong linear positive associations between As and V and CKD. Higher urinary levels of the mixture were significantly associated with higher odds of CKD in a dose-response pattern. As and V showed the highest posterior inclusion probabilities. CONCLUSION: Urine As and V were positively associated with CKD in older adults with diabetes mellitus, separately and in a mixture. The metals mixture showed a linear dose-response association with the odds of CKD. The analyses of mixtures, rather than of single metals, may provide a real-world perspective on the relationship between metals and kidney function.

cd44 deletion suppresses atypia in the precancerous mouse testis.

Loss-of-function of RHAMM causes hypofertility and testicular atrophy in young mice, followed by germ cell neoplasia in situ (GCNIS) of the testis, cellular atypia, and development of the testicular germ cell tumor (TGCT) seminoma. These pathologies reflect the risk factors and phenotypes that precede seminoma development in humans and-given the high prevalence of RHAMM downregulation in human seminoma-link RHAMM dysfunction with the aetiology of male hypofertility and GCNIS-related TGCTs. The initiating event underlying these pathologies, in RHAMM mutant testis, is premature displacement of undifferentiated progenitors from the basal compartment. We hypothesized that cd44 (both cancer initiating cell- and oncogenic progression marker) will drive GCNIS development, induced by RHAMM-loss-of-function in the mouse. We report that cd44 is expressed in a specific subset of GCNIS testes. Its genetic deletion has no effect on GCNIS onset, but it ameliorates oncogenic progression. We conclude that cd44 expression, combined with RHAMM dysfunction, promotes oncogenic progression in the testis.

hnRNPA2B1 represses the disassembly of arsenite-induced stress granules and is essential for male fertility.

Although the composition and assembly of stress granules (SGs) are well understood, the molecular mechanisms underlying SG disassembly remain unclear. Here, we identify that heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1) is associated with SGs and that its absence specifically enhances the disassembly of arsenite-induced SGs depending on the ubiquitination-proteasome system but not the autophagy pathway. hnRNPA2B1 interacts with many core SG proteins, including G3BP1, G3BP2, USP10, and Caprin-1; USP10 can deubiquitinate G3BP1; and hnRNPA2B1 depletion attenuates the G3BP1-USP10/Caprin-1 interaction but elevates the G3BP1 ubiquitination level under arsenite treatment. Moreover, the disease-causing mutation FUSR521C also disassembles faster from SGs in HNRNPA2B1 mutant cells. Furthermore, knockout of hnRNPA2B1 in mice leads to Sertoli cell-only syndrome (SCOS), causing complete male infertility. Consistent with this, arsenite-induced SGs disassemble faster in Hnrnpa2b1 knockout (KO) mouse Sertoli cells as well. These findings reveal the essential roles of hnRNPA2B1 in regulating SG disassembly and male mouse fertility.

The Association Between Essential Metal Element Mixture and Sleep Quality in Chinese Community-Dwelling Older Adults.

Previous studies have related single essential metal elements (EMEs) to sleep quality among older adults, however, the association of the EME mixture with sleep quality remained poorly understood. This study aimed to investigate the relationships between single EMEs and the EME mixture and sleep quality in older adults living in Chinese communities. This study consisted of 3957 older adults aged 60 years or over. Urinary concentrations of cobalt (Co), vanadium (V), selenium (Se), molybdenum (Mo), strontium (Sr), calcium (Ca), and magnesium (Mg) were detected using inductively coupled plasma mass spectrometry. Sleep quality was evaluated using Pittsburgh Sleep Quality Index (PSQI). The associations of single EMEs and EME mixture with sleep quality were assessed using logistic regression and Bayesian kernel machine regression (BKMR) models, respectively. Adjusted single-element logistic regression models showed that Mo (OR = 0.927, 95%CI:0.867-0.990), Sr (OR = 0.927, 95%CI:0.864-0.994), and Mg (OR = 0.934, 95%CI:0.873-0.997) were negatively related to poor sleep quality. BKMR models exhibited similar results. Also, higher levels of the EME mixture in urine were inversely related to the odds of poor sleep quality after adjustment for covariates, and Mo had the largest conditional posterior inclusion probability (condPIP) value in the mixture. Mo, Sr, and Mg were negatively related to poor sleep quality, separately and as the mixture. The EME mixture in urine was associated with decreased odds of poor sleep quality in older adults, and Mo was the greatest contributor within the mixture. Additional cohort research is warranted to clarify the relationship of multiple EMEs with sleep quality.

Physical activity attenuates the association of long-term exposure to nitrogen dioxide with sleep quality and its dimensions in Chinese rural older adults.

BACKGROUND: Joint impacts of air pollution and physical activity (PA) on sleep quality remain unaddressed. We aimed to investigate whether PA attenuates the association of long-term exposure to nitrogen dioxide (NO2) with sleep quality and its dimensions in older adults. METHODS: This study included 3408 Chinese rural older adults. Annual NO2 was estimated using the Space-Time Extra-Trees model. PA was assessed by International Physical Activity Questionnaire. Sleep quality was evaluated using Pittsburgh Sleep Quality Index (PSQI) scale. Linear regression models were used to assess the associations of long-term NO2 exposure and PA with sleep quality and its dimensions, and interaction plots were used to depict the attenuating effect of PA on associations of NO2 with sleep quality and its dimensions. RESULTS: Three-year (3-y) average NO2 (per 0.64-µg/m3 increment) was positively associated with global PSQI (ß = 0.41, 95 % CI: 0.23, 0.59), sleep duration (ß = 0.16, 95 % CI: 0.11, 0.21), and habitual sleep efficiency (ß = 0.22, 95 % CI: 0.17, 0.27), while PA was negatively associated with global PSQI (ß = -0.33, 95 % CI: -0.46, -0.20) and five domains of PSQI other than sleep duration and sleep disturbances. The associations of NO2 with global PSQI, sleep duration, and habitual sleep efficiency were attenuated with increased PA (Pinteraction were 0.037, 0.020, and 0.079, respectively). CONCLUSIONS: PA attenuates the adverse impacts of long-term NO2 exposure on sleep quality, especially on sleep duration, and habitual sleep efficiency, in Chinese rural elderly people. Participating in PA should be encouraged in this population, and continued efforts are still needed to reduce air pollution.

The interaction between physical activity and ambient particulate matters on cognitive function among Chinese community-dwelling older adults.

BACKGROUND: The interaction between physical activity (PA) and ambient particulate matters (PMs) on cognition is rarely investigated. Our study aimed to assess the interactions of PA and PMs on cognitive function in older adults. METHODS: Our study comprised 3937 Chinese community-dwelling older adults. Cognition was evaluated using the Mini-Mental State Examination. PA information was gathered using the International Physical Activity Questionnaire. The data of PMs were obtained from China High Air Pollutants (CHAP). Linear regressions model and interaction plots were applied to assess and visualize the interaction of PA and PMs on cognition, respectively. Bayesian kernel machine regression (BKMR) method was employed to visualize discernible thresholds for the interaction. RESULTS: PMs were negatively associated with MMSE scores (PM1: ß = -0.40, 95 % CI: -0.58, -0.28; PM2.5: ß = -0.46, 95 % CI: -0.64, -0.29; PM10: ß = -0.44, 95 % CI: -0.61, -0.26), and PA was positively affiliated with MMSE scores (ß = 0.18, 95 % CI: -0.01, 0.38). Interaction plots and BKMR demonstrated that adverse connotations of PMs with MMSE increased with the elevated PA levels, and the positive associations of PA with MMSE scores were attenuated by increased PMs (all Pinteraction < 0.20). Discernible thresholds for the interaction between PMs and PA on MMSE were found. CONCLUSIONS: Our findings suggest that PA should not be taken at higher PMs concentrations, and that low level of PA could be performed in PMs polluted environment to improve cognitive function. Further experimental and cohort researches are required to reproduce our discovery.

Enhancing Oocyte Quality in Aging Mice: Insights from Mesenchymal Stem Cell Therapy and FOXO3a Signaling Pathway Activation.

Ovarian aging reduced the quality of oocytes, resulting in age-related female infertility. It is reported that mesenchymal stem cells (MSCs) therapy can improve age-related ovarian function decline and the success rate of in vitro maturation (IVM) in assisted reproductive therapy. In order to investigate the effectiveness and mechanisms of MSCs to enhance oocyte quality of cumulus oocyte complexes (COCs) in advanced age, this study focus on the respective functional improvement of oocytes and granulosa cells (GCs) from aging mice and further to explore and verify the possible mechanisms. Here, we studied a popular but significant protein of follicular development, Forkhead box O-3a (FOXO3a), which is a transcription factor that mediates a variety of cellular processes, but the functions of which in regulating oocyte quality in MSCs therapy still remain inconclusive. In this study, the RNA-seq data of metaphase II (MII) oocytes and GCs isolated from COCs confirmed that, GCs of immature follicles show the most potential to be the targeted cells of bone marrow mesenchymal stem cells (BMSCs) by FOXO3a signaling pathway. Furthermore, we demonstrated the effectiveness of BMSCs co-culture with aging COCs to enhance oocyte quality and found its mechanism to function via ameliorating the biological function of GCs by alleviating FOXO3a levels. These results provide significant fundamental research on MSCs therapy on ovarian aging, as well as offering guidance for raising the success rate of assisted reproductive technology such IVM in clinical and non-clinical settings.

Combining Endometrial Assembloids and Blastoids to Delineate the Molecular Roadmap of Implantation.

Implantation is the process by which a competent blastocyst burrows into the receptive uterus to support embryo development. Successful implantation is of the utmost importance to pregnancy. However, due to the short window and difficulty in accessing the uterus in vivo during implantation, including ethical considerations, our understanding of the molecular network that safeguards this process remains incomplete. The use of three-dimensional (3D) culture systems has significant advantages as it recapitulates many aspects of the tissue organization and cell composition seen in vivo. With the recent advent of endometrial organoids and blastoids, it is now feasible to establish an in vitro implantation culture model to dissect the molecular signaling networks that are critical for implantation. In this review, we briefly summarize the current methodology for generating endometrial organoids and blastoids, along with the applications of these organoids for research on implantation. Incorporating stromal and immune cells, blood vessels, and others into the current endometrial organoid could build a more complete model of the endometrium, which can be combined with blastoids to model blastocyst implantation in vitro. We envision that this novel 3D system can be employed to elucidate the molecular mechanisms required for successful implantation.

CFIm-mediated alternative polyadenylation safeguards the development of mammalian pre-implantation embryos.

Alternative polyadenylation (APA) gives rise to transcripts with distinct 3' untranslated regions (3' UTRs), thereby affecting the fate of mRNAs. APA is strongly associated with cell proliferation and differentiation status, and thus likely plays a critical role in the embryo development. However, the pattern of APA in mammalian early embryos is still unknown. Here, we analyzed the 3' UTR lengths in human and mouse pre-implantation embryos using available single cell RNA-seq datasets and explored the underlying mechanism driving the changes. Although human and mouse early embryos displayed distinct patterns of 3' UTR changing, RNA metabolism pathways were involved in both species. The 3' UTR lengths are likely determined by the abundance of the cleavage factor I complex (CFIm) components NUDT21 and CPSF6 in the nucleus. Importantly, depletion of either component resulted in early embryo development arrest and 3' UTR shortening. Collectively, these data highlight an essential role for APA in the development of mammalian early embryos.

miR-484 mediates oxidative stress-induced ovarian dysfunction and promotes granulosa cell apoptosis via SESN2 downregulation.

Ovarian dysfunction is a common cause of female infertility, which is associated with genetic, autoimmune and environmental factors. Granulosa cells (GCs) constitute the largest cell population of ovarian follicles. Changes in GCs, including oxidative stress (OS) and excessive reactive oxygen species (ROS), are involved in regulating ovary function. miR-484 is highly expressed in 3-NP-induced oxidative stress models of ovaries and GCs. miR-484 overexpression aggravated GCs dysfunction and thereby intensified ovarian oxidative stress injury in mice. Moreover, bioinformatic analyses, luciferase assays and pull-down assays indicated that LINC00958 acted as a competing endogenous RNA (ceRNA) for miR-484 and formed a signaling axis with Sestrin2(SESN2) under oxidative stress conditions, which in turn regulated mitochondrial functions and mitochondrial-related apoptosis in GCs. Additionally, the inhibition of miR-484 alleviated GCs dysfunction under ovarian oxidative stress condition. Our present study revealed the role of miR-484 in oxidative stress of ovaries and GCs and the function of LINC00958/miR-484/SESN2 axis in mitochondrial function and mitochondria-related apoptosis.

Ambient nitrogen dioxide and cardiovascular diseases in rural regions: a time-series analyses using data from the new rural cooperative medical scheme in Fuyang, East China.

Most of studies relating ambient nitrogen dioxide (NO2) exposure to hospital admissions for cardiovascular diseases (CVDs) were conducted among urban population. Whether and to what extent these results could be generalizable to rural population remains unknown. We addressed this question using data from the New Rural Cooperative Medical Scheme (NRCMS) in Fuyang, Anhui, China. Daily hospital admissions for total CVDs, ischaemic heart disease, heart failure, heart rhythm disturbances, ischaemic stroke, and haemorrhagic stroke in rural regions of Fuyang, China, were extracted from NRCMS between January 2015 and June 2017. A two-stage time-series analysis method was used to assess the associations between NO2 and CVD hospital admissions and the disease burden fractions attributable to NO2. In our study period, the average number (standard deviation) of hospital admissions per day were 488.2 (117.1) for total CVDs, 179.8 (45.6) for ischaemic heart disease, 7.0 (3.3) for heart rhythm disturbances, 13.2 (7.2) for heart failure, 267.9 (67.7) for ischaemic stroke, and 20.2 (6.4) for haemorrhagic stroke. The 10-µg/m3 increase of NO2 was related to an elevated risk of 1.9% (RR: 1.019, 95% CI: 1.005 to 1.032) for hospital admissions of total CVDs at lag0-2 days, 2.1% (1.021, 1.006 to 1.036) for ischaemic heart disease, and 2.1% (1.021, 1.006 to 1.035) for ischaemic stroke, respectively, while no significant association was observed between NO2 and hospital admissions for heart rhythm disturbances, heart failure, and haemorrhagic stroke. The attributable fractions of total CVDs, ischaemic heart disease, and ischaemic stroke to NO2 were 6.52% (1.87 to 10.94%), 7.31% (2.19 to 12.17%), and 7.12% (2.14 to 11.85%), respectively. Our findings suggest that CVD burdens in rural population are also partly attributed to short-term exposure to NO2. More studies across rural regions are required to replicate our findings.