Project description:The shift from maternal to embryonic control is a critical developmental milestone in preimplantation development. Widespread transcriptomic and epigenetic remodeling facilitate this transition from terminally differentiated gametes to totipotent blastomeres, but the identity of transcription factors (TF) and genomic elements regulating embryonic genome activation (EGA) are poorly defined. The timing of EGA is species-specific, e.g., the timing of murine and human EGA differ significantly. To deepen our understanding of mammalian EGA, here we profile changes in open chromatin during bovine preimplantation development. Before EGA, open chromatin is enriched for maternal TF binding, similar to that observed in humans and mice. During EGA, homeobox factor binding becomes more prevalent and requires embryonic transcription. A cross-species comparison of open chromatin during preimplantation development reveals strong similarity in the regulatory circuitry underlying bovine and human EGA compared to mouse. Moreover, TFs associated with murine EGA are not enriched in cattle or humans, indicating that cattle may be a more informative model for human preimplantation development than mice.
Project description:To evaluate whether there is increased mother-to-child transmission of human immunodeficiency virus (HIV)-1 associated with deliveries at 40 weeks of estimated gestational age (EGA) or greater in pregnant women with HIV-1 viral loads of 1,000 copies/mL or less.We performed a secondary analysis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development International Site Development Initiative Perinatal and Longitudinal Study in Latin American Countries and International Maternal Pediatric Adolescent AIDS Clinical Trials P1025 cohorts. We included pregnant women with HIV-1 with recent viral loads of 1,000 copies/mL or less at the time of delivery and compared delivery outcomes at between 38 and less than 40 weeks EGA with delivery outcomes at 40 weeks EGA or greater, the exposure of interest. Our primary outcome of interest was mother-to-child transmission, and secondary outcomes included indicators of maternal and neonatal morbidity. We examined the association between EGA and mother-to-child transmission using Poisson distribution. Associations between EGA and secondary outcomes were examined through bivariate analyses using Pearson ? and Fisher exact test or the nonparametric Mann-Whitney U test.Among the 2,250 eligible neonates, eight neonates were infected with HIV-1 (overall transmission rate 0.4%, 95% CI 0.2-8.1%, 40 weeks EGA or greater 0.5% [3/621, 95% CI 0.2-1.4%], less than 40 weeks EGA 0.3% [5/1,629, 95% CI 0.1-0.7%]); there was no significant difference in transmission by EGA (rate ratio 1.57, 95% CI 0.24-8.09, P=.77). There was no difference in maternal viral load between the two groups nor was there a difference in timing of transmission among neonates born with HIV-1.In pregnant women with well-controlled HIV-1, the risk of mother-to-child transmission did not differ significantly by EGA at delivery, although we were not powered to demonstrate equivalence of proportions of mother-to-child transmission between EGA groups.
Project description:Maternal effect factors derived from oocytes are important for sustaining early embryonic development before the major wave of embryonic genome activation (EGA). In this study, we report a two-cell-stage arrest of embryos lacking maternal 3-phosphoinositide-dependent protein kinase 1 as a result of suppressed EGA. Concurrent deletion of maternal Pten completely rescued the suppressed EGA and embryonic progression through restored AKT signalling, which fully restored the fertility of double-mutant females. Our study identifies maternal phosphatidylinositol 3-kinase signalling as a new maternal effect factor that regulates EGA and preimplantation embryogenesis in mice.
Project description:Fertilization is followed by complex changes in cytoplasmic composition and extensive chromatin reprogramming which results in the abundant activation of totipotent embryonic genome at embryonic genome activation (EGA). While chromatin reprogramming has been widely studied in several species, only a handful of reports characterize changing transcriptome profiles and resulting metabolic changes in cleavage stage embryos. The aims of the current study were to investigate RNA profiles of in vivo developed (ivv) and in vitro produced (ivt) porcine embryos before (2-cell stage) and after (late 4-cell stage) EGA and determine major metabolic changes that regulate totipotency. The period before EGA was dominated by transcripts responsible for cell cycle regulation, mitosis, RNA translation and processing (including ribosomal machinery), protein catabolism, and chromatin remodelling. Following EGA an increase in the abundance of transcripts involved in transcription, translation, DNA metabolism, histone and chromatin modification, as well as protein catabolism was detected. The further analysis of members of overlapping GO terms revealed that despite that comparable cellular processes are taking place before and after EGA (RNA splicing, protein catabolism), different metabolic pathways are involved. This strongly suggests that a complex metabolic switch accompanies EGA. In vitro conditions significantly altered RNA profiles before EGA, and the character of these changes indicates that they originate from oocyte and are imposed either before oocyte aspiration or during in vitro maturation. IVT embryos have altered content of apoptotic factors, cell cycle regulation factors and spindle components, and transcription factors, which all may contribute to reduced developmental competence of embryos produced in vitro. Overall, our data are in good accordance with previously published, genome-wide profiling data in other species. Moreover, comparison with mouse and human embryos showed striking overlap in functional annotation of transcripts during the EGA, suggesting conserved basic mechanisms regulating establishment of totipotency in mammalian development.
Project description:OBJECTIVE:Patient-physician discordance in health status ratings may arise because patients use temporal comparisons (comparing their current status with their previous status), while clinicians use social comparisons (comparing this patient's status to that of other patients, or to the full range of disease severity possible) to guide their assessments. We compared discordance between patients with rheumatoid arthritis (RA) and clinicians, using either the conventional patient global assessment (PGA) or a rating scale with 5 anchors describing different health states. We hypothesized that discordance would be smaller with the rating scale because clinicians likely used similar social comparisons when making global assessments. METHODS:We prospectively studied 206 patients with active RA and assessed the PGA (range 0-100), rating scale (range 0-100), and evaluator global assessment (EGA; range 0-100) on each of 2 visits (total visits?=?401). We compared the PGA/EGA discordance and the rating scale/EGA discordance at each visit. RESULTS:The mean?±?SD PGA/EGA discordance was 8.5?±?22.4, and the mean?±?SD rating scale/EGA discordance was 2.3?±?24.0. The intraclass correlation, measuring agreement, was higher between the rating scale and EGA than between the PGA and EGA (0.39 versus 0.31). Agreement was larger at low levels of RA activity on both pairs of measures. CONCLUSION:Discordance between patients' global assessments and evaluators' global assessments was smaller when patients used a social standard of comparison than when they marked the PGA, suggesting that differences in standards of comparison contribute to patient-clinician discordance when the PGA is used.
Project description:Embryos utilize oocyte-donated RNAs until they become capable of producing RNAs through embryonic genome activation (EGA). The sperm's influence over pre-EGA RNA content of embryos remains unknown. Recent studies have revealed that sperm donate non-genomic components upon fertilization. Thus, sperm may also contribute to RNA presence in pre-EGA embryos. The first objective of this study was to investigate whether male fertility status is associated with the RNAs present in the bovine embryo prior to EGA. A total of 65 RNAs were found to be differentially expressed between 2-4 cell bovine embryos derived from high and low fertility sires. Expression patterns were confirmed for protein phosphatase 1 regulatory subunit 36 (PPP1R36) and ataxin 2 like (ATXN2L) in three new biological replicates. The knockdown of ATXN2L led to a 22.9% increase in blastocyst development. The second objective of this study was to characterize the parental origin of RNAs present in pre-EGA embryos. Results revealed 472 sperm-derived RNAs, 2575 oocyte-derived RNAs, 2675 RNAs derived from both sperm and oocytes, and 663 embryo-exclusive RNAs. This study uncovers an association of male fertility with developmentally impactful RNAs in 2-4 cell embryos. This study also provides an initial characterization of paternally-contributed RNAs to pre-EGA embryos. Furthermore, a subset of 2-4 cell embryo-specific RNAs was identified.
Project description:Animals underwent combined general-epidural anesthesia (EGA) is reported to have better long-time outcome than general anesthesia (GA). This study aimed to make overall evaluation of the association between these two anesthetic techniques and prognosis of cancer patients undergoing surgery.Related databases such as PubMed and EMbase were searched for eligible studies that evaluated the influence of EGA and GA on the prognosis of cancer patients undergoing surgery. Selected studies were evaluated according to the inclusion criteria by two reviewers respectively, followed by data extraction and quality assessment. The odds ratio (OR) with their 95% confidence intervals (CIs) were calculated to assess the influence strength of EGA and GA on prognosis of cancer patients.A total of ten studies involving 3254 patients were included. The overall results demonstrated that there was no significant difference between EGA and GA group (OR?=?0.88, 95% CI 0.73 to 1.06, P?=?0.187) concerning postoperative recurrence and metastasis rate. In regard to the following two factors: cancer category and time of follow-up, subgroup analysis identified significant differences between EGA and GA in the group of patients with prostate cancer and the group with follow-up less than or equal to two years (OR?=?0.66, 95% CI 0.46 to 0.95, P?=?0.027; OR?=?0.70, 95% CI 0.51 to 0.98, P?=?0.035; respectively) concerning postoperative recurrence and metastasis rate. However, no significant difference was found in the group of patients with colorectal cancer (OR?=?1.06, 95% CI 0.84-1.33, P?=?0.62).This meta-analysis showed that EGA might be associated with improvement in prognosis of patients with operable prostate cancer and the cancer patients with follow-up less than or equal to two years. However, no obvious relationship between the improvement in prognosis of colorectal cancer and EGA were detected, comparing to GA. Furthermore, all the results should be interpreted cautiously, as heterogeneous data were used for analyzing.
Project description:BackgroundThis study was conducted retrospectively to investigate the survival of patients undergoing gastric cancer surgery with epidural combined with general anesthesia (EGA) and general anesthesia alone (GA).MethodsWe retrospectively analyzed 596 patients with gastric cancer who were scheduled for radical resection. Propensity score matching was performed at a 1:1 ratio between GA (n=97) and EGA (n=97) to reduce selection bias. Univariate and multivariate analyses were used to identify factors significantly correlated with recurrence and/or metastasis and prognosis. The 5-year overall survival rates of patients receiving EGA and GA alone were compared.ResultsAfter the propensity scores were matched, there were 97 patients who underwent EGA and 97 patients who underwent GA. For the entire population, reconstruction type, pN stage, and complications were significantly correlated with prognosis based on multivariate analyses. For patients with a recurrence and/or metastasis, lymphadenectomy and pN stage were shown to be independent prognostic factors by multivariate analysis.ConclusionsIn summary, patients might benefit from EGA as a result of better analgesic and anti-inflammatory effects, fewer postoperative complications, higher safety, and a lower rate of metastasis and recurrence is conducive to postoperative recovery in patients with gastric cancer.
Project description:Botulinum neurotoxins (BoNTs) form a large class of potent and deadly neurotoxins. Given their growing number, it is of paramount importance to discover novel inhibitors targeting common steps of their intoxication process. Recently, EGA was shown to inhibit the action of bacterial toxins and viruses exhibiting a pH-dependent translocation step in mammalian cells, by interfering with their entry route. As BoNTs act in the cytosol of nerve terminals, the entry into an appropriate compartment wherefrom they translocate the catalytic moiety is essential for toxicity. Herein we propose an optimized procedure to synthesize EGA and we show that, in vitro, it prevents the neurotoxicity of different BoNT serotypes by interfering with their trafficking. Furthermore, in mice, EGA mitigates botulism symptoms induced by BoNT/A and significantly decreases the lethality of BoNT/B and BoNT/D. This opens the possibility of using EGA as a lead compound to develop novel inhibitors of botulinum neurotoxins.
Project description:The mannose-6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) encodes a protein that plays a critical role in tumor suppression, in part by modulating bioavailability of a potent mitogen, insulin-like growth factor-2 (IGF2). We tested the hypothesis that the common nonsynonymous genetic variants in M6P/IGF2R c.901C > G (Leu > Val) in exon 6 and c.5002G > A (Gly > Arg) in exon 34 are associated with risk of esophageal and gastric cancers. Study participants in this population-based study comprise 197 controls and 182 cases, including 105 with esophageal-gastric cardia adenocarcinoma (EGA), 57 with noncardia gastric adenocarcinoma and 20 with esophageal squamous (ES) cell carcinoma. Among white males, odds ratios (ORs) were elevated in relation to carrying at least 1 c.901C > G allele for EGA [OR = 1.9; 95% confidence intervals (CIs) = 1.0-3.6] and noncardia gastric cancer (OR = 2.5; 95% CI = 1.2-5.5), but not ES. Exploratory subgroup analyses suggested that associations between EGA and this variant were stronger among irregular or nonusers of nonsteroidal anti-inflammatory drugs (NSAIDs) (OR = 2.3; 95% CI = 1.2-4.2) and cigarette smokers (OR = 2.1; 95% CI = 1.0-4.2). An association between carrying the c.5002G > A genotype and EGA was not evident. These findings suggest that nonsynonymous polymorphisms in M6P/IGF2R may contribute to the risks of EGA and noncardia adenocarcinomas. Larger studies are required to confirm these findings.