Meiotic resumption‐coupled degradation of maternal transcripts occurs during oocyte maturation in the absence of mRNA transcription. The CCR4–NOT complex has been identified as the main eukaryotic ...mRNA deadenylase. In vivo functional and mechanistic information regarding its multiple subunits remains insufficient. Cnot6l, one of four genes encoding CCR4–NOT catalytic subunits, is preferentially expressed in mouse oocytes. Genetic deletion of Cnot6l impaired deadenylation and degradation of a subset of maternal mRNAs during oocyte maturation. Overtranslation of these undegraded mRNAs caused microtubule–chromosome organization defects, which led to activation of spindle assembly checkpoint and meiotic cell cycle arrest at prometaphase. Consequently, Cnot6l−/− female mice were severely subfertile. The function of CNOT6L in maturing oocytes is mediated by RNA‐binding protein ZFP36L2, not maternal‐to‐zygotic transition licensing factor BTG4, which interacts with catalytic subunits CNOT7 and CNOT8 of CCR4–NOT. Thus, recruitment of different adaptors by different catalytic subunits ensures stage‐specific degradation of maternal mRNAs by CCR4–NOT. This study provides the first direct genetic evidence that CCR4–NOT‐dependent and particularly CNOT6L‐dependent decay of selective maternal mRNAs is a prerequisite for meiotic maturation of oocytes.
Synopsis
Maternal transcripts are degraded during oocyte maturation. A new mouse model demonstrates that Cnot6l, one of four genes encoding catalytic subunits of the mRNA deadenylation complex CCR4–NOT, is preferentially expressed in oocytes and mediates meiosis‐coupled maternal mRNA decay.
Genetic deletion of Cnot6l impaired deadenylation and degradation of a subset of maternal mRNAs during mouse oocyte maturation.
Cnot6l‐deficient female mice were severely subfertile.
Aberrant translation of undegraded mRNAs in the Cnot6l knockout caused microtubule–chromosome organization defects, activation of spindle assembly checkpoint and meiotic cell cycle arrest at prometaphase.
Recruitment of distinct RNA‐binding adaptor proteins by different CCR4–NOT subunits ensures stage‐specific degradation of maternal mRNAs.
CNOT6L and other CCR4–NOT components are important downstream effectors of ERK1 and ERK2 in regulating spindle assembly and meiotic cell cycle progression in oocytes.
A new mouse model shows that the CCR4‐NOT complex ensures timely clearance of maternal mRNAs in developing oocytes, thereby preventing aberrant translation and meiotic defects.
Abstract
Mira variables are asymptotic giant-branch pulsating stars with long pulsation periods and large amplitudes in optical bands. By applying the random forest algorithm to the
I
-band light ...curves for the Miras in the Magellanic Clouds, we have classified these Miras into regular Miras and nonregular Miras. Nonregular Miras exhibit a long-term variation in addition to their primary pulsation periods. Our results confirm that the period–luminosity relation for maximum light has a small dispersion, but only occurs on the regular oxygen-rich Miras, which we recommend to be applied in future distance-scale work. We have also collected multiband photometry for these Miras to perform a spectral energy distribution fitting with stellar and dust components, showing that a significant fraction of dust is present around the nonregular Miras. According to our results, we believe that the periodic long-term variations seen in the nonregular Miras might be due to the presence of dust.
Abstract
We present a systematic analysis to determine and improve the pulsation periods of 1637 known long-period Mira variables in M33 using
gri
-band light curves spanning ∼18 yr from several ...surveys, including the M33 variability survey, Panoramic Survey Telescope and Rapid Response System, Palomar Transient Factory (PTF), intermediate PTF, and Zwicky Transient Facility. Based on these collections of light curves, we found that optical-band light curves that are as complete as possible are crucial to determine the periods of distant Miras. We demonstrated that the machine-learning techniques can be used to classify Miras into O-rich and C-rich based on the (
J
−
K
s
) period–color plane. Finally, We derived the distance modulus to M33 using O-rich Miras at maximum light together with our improved periods as 24.67 ± 0.06 mag, which is in good agreement with the recommended value given in the literature.
Abstract
Based on 14 Miras located in seven globular clusters, we derived the first
gr
-band period–luminosity (PL) at maximum light for the large-amplitude Mira variables using the multiyear ...light-curve data collected from the Zwicky Transient Facility (ZTF). Since Miras are red variables, we applied a color-term correction to subsets of ZTF light curves, and found that such corrections do not have a large impact on period determinations. We applied our derived PL relations to the known extragalactic Miras in five local galaxies (Sextans, Leo I, Leo II, NGC 6822 and IC 1613), and determined their Mira-based distances. We demonstrated that our PL relations can be applied to short-period (≲300 days) Miras, including those in the two most distant galaxies (NGC 6822 and IC 1613) in our sample even when only a portion of the light curves around maximum light have detections. We have also shown that the long-period extragalactic Miras do not follow the PL relations extrapolated to longer periods. Hence, our derived PL relations are only applicable to the short-period Miras, which will be discovered in abundance in local galaxies within the era of Vera C. Rubin Observatory’s Legacy Survey of Space and Time.
We present Period-Luminosity and Period-Luminosity-Color relations at maximum light for Mira variables in the Magellanic Clouds using time-series data from the Optical Gravitational Lensing ...Experiment (OGLE-III) and Gaia data release 2. The maximum-light relations exhibit a scatter typically up to ∼30% smaller than their mean-light counterparts. The apparent magnitudes of oxygen-rich Miras at maximum light display significantly smaller cycle-to-cycle variations than at minimum light. High-precision photometric data for Kepler Mira candidates also exhibit stable magnitude variations at the brightest epochs, while their multi-epoch spectra display strong Balmer emission lines and weak molecular absorption at maximum light. The stability of maximum-light magnitudes for Miras possibly occurs due to the decrease in the sensitivity to molecular bands at their warmest phase. At near-infrared wavelengths, the period-luminosity relations (PLRs) of Miras display similar dispersion at mean and maximum light with limited time-series data in the Magellanic Clouds. A kink in the oxygen-rich Mira PLRs is found at 300 days in the VI-bands, which shifts to longer periods (∼350 days) at near-infrared wavelengths. Oxygen-rich Mira PLRs at maximum light provide a relative distance modulus, Δ = 0.48 0.08 mag, between the Magellanic Clouds with a smaller statistical uncertainty than the mean-light relations. The maximum-light properties of Miras can be very useful for stellar atmosphere modeling and distance scale studies provided their stability and the universality can be established in other stellar environments in the era of extremely large telescopes.
During mammalian oocyte growth, chromatin configuration transition from the nonsurrounded nucleolus (NSN) to surrounded nucleolus (SN) type plays a key role in the regulation of gene expression and ...acquisition of meiotic and developmental competence by the oocyte. Nonetheless, the mechanism underlying chromatin configuration maturation in oocytes is poorly understood. Here we show that nucleolar protein DCAF13 is an important component of the ribosomal RNA (rRNA)-processing complex and is essential for oocyte NSN-SN transition in mice. A conditional knockout of Dcaf13 in oocytes led to the arrest of oocyte development in the NSN configuration, follicular atresia, premature ovarian failure, and female sterility. The DCAF13 deficiency resulted in pre-rRNA accumulation in oocytes, whereas the total mRNA level was not altered. Further exploration showed that DCAF13 participated in the 18S rRNA processing in growing oocytes. The lack of 18S rRNA because of DCAF13 deletion caused a ribosome assembly disorder and then reduced global protein synthesis. DCAF13 interacted with a protein of the core box C/D ribonucleoprotein, fibrillarin, i.e., a factor of early pre-rRNA processing. When fibrillarin was knocked down in the oocytes from primary follicles, follicle development was inhibited as well, indicating that an rRNA processing defect in the oocyte indeed stunts chromatin configuration transition and follicle development. Taken together, these results elucidated the in vivo function of novel nucleolar protein DCAF13 in maintaining mammalian oogenesis.
Ferroptosis is a novel cell death mechanism that is mediated by iron-dependent lipid peroxidation. It may be involved in atherosclerosis development. Products of phospholipid oxidation play a key ...role in atherosclerosis. 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) is a phospholipid oxidation product present in atherosclerotic lesions. It remains unclear whether PGPC causes atherosclerosis by inducing endothelial cell ferroptosis. In this study, human umbilical vein endothelial cells (HUVECs) were treated with PGPC. Intracellular levels of ferrous iron, lipid peroxidation, superoxide anions (O2•−), and glutathione were detected, and expression of fatty acid binding protein-3 (FABP3), glutathione peroxidase 4 (GPX4), and CD36 were measured. Additionally, the mitochondrial membrane potential (MMP) was determined. Aortas from C57BL6 mice were isolated for vasodilation testing. Results showed that PGPC increased ferrous iron levels, the production of lipid peroxidation and O2•−, and FABP3 expression. However, PGPC inhibited the expression of GPX4 and glutathione production and destroyed normal MMP. These effects were also blocked by ferrostatin-1, an inhibitor of ferroptosis. FABP3 silencing significantly reversed the effect of PGPC. Furthermore, PGPC stimulated CD36 expression. Conversely, CD36 silencing reversed the effects of PGPC, including PGPC-induced FABP3 expression. Importantly, E06, a direct inhibitor of the oxidized 1-palmitoyl-2-arachidonoyl-phosphatidylcholine IgM natural antibody, inhibited the effects of PGPC. Finally, PGPC impaired endothelium-dependent vasodilation, ferrostatin-1 or FABP3 inhibitors inhibited this impairment. Our data demonstrate that PGPC impairs endothelial function by inducing endothelial cell ferroptosis through the CD36 receptor to increase FABP3 expression. Our findings provide new insights into the mechanisms of atherosclerosis and a therapeutic target for atherosclerosis.
Arterial calcification is highly prevalent, particularly in patients with end-stage renal disease (ESRD). The osteogenic differentiation of vascular smooth muscle cells (VSMCs) is the critical ...process for the development of arterial calcification. However, the detailed mechanism of VSMCs calcification remains to be elucidated. Here, we investigated the role of exosomes (Exos) derived from endothelial cells (ECs) in arterial calcification and its potential mechanisms in ESRD. Accelerated VSMCs calcification was observed when VSMCs were exposed to ECs culture media stimulated by uremic serum or high concentration of inorganic phosphate (3.5 mM Pi). and the pro-calcification effect of the ECs culture media was attenuated by exosome depletion. Exosomes derived from high concentrations of inorganic phosphate-induced ECs (ECs
-Exos) could be uptaken by VSMCs and promoted VSMCs calcification. Microarray analysis showed that miR-670-3p was dramatically increased in ECs
-Exos compared with exosomes derived from normal concentrations of inorganic phosphate (0.9 mM Pi) induced ECs (ECs
-Exos). Mechanistically, insulin-like growth factor 1 (IGF-1) was identified as the downstream target of miR-670-3p in regulating VSMCs calcification. Notably, ECs-specific knock-in of miR-670-3p of the 5/6 nephrectomy with a high-phosphate diet (miR-670-3p
+ NTP) mice that upregulated the level of miR-670-3p in artery tissues and significantly increased artery calcification. Finally, we validated that the level of circulation of plasma exosomal miR-670-3p was much higher in patients with ESRD compared with healthy controls. Elevated levels of plasma exosomal miR-670-3p were associated with a decline in IGF-1 and more severe artery calcification in patients with ESRD. Collectively, these findings suggested that ECs-derived exosomal miR-670-3p could promote arterial calcification by targeting IGF-1, which may serve as a potential therapeutic target for arterial calcification in ESRD patients.
BACKGROUNDIt is unknown whether the sex difference whereby female transcatheter aortic valve replacement (TAVR) candidates had a lower risk profile, a higher incidence of in-hospital complications, ...but more favorable short- and long-term survival observed in tricuspid cohorts undergoing TAVR would persist in patients with bicuspid aortic valves (BAVs). OBJECTIVESThe aim of this study was to reexamine the impact of sex on outcomes following TAVR in patients with BAVs. METHODSIn this single-center study, patients with BAVs undergoing TAVR for severe aortic stenosis from 2012 to 2021 were retrospectively included. Baseline characteristics, aortic root anatomy, and in-hospital and 1-year valve hemodynamic status and survival were compared between sexes. RESULTSA total of 510 patients with BAVs were included. At baseline, women presented with fewer comorbidities. Men had a greater proportion of Sievers type 1 BAV, higher calcium volumes (549.2 ± 408.4 mm3 vs 920.8 ± 654.3 mm3; P < 0.001), and larger aortic root structures. Women experienced more vascular complications (12.9% vs 4.9%; P = 0.002) and bleeding (11.1% vs 5.3%; P = 0.019) and higher residual gradients (16.9 ± 7.7 mm Hg vs 13.2 ± 6.4 mm Hg; P < 0.001), while men were more likely to undergo second valve implantations during index TAVR (6.3% vs 15.9%; P = 0.001). Death at 1 year was not significantly different between sexes (HR: 1.15; 95% CI: 0.56-2.35; P = 0.70). Bleeding (adjusted HR: 4.62; 95% CI: 1.51-14.12; P = 0.007) was the single independent predictor of 1-year death for women. CONCLUSIONSIn patients with BAVs undergoing TAVR, women presented with fewer comorbidities, while men had a greater proportion of type 1 BAV, more calcification, and larger aortic roots. In-hospital outcomes favored men, with fewer complications except for the need for second valve implantation, but 1-year survival was comparable between sexes.
This study aimed to systematically assess the quality of CPGs for motor neuron diseases (MNDs) or related disorders and identify the gaps that limit evidence-based practice.
Four scientific databases ...and six guideline repositories were searched for eligible CPGs. Three researchers assessed the eligible CPGs using the Appraisal of Guidelines Research and Evaluation II instrument. The distribution of the level of evidence and strength of recommendation of these CPGs were determined. The univariate regression analysis was used to explore the characteristic factors affecting the quality of CPGs.
Fifteen CPGs met the eligibility criteria: 10 were for MND and 5 were for spinal muscular atrophy. The mean overall rating score was 44.5%, and only 3 of 15 CPGs were of high quality. The domains that achieved low mean scores were applicability (24.4%), rigor of development (39.9%), and stakeholder involvement (40.3%). Most recommendations were based on low-quality evidence and had a weak strength. The CPGs that were updated, meant for adults, and evidence based, and used a CPG quality tool and a grading system were associated with higher scores in certain specific domains and overall rating.
The overall quality of CPGs for MNDs or related disorders was poor and recommendations were largely based on low-quality evidence. Many areas still need improvement to develop high-quality CPGs, and the use of CPG quality tools should be emphasized. A great deal of research on MNDs or related disorders is still needed to fill the large evidence gap.
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