Loss of UBE2S causes meiosis I arrest with normal spindle assembly checkpoint dynamics in mouse oocytes.

The timely degradation of proteins that regulate the cell cycle is essential for oocyte maturation. Oocytes are equipped to degrade proteins via the ubiquitin-proteasome system. In meiosis, anaphase promoting complex/cyclosome (APC/C), an E3 ubiquitin-ligase, is responsible for the degradation of proteins. Ubiquitin-conjugating enzyme E2 S (UBE2S), an E2 ubiquitin-conjugating enzyme, delivers ubiquitin to APC/C. APC/C has been extensively studied, but the functions of UBE2S in oocyte maturation and mouse fertility are not clear. In this study, we used Ube2s knockout mice to explore the role of UBE2S in mouse oocytes. Ube2s-deleted oocytes were characterized by meiosis I arrest with normal spindle assembly and spindle assembly checkpoint dynamics. However, the absence of UBE2S affected the activity of APC/C. Cyclin B1 and securin are two substrates of APC/C, and their levels were consistently high, resulting in the failure of homologous chromosome separation. Unexpectedly, the oocytes arrested in meiosis I could be fertilized and the embryos could become implanted normally, but died before embryonic day 10.5. In conclusion, our findings reveal an indispensable regulatory role of UBE2S in mouse oocyte meiosis and female fertility.

Mad2 is dispensable for accurate chromosome segregation but becomes essential when oocytes are subjected to environmental stress.

Accurate chromosome segregation, monitored by the spindle assembly checkpoint (SAC), is crucial for the production of euploid cells. Previous in vitro studies by us and others showed that Mad2, a core member of the SAC, performs a checkpoint function in oocyte meiosis. Here, through an oocyte-specific knockout approach in mouse, we reconfirmed that Mad2-deficient oocytes exhibit an accelerated metaphase-to-anaphase transition caused by premature degradation of securin and cyclin B1 and subsequent activation of separase in meiosis I. However, it was surprising that the knockout mice were completely fertile and the resulting oocytes were euploid. In the absence of Mad2, other SAC proteins, including BubR1, Bub3 and Mad1, were normally recruited to the kinetochores, which likely explains the balanced chromosome separation. Further studies showed that the chromosome separation in Mad2-null oocytes was particularly sensitive to environmental changes and, when matured in vitro, showed chromosome misalignment, lagging chromosomes, and aneuploidy with premature separation of sister chromatids, which was exacerbated at a lower temperature. We reveal for the first time that Mad2 is dispensable for proper chromosome segregation but acts to mitigate environmental stress in meiotic oocytes.

PPP4C facilitates homologous recombination DNA repair by dephosphorylating PLK1 during early embryo development.

Mammalian early embryo cells have complex DNA repair mechanisms to maintain genomic integrity, and homologous recombination (HR) plays the main role in response to double-strand DNA breaks (DSBs) in these cells. Polo-like kinase 1 (PLK1) participates in the HR process and its overexpression has been shown to occur in a variety of human cancers. Nevertheless, the regulatory mechanism of PLK1 remains poorly understood, especially during the S and G2 phase. Here, we show that protein phosphatase 4 catalytic subunit (PPP4C) deletion causes severe female subfertility due to accumulation of DNA damage in oocytes and early embryos. PPP4C dephosphorylated PLK1 at the S137 site, negatively regulating its activity in the DSB response in early embryonic cells. Depletion of PPP4C induced sustained activity of PLK1 when cells exhibited DNA lesions that inhibited CHK2 and upregulated the activation of CDK1, resulting in inefficient loading of the essential HR factor RAD51. On the other hand, when inhibiting PLK1 in the S phase, DNA end resection was restricted. These results demonstrate that PPP4C orchestrates the switch between high-PLK1 and low-PLK1 periods, which couple the checkpoint to HR.

Ethane/Ethylene Separations in Flexible Diamondoid Coordination Networks via an Ethane-Induced Gate-Opening Mechanism.

Separating ethane (C2H6) from ethylene (C2H4) is an essential and energy-intensive process in the chemical industry. Here, we report two flexible diamondoid coordination networks, X-dia-1-Ni and X-dia-1-Ni0.89Co0.11, that exhibit gate-opening between narrow-pore (NP) and large-pore (LP) phases for C2H6, but not for C2H4. X-dia-1-Ni0.89Co0.11 thereby exhibited a type F-IV isotherm at 273 K with no C2H6 uptake and a high uptake (111 cm3 g-1, 1 atm) for the NP and LP phases, respectively. Conversely, the LP phase exhibited a low uptake of C2H4 (12.2 cm3 g-1). This C2H6/C2H4 uptake ratio of 9.1 for X-dia-1-Ni0.89Co0.11 far surpassed those of previously reported physisorbents, many of which are C2H4-selective. In situ variable-pressure X-ray diffraction and modeling studies provided insight into the abrupt C2H6-induced structural NP to LP transformation. The promise of pure gas isotherms and, more generally, flexible coordination networks for gas separations was validated by dynamic breakthrough studies, which afforded high-purity (99.9%) C2H4 in one step.

Cross-Linking CdSO4-Type Nets with Hexafluorosilicate Anions to Form an Ultramicroporous Material for Efficient C2H2/CO2 and C2H2/C2H4 Separation.

A 44.610.8 topology hybrid ultramicroporous material (HUM), {[Cu1.5F(SiF6)(L)2.5]·G}n, (L = 4,4'-bisimidazolylbiphenyl, G = guest molecules), 1, formed by cross-linking interpenetrated 3D four-connected CdSO4-type nets with hexafluorosilicate anions is synthesized and evaluated in the context of gas sorption and separation herein. 1 is the first HUM functionalized with two different types of fluorinated sites (SiF6 2- and F- anions) lining along the pore surface. The optimal pore size (≈5 Å) combining mixed and high-density electronegative fluorinated sites enable 1 to preferentially adsorb C2H2 over CO2 and C2H4 by hydrogen bonding interactions with a high C2H2 isosteric heat of adsorption (Qst) of ≈42.3 kJ mol-1 at zero loading. The pronounced discriminatory sorption behaviors lead to excellent separation performance for C2H2/CO2 and C2H2/C2H4 that surpasses many well-known sorbents. Dynamic breakthrough experiments are conducted to confirm the practical separation capability of 1, which reveal an impressive separation factor of 6.1 for equimolar C2H2/CO2 mixture. Furthermore, molecular simulation and density functional theory (DFT) calculations validate the strong binding of C2H2 stems from the chelating fix of C2H2 between SiF6 2- anion and coordinated F- anion.

Amino-Functionalized Metal-Organic Frameworks Featuring Ultra-Strong Ethane Nano-Traps for Efficient C2H6/C2H4 Separation.

Developing high-performance porous materials to separate ethane from ethylene is an important but challenging task in the chemical industry, given their similar sizes and physicochemical properties. Herein, a new type of ultra-strong C2H6 nano-trap, CuIn(3-ain)4 is presented, which utilizes multiple guest-host interactions to efficiently capture C2H6 molecules and separate mixtures of C2H6 and C2H4. The ultra-strong C2H6 nano-trap exhibits the high C2H6 (2.38 mmol g-1) uptake at 6.25 kPa and 298 K and demonstrates a remarkable selectivity of 3.42 for C2H6/C2H4 (10:90). Additionally, equimolar C2H6/C2H4 exhibited a superior high separation potential ∆Q (2286 mmol L-1) at 298 K. Kinetic adsorption tests demonstrated that CuIn(3-ain)4 has a high adsorption rate for C2H6, establishing it as a new benchmark material for the capture of C2H6 and the separation of C2H6/C2H4. Notably, this exceptional performance is maintained even at a higher temperature of 333 K, a phenomenon not observed before. Theoretical simulations and single-crystal X-ray diffraction provide critical insights into how selective adsorption properties can be tuned by manipulating pore dimensions and geometry. The excellent separation performance of CuIn(3-ain)4 has been confirmed through breakthrough experiments for C2H6/C2H4 gas mixtures.

Ligand Defect-Induced Active Sites in Ni-MOF-74 for Efficient Photocatalytic CO2 Reduction to CO.

The conversion of CO2 into valuable carbon-based products using clean and renewable solar energy has been a significant challenge in photocatalysis. It is of paramount importance to develop efficient photocatalysts for the catalytic conversion of CO2 using visible light. In this study, the Ni-MOF-74 material is successfully modified to achieve a highly porous structure (Ni-74-Am) through temperature and solvent modulation. Compared to the original Ni-MOF-74, Ni-74-Am contains more unsaturated Ni active sites resulting from defects, thereby enhancing the performance of CO2 photocatalytic conversion. Remarkably, Ni-74-Am exhibits outstanding photocatalytic performance, with a CO generation rate of 1380 µmol g-1 h-1 and 94% CO selectivity under visible light, significantly surpassing the majority of MOF-based photocatalysts reported to date. Furthermore, experimental characterizations reveal that Ni-74-Am has significantly higher efficiency of photogenerated electron-hole separation and faster carrier migration rate for photocatalytic CO2 reduction. This work enriches the design and application of defective MOFs and provides new insights into the design of MOF-based photocatalysts for renewable energy and environmental sustainability. The findings of this study hold significant promise for developing efficient photocatalysts for CO2 reduction under visible-light conditions.

MEIKIN expression and its C-terminal phosphorylation by PLK1 is closely related the metaphase-anaphase transition by affecting cyclin B1 and Securin stabilization in meiotic oocyte.

Oocyte meiotic maturation failure and chromosome abnormality is one of the main causes of infertility, abortion, and diseases. The mono-orientation of sister chromatids during the first meiosis is important for ensuring accurate chromosome segregation in oocytes. MEIKIN is a germ cell-specific protein that can regulate the mono-orientation of sister chromatids and the protection of the centromeric cohesin complex during meiosis I. Here we found that MEIKIN is a maternal protein that was highly expressed in mouse oocytes before the metaphase I (MI) stage, but became degraded by the MII stage and dramatically reduced after fertilization. Strikingly, MEIKIN underwent phosphorylation modification after germinal vesicle breakdown (GVBD), indicating its possible function in subsequent cellular event regulation. We further showed that MEIKIN phosphorylation was mediated by PLK1 at its carboxyl terminal region and its C-terminus was its key functional domain. To clarify the biological significance of meikin degradation during later stages of oocyte maturation, exogenous expression of MEIKIN was employed, which showed that suppression of MEIKIN degradation resulted in chromosome misalignment, cyclin B1 and Securin degradation failure, and MI arrest through a spindle assembly checkpoint (SAC)-independent mechanism. Exogenous expression of MEIKIN also inhibited metaphase II (MII) exit and early embryo development. These results indicate that proper MEIKIN expression level and its C-terminal phosphorylation by PLK1 are critical for regulating the metaphase-anaphase transition in meiotic oocyte. The findings of this study are important for understanding the regulation of chromosome segregation and the prevention meiotic abnormality.

Rational Synthesis of Spongy Fe3N@N-Doped Carbon Nanorods with Controlled Topography and Porosity for Enhanced Energy Storage Anodes in Lithium-Ion Batteries.

Iron nitrides with the merits of high theoretical capacities, cost-effectiveness, and good electronic/ionic conductivity have been recognized as attractive anode candidates for lithium-ion batteries (LIBs). Carbon compositing, pore engineering, and nanostructure construction have proved to be effective strategies to prepare high-performance metal nitride anodes for LIBs. Herein, we synthesized a series of Fe3N-embedded and N-doped carbon nanorods (Fe3N@NCNR) with a hierarchical porous system and controllable topography by metal-catalyzed graphitization-nitridization of the Fe(III)-triazole framework (Fe-MOF) and thermal evaporation of the triblock copolymer F127 template assembled in Fe-MOF via hydrogen bonding interaction, followed by the air oxidation and urea-assisted ammonolysis processes. The Fe3N@NCNR as anodes for LIBs display extraordinary lithium storage capabilities with a high reversible capacity of 830 mA h g-1 at 0.1 C, a good rate performance of 576 mAh g-1 at 5 C, and a long-term cycling stability of 742 mA h g-1 over 600 cycles at 1 C. Such outstanding performance benefits from the spongy carbon nanorods with rich macropores for rapid electronic/ionic transport and effective accommodation of electrode volume expansion, abundant N-doped meso-/microporous carbon for the additional storage of Li+ via capacitive effect, and the efficient utilization of Fe3N nanoparticles uniformly distributed through carbon nanorods. Importantly, this work introduces an effective strategy to construct superior performance nitride anodes from MOF surfactants based on hydrogen bonding-driven interface self-assembly and provides insight into the preparation of highly efficient nanoarchitectures for Li+ storage.

Safety and efficacy of baricitinib in steroid-resistant or relapsed immune thrombocytopenia: An open-label pilot study.

Patients with steroid-resistant or relapsed immune thrombocytopenia (ITP) suffer increased bleeding risk and impaired quality of life. Baricitinib, an oral Janus-associated kinases (JAK) inhibitor, could alleviate both innate and adaptive immune disorders without inducing thrombocytopenia in several autoimmune diseases. Accordingly, an open-label, single-arm, phase 2 trial (NCT05446831) was initiated to explore the safety and efficacy of baricitinib in ITP. Eligible patients were adults with primary ITP who were refractory to corticosteroids and at least one subsequent treatment, and had platelet counts below 30 × 109/L at enrolment. Participants received baricitinib 4 mg daily for 6 months. The primary endpoint was durable response at the 6-month follow-up. A total of 35 patients were enrolled. Durable response was achieved in 20 patients (57.1%, 95% confidence interval, 39.9 to 74.4), and initial response in 23 (65.7%) patients. For patients responding to baricitinib, the median time to response was 12 (IQR 6-20) days, and the median peak platelet count was 94 (IQR 72-128) × 109/L. Among the 27 patients undergoing extend observation, 12 (44.4%) remained responsive for a median duration of approximately 20 weeks after baricitinib discontinuation. Adverse events were reported in 11 (31.4%) patients, including infections in 6 (17.1%) patients during the treatment period. Treatment discontinuation due to an adverse event was reported in 2 (5.7%) patients. Evidence from this pilot study suggested that baricitinib might be a novel candidate for the armamentarium of ITP-modifying agents. Future studies are warranted to validate the safety, efficacy, and optimal dosing of baricitinib in patients with ITP.

The effect of curcumin supplementation on endothelial function and blood pressure in patients with metabolic disorders: A meta-analysis of meta-analyses.

Several interventional studies have revealed the beneficial impact of curcumin supplementation on blood pressure and endothelial function, but the findings are conflicting. Therefore, this study was conducted to investigate the effects of curcumin supplementation on blood pressure and endothelial function. A meta-analyses of randomized clinical trials were performed by searching PubMed, Embase, Scopus, and Web of Science were searched up to March 31, 2024. Random effects models were used to calculate weighted mean differences (WMD). Pooled estimates of 10 studies revealed that curcumin decreased diastolic blood pressure (DBP) [WMD = -0.94, 95 % CI: -1.59, -0.30; p = 0.004], pulse wave velocity (PWV) [WMD = -45.60, 95 % CI: -88.16, -3.04; p = 0.03, I2 = 0.0 %, p = 0.59], and vascular cell adhesion molecule-1 (VCAM-1) [WMD = -39.19; 95 % CI: -66.15, -12.23, p =0.004; I2=73.0 %, p = 0.005] significantly, and increased flow-mediated dilation (FMD) [WMD = 1.64, 95 % CI: 1.06, 2.22; p < 0.001, I2 = 0.0 %, p = 0.61. However, curcumin did not significantly change systolic blood pressure (SBP) [WMD = -0.64, 95 % CI: -1.96, 0.67; p =0.34, I2 = 83.5 %, p <0.001], and Intercellular Adhesion Molecule 1 (ICAM1) [WMD = -17.05; 95 % CI: -80.79, 46.70, p =0.601; I2=94.1 %, p < 0.001]. These results suggest that curcumin has a beneficial effect on DBP, PWV, VCAM-1 and FMD levels and may be an effective adjunctive therapy for improving blood pressure and endothelial function.

Separase is recruited to mitotic chromosomes to dissolve sister chromatid cohesion in a DNA-dependent manner.

Sister chromatid separation is triggered by the separase-catalyzed cleavage of cohesin. This process is temporally controlled by cell-cycle-dependent factors, but its biochemical mechanism and spatial regulation remain poorly understood. We report that cohesin cleavage by human separase requires DNA in a sequence-nonspecific manner. Separase binds to DNA in vitro, but its proteolytic activity, measured by its autocleavage, is not stimulated by DNA. Instead, biochemical characterizations suggest that DNA mediates cohesin cleavage by bridging the interaction between separase and cohesin. In human cells, a fraction of separase localizes to the mitotic chromosome. The importance of the chromosomal DNA in cohesin cleavage is further demonstrated by the observation that the cleavage of the chromosome-associated cohesins is sensitive to nuclease treatment. Our observations explain why chromosome-associated cohesins are specifically cleaved by separase and the soluble cohesins are left intact in anaphase.

USP7 reduction leads to developmental failure of mouse early embryos.

As a member of Ubiquitin-specific protease subfamily, ubiquitin specific protease 7 (USP7) has been reported to participate in a variety of cellular processes, including cell cycle, apoptosis, DNA damage response, and epigenetic modification. However, its function in preimplantation embryos is still obscure. To investigate the functions of USP7 during preimplantation embryo development, we used siRNA to degrade endogenous USP7 messenger RNA. We found that USP7 knockdown significantly decreased the development rate of mouse early embryos. Moreover, depletion of USP7 induced the accumulation of the DNA lesions and apoptotic blastomeres in early embryos. In addition, USP7 knockdown caused an abnormal H3K27me3 modification in 2-cell embryos. Overall, our results indicate that USP7 maintains genome stability perhaps via regulating H3K27me3 and DNA damage, consequently controlling the embryo quality.

Dietary vitamin C and vitamin E with the risk of aortic aneurysm and dissection: A prospective population-based cohort study.

BACKGROUND AND AIMS: The associations between dietary vitamin C (VC), vitamin E (VE) intake and aortic aneurysm and dissection (AAD) remain unclear. This study aimed to prospectively investigate the associations between dietary VC and VE with the incident risk of AAD. METHODS AND RESULTS: A total of 139 477 participants of UK Biobank cohort were included in the analysis. Dietary VC and VE consumptions were acquired through a 24-h recall questionnaire. Cox proportional regression models were used to examine the associations between VC, VE intake and the risk of AAD. Incident AAD was ascertained through hospital inpatient records and death registers. During a median follow-up of 12.5 years, 962 incident AAD events were documented. Both dietary VC [adjusted hazard ratio (HR), 0.77; 95 % confidence intervals (CI), 0.63-0.93; P-trend = 0.008] and VE (adjusted HR, 0.70; 95 % CI, 0.57-0.87; P-trend = 0.002) were inversely associated with incident AAD when comparing the participants in the highest quartile with those in the lowest. In subgroup analyses, the associations were more pronounced in participants who were over 60 years old, participants with smoking history, hypertension or hyperlipidemia, who were under the high risk of AAD. CONCLUSION: Higher dietary VC and VE intakes are associated with reduced risk of AAD. Our study emphasizes the importance of diet adjustment strategies targeted on VC and VE to lower the incidence rate of AAD especially in the high-risk population.

Cordycepin delays postovulatory aging of oocytes through inhibition of maternal mRNAs degradation via DCP1A polyadenylation suppression.

Postovulatory aging leads to the decline in oocyte quality and subsequent impairment of embryonic development, thereby reducing the success rate of assisted reproductive technology (ART). Potential preventative strategies preventing oocytes from aging and the associated underlying mechanisms warrant investigation. In this study, we identified that cordycepin, a natural nucleoside analogue, promoted the quality of oocytes aging in vitro, as indicated by reduced oocyte fragmentation, improved spindle/chromosomes morphology and mitochondrial function, as well as increased embryonic developmental competence. Proteomic and RNA sequencing analyses revealed that cordycepin inhibited the degradation of several crucial maternal proteins and mRNAs caused by aging. Strikingly, cordycepin was found to suppress the elevation of DCP1A protein by inhibiting polyadenylation during postovulatory aging, consequently impeding the decapping of maternal mRNAs. In humans, the increased degradation of DCP1A and total mRNA during postovulatory aging was also inhibited by cordycepin. Collectively, our findings demonstrate that cordycepin prevents postovulatory aging of mammalian oocytes by inhibition of maternal mRNAs degradation via suppressing polyadenylation of DCP1A mRNA, thereby promoting oocyte developmental competence.

LSM14B controls oocyte mRNA storage and stability to ensure female fertility.

Controlled mRNA storage and stability is essential for oocyte meiosis and early embryonic development. However, how to regulate mRNA storage and stability in mammalian oogenesis remains elusive. Here we showed that LSM14B, a component of membraneless compartments including P-body-like granules and mitochondria-associated ribonucleoprotein domain (MARDO) in germ cell, is indispensable for female fertility. To reveal loss of LSM14B disrupted primordial follicle assembly and caused mRNA reduction in non-growing oocytes, which was concomitant with the impaired assembly of P-body-like granules. 10× Genomics single-cell RNA-sequencing and immunostaining were performed. Meanwhile, we conducted RNA-seq analysis of GV-stage oocytes and found that Lsm14b deficiency not only impaired the maternal mRNA accumulation but also disrupted the translation in fully grown oocytes, which was closely associated with dissolution of MARDO components. Moreover, Lsm14b-deficient oocytes reassembled a pronucleus containing decondensed chromatin after extrusion of the first polar body, through compromising the activation of maturation promoting factor, while the defects were restored via WEE1/2 inhibitor. Together, our findings reveal that Lsm14b plays a pivotal role in mammalian oogenesis by specifically controlling of oocyte mRNA storage and stability.

Primary spinal epidural abscess: magnetic resonance imaging characteristics and diagnosis.

RATIONALE AND OBJECTIVE: To investigate the MR characteristics of phlegmonous stage and abscess stage primary spinal epidural abscess. MATERIALS AND METHODS: This study retrospectively analyzed the clinical and imaging characteristics of 27 cases of pathologically confirmed primary spinal epidural abscess. Predisposing conditions of all patients were collected. All patients underwent conventional magnetic resonance imaging, while fifteen patients also underwent post-contrast magnetic resonance imaging. RESULTS: The initial symptoms included back pain in 25 patients, fever in 18, motor deficit in five, and sensory changes in 13. Underlying diseases included distant site of infection in seven, injection therapy in five, neoplasm in five, chronic inflammatory disease in five, diabetes mellitus in four, alcoholism in three, metabolic disorder in three, hepatopathy in three, and obesity in two. Abscess location was ventral epidural space in 15 patients (55.6%) and dorsal epidural space in 12 (44.4%). On T1-weighted image, the abscess was hypointense to the spinal cord in 23 patients (85%) and isointense in four (15%). All abscesses were hyperintense to the spinal cord on T2-weighted image. Among the 15 patients who underwent contrast-enhanced imaging, ring enhancement was present in 13 and homogeneous enhancement in two. Adjacent vertebrae body edema was present in four patients. The abscess was purely intraspinal in 25 patients (92.6%). Paraspinal extension was present in two (7.4%). CONCLUSION: Primary spinal epidural abscess patients have one or more predisposing conditions. Phlegmonous stage primary spinal epidural abscess appears isointense on T1WI and hyperintense on T2WI and enhancement is homogeneous. Abscess stage primary spinal epidural abscess hyperintense on T2WI and hypointense on T1WI and ring enhancement. Presence of vertebral body edema is an important sign to help diagnose primary spinal epidural abscess.

Maternal exposure to 4-vinylcyclohexene diepoxide during pregnancy leads to disorder of gut microbiota and bile acid metabolism in offspring.

Our previous study reveals that maternal exposure to 4-vinylcyclohexene diepoxide (VCD) during pregnancy causes insufficient ovarian follicle reserve and decreased fertility in offspring. The present study aims to further explore the reasons for the significant decline of fecundity in mice caused by VCD, and to clarify the changes of gut microbiota and microbial metabolites in F1 mice. The ovarian metabolomics, gut microbiota and microbial metabolites were analyzed. The results of ovarian metabolomics analysis showed that maternal VCD exposure during pregnancy significantly reduced the concentration of carnitine in the ovaries of F1 mice, while supplementation with carnitine (isovalerylcarnitine and valerylcarnitine) significantly increased the number of ovulation. The results of 16 S rDNA-seq and microbial metabolites analysis showed that maternal VCD exposure during pregnancy caused disordered gut microbiota, increased abundance of Parabacteroides and Flexispira bacteria that are involved in secondary bile acid synthesis. The concentrations of NorDCA, LCA-3S, DCA and other secondary bile acids increased significantly. Our results indicate that maternal exposure to VCD during pregnancy leads to disorder in gut microbiota and bile acid metabolism in F1 mice, accompanying with decreased ovarian function, providing further evidence that maternal exposure to VCD during pregnancy has intergenerational deleterious effects on offspring.

Inheritance of perturbed methylation and metabolism caused by uterine malnutrition via oocytes.

BACKGROUND: Undernourishment in utero has deleterious effects on the metabolism of offspring, but the mechanism of the transgenerational transmission of metabolic disorders is not well known. In the present study, we found that undernourishment in utero resulted in metabolic disorders of female F1 and F2 in mouse model. RESULTS: Undernutrition in utero induced metabolic disorders of F1 females, which was transmitted to F2 females. The global methylation in oocytes of F1 exposed to undernutrition in utero was decreased compared with the control. KEGG analysis showed that genes with differential methylation regions (DMRs) in promoters were significantly enriched in metabolic pathways. The altered methylation of some DMRs in F1 oocytes located at the promoters of metabolic-related genes were partially observed in F2 tissues, and the expressions of these genes were also changed. Meanwhile, the abnormal DNA methylation of the validated DMRs in F1 oocytes was also observed in F2 oocytes. CONCLUSIONS: These results indicate that DNA methylation may mediate the transgenerational inheritance of metabolic disorders induced by undernourishment in utero via female germline.

SRSF2 is required for mRNA splicing during spermatogenesis.

BACKGROUND: RNA splicing plays significant roles in fundamental biological activities. However, our knowledge about the roles of alternative splicing and underlying mechanisms during spermatogenesis is limited. RESULTS: Here, we report that Serine/arginine-rich splicing factor 2 (SRSF2), also known as SC35, plays critical roles in alternative splicing and male reproduction. Male germ cell-specific deletion of Srsf2 by Stra8-Cre caused complete infertility and defective spermatogenesis. Further analyses revealed that deletion of Srsf2 disrupted differentiation and meiosis initiation of spermatogonia. Mechanistically, by combining RNA-seq data with LACE-seq data, we showed that SRSF2 regulatory networks play critical roles in several major events including reproductive development, spermatogenesis, meiotic cell cycle, synapse organization, DNA recombination, chromosome segregation, and male sex differentiation. Furthermore, SRSF2 affected expression and alternative splicing of Stra8, Stag3 and Atr encoding critical factors for spermatogenesis in a direct manner. CONCLUSIONS: Taken together, our results demonstrate that SRSF2 has important functions in spermatogenesis and male fertility by regulating alternative splicing.