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STUDY QUESTION Could actin-related protein T1 (ACTRT1) deficiency be a potential pathogenic factor of human male infertility? SUMMARY ANSWER A 110-kb microdeletion of the X chromosome, only including the ACTRT1 gene, was identified as responsible for infertility in two Chinese males with sperm showing acrosomal ultrastructural defects and fertilization failure. WHAT IS KNOWN ALREADY The actin-related proteins (e.g. ACTRT1, ACTRT2, ACTL7A, and ACTL9) interact with each other to form a multimeric complex in the subacrosomal region of spermatids, which is crucial for the acrosome-nucleus junction. Actrt1 -knockout (KO) mice are severely subfertile owing to malformed sperm heads with detached acrosomes and partial fertilization failure. There are currently no reports on the association between ACTRT1 deletion and male infertility in humans. STUDY DESIGN, SIZE, DURATION We recruited a cohort of 120 infertile males with sperm head deformations at a large tertiary hospital from August 2019 to August 2023. Genomic DNA extracted from the affected individuals underwent whole exome sequencing (WES), and in silico analyses were performed to identify genetic variants. Morphological analysis, functional assays, and ART were performed in 2022 and 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS The ACTRT1 deficiency was identified by WES and confirmed by whole genome sequencing, PCR, and quantitative PCR. Genomic DNA of all family members was collected to define the hereditary mode. Papanicolaou staining and electronic microscopy were performed to reveal sperm morphological changes. Western blotting and immunostaining were performed to explore the pathological mechanism of ACTRT1 deficiency. ICSI combined with artificial oocyte activation (AOA) was applied for one proband. MAIN RESULTS AND THE ROLE OF CHANCE We identified a whole-gene deletion variant of ACTRT1 in two infertile males, which was inherited from their mothers, respectively. The probands exhibited sperm head deformations owing to acrosomal detachment, which is consistent with our previous observations on Actrt1 -KO mice. Decreased expression and ectopic distribution of ACTL7A and phospholipase C zeta were observed in sperm samples from the probands. ICSI combined with AOA effectively solved the fertilization problem in Actrt1 -KO mice and in one of the two probands. LIMITATIONS, REASONS FOR CAUTION Additional cases are needed to further confirm the genetic contribution of ACTRT1 variants to male infertility. WIDER IMPLICATIONS OF THE FINDINGS Our results reveal a gene–disease relation between the ACTRT1 deletion described here and human male infertility owing to acrosomal detachment and fertilization failure. This report also describes a good reproductive outcome of ART with ICSI-AOA for a proband. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the Chongqing medical scientific research project (Joint project of Chongqing Health Commission and Science and Technology Bureau, 2023MSXM008 and 2023MSXM054). There are no competing interests to declare. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Lactate is present at a high level in the microenvironment of mammalian preimplantation embryos in vivo and in vitro. However, its role in preimplantation development is unclear. Here, we report that lactate is highly enriched in the nuclei of early embryos when major zygotic genome activation (ZGA) occurs in humans and mice. The inhibition of its production and uptake results in developmental arrest at the 2-cell stage, major ZGA failure, and loss of lactate-derived H3K18lac, which could be rescued by the addition of Lac-CoA and recapitulated by overexpression of H3K18R mutation. By profiling the landscape of H3K18lac during mouse preimplantation development, we show that H3K18lac is enriched on the promoter regions of most major ZGA genes and correlates with their expressions. In humans, H3K18lac is also enriched in ZGA markers and temporally concomitant with their expressions. Taken together, we profile the landscapes of H3K18lac in mouse and human preimplantation embryos, and demonstrate the important role for H3K18lac in major ZGA, showing that a conserved metabolic mechanism underlies preimplantation development of mammalian embryos. [ABSTRACT FROM AUTHOR]

Background: Multiple morphological abnormalities of sperm flagella is an idiopathic asthenoteratozoospermia characterized by absent, short, coiled, angulation, and irregular‐caliber flagella. Genetic variants of DNAH1 gene have been identified as a causative factor of multiple morphological abnormalities of sperm flagella and intracytoplasmic sperm injection is an available strategy for infertile males with dynein axonemal heavy chain 1 defects to conceive. Objectives: To identify novel variants and candidate mutant hotspots of DNAH1 gene related to multiple morphological abnormalities of sperm flagella and male infertility in humans. Materials and methods: The DNAH1 variants were identified by whole exome sequencing and confirmed with Sanger sequencing. Papanicolaou staining, scanning and transmission electron microscopy, and immunostaining were performed to investigate the morphological and ultrastructural characteristics of spermatozoa. Intracytoplasmic sperm injection was applied for the assisted reproductive therapy of males harboring biallelic DNAH1 variants. Results: We identified 18 different DNAH1 variants in 11 unrelated families, including nine missense variants (p.A2564T, p.T3657R, p.G1862R, p.L2296P, p.T4041I, p.L611P, p.A913D, p.R1932Q, p.R2356W) and nine loss‐of‐function variants (c.2301‐1G>T, p.Q1518*, p.R1702*, p.D2845Mfs*2, p.P3909Rfs*33, p.Q4040Dfs*33, p.Q4058*, p.E4060Pfs*61, p.V4071Cfs*54). A total of 66.7% (12/18) of the identified variants were novel. Morphological analysis based on Papanicolaou staining and scanning electron microscopy demonstrated the typical multiple morphological abnormalities of sperm flagella characteristics of dynein axonemal heavy chain 1‐deficient spermatozoa. Immunostaining further revealed the absence of inner dynein arms but not outer dynein arms, which induced a general ultrastructural disorganization, such as the loss of central pair and mis‐localization of the microtubule doublets and outer dense fibers. To date, seven affected couples have accepted the intracytoplasmic sperm injection treatment, and three of them have given birth to five healthy babies. Discussion and conclusion: These findings further expand the variant spectrum of DNAH1 gene related to multiple morphological abnormalities of sperm flagella and male infertility in humans, thus providing new information for the molecular diagnosis of asthenoteratozoospermia. The favorable fertility outcomes of intracytoplasmic sperm injection will facilitate the genetic counseling and clinical treatment of infertile males with multiple morphological abnormalities of sperm flagella in the future. [ABSTRACT FROM AUTHOR]

The aeroelastic effect of gust generator vanes with a high aspect ratio is more significant in large-scale wind tunnels. High-fidelity numerical results based on the computational fluid dynamics (CFD) and computational structural mechanics (CSM) coupling methodology have an extremely high computational cost. To this end, a data-driven method for rapidly estimating unsteady flexible deformations of gust generators vanes is developed. The aeroelastic rigid-elastic reduced-order model is built by the dynamic mode decomposition with control and prediction error minimization (DMDcP) methods. For all cases validated with various pitching amplitudes and frequencies of gust vanes, the maximum cumulative errors of DMDcP reduced-order model solutions are all under 2%. The efficiency of the presented method has the potential to fast estimate unsteady flexible deformations and reduce computational cost in the early stages of gust generator design while maintaining adequate accuracy as the CFD-CSM coupling methodology. [ABSTRACT FROM AUTHOR]

Meckel syndrome (MKS), also known as the Meckel–Gruber syndrome, is a severe pleiotropic autosomal recessive developmental disorder caused by dysfunction of the primary cilia during early embryogenesis. The diagnostic criteria are based on clinical variability and genetic heterogeneity. Mutations in the MKS1 gene constitute approximately 7% of all MKS cases. Herein, we present a non-consanguineous couple with three abnormal pregnancies as the fetuses showed MKS-related phenotypes of the central nervous system malformation and postaxial polydactyly. Whole-exome sequencing identified two novel heterozygous mutations of MKS1 : c.350C>A and c.1408-14A>G. The nonsense mutation c.350C>A produced a premature stop codon and induced the truncation of the MKS1 protein (p.S117*). Reverse-transcription polymerase chain reaction (RT-PCR) showed that c.1408-14A>G skipped exon 16 and encoded the mutant MKS1 p.E471Lfs*92. Functional studies showed that these two mutations disrupted the B9–C2 domain of the MKS1 protein and attenuated the interactions with B9D2, the essential component of the ciliary transition zone. The couple finally got a healthy baby through preimplantation genetic testing for monogenic disorder (PGT-M) with haplotype linkage analysis. Thus, this study expanded the mutation spectrum of MKS1 and elucidated the genetic heterogeneity of MKS1 in clinical cases. [ABSTRACT FROM AUTHOR]

Although vitrification has been widely applied in assisted reproductive technology, it is unknown whether storage time has any impact on the mRNA and lncRNA expression profiles in human embryos. Eleven women (aged 23–35 years) who had undergone in vitro fertilization treatment were recruited for this study. The transcriptomes of 3 fresh eight-cell embryos and 8 surviving vitrified-warmed eight-cell embryos (4 embryos were cryostored for 3 years, and the others were cryostored for 8 years) were analyzed through single-cell RNA-Seq. No differentially expressed mRNAs or lncRNAs were identified between the 3-years group and 8-years group. A total of 128 mRNAs and 365 lncRNAs were differentially expressed in the 8 vitrified-warmed embryos compared with the fresh embryos. The vitrification-warming impact was moderate, and it was mainly related to the pathways of metabolism, stress response, apoptosis, cell cycle, cell adhesion, and signaling for TFG-β and Hippo. The analysis of target mRNAs suggested that lncRNAs might contribute to the regulation of mRNAs after vitrification-warming. Our findings indicated that long-term storage after vitrification does not affect the mRNA and lncRNA expression profiles in human embryos, however, the procedure of vitrification-warming would lead to minor alteration of transcriptome. [ABSTRACT FROM AUTHOR]

Summary: Embryos undergo chaotic division and decrease in quality on day 3 with a reduction in the rates of subsequent blastocyst formation. Disordered cleavage causes a deterioration in embryonic quality, here we assessed the relationship between an cleavage model in first mitosis and the chromosomal status of human embryos, and discuss the potential biological and clinical implications for the cleavage model as a single parameter that can be used to assess embryonic quality. Thirty-two infertile couples, with normal karyotypes and who underwent their first IVF cycle were recruited to donate one normal two-cell-stage embryo each for this study between 2019 and 2020. Twenty-eight two-cell embryos underwent preimplantation genetic testing of each blastomere, and four chaotic-division embryos were stained with Hoechst and cultured in a confocal laser-scanning microscopy incubator system. This system showed high specificity and PPV but low sensitivity and NPV using the CM in the prediction of euploidy, indicating that CM could be considered a screening method for embryo selection; additional observational studies using the CM to select transferable embryos are needed before it can be used in clinical practice. [ABSTRACT FROM AUTHOR]

Correct placental development and function are critical to both the mother's and the foetus' health during pregnancy. Placental function depends on the correct development of the vascular network, which requires proper angiogenesis. Impaired angiogenesis in the placenta can induce foetal growth restriction, preeclampsia, and even foetal death. Placental angiogenesis is finely controlled by ubiquitous and pregnancy-specific angiogenic factors. Jumonji domain-containing protein 6 (JMJD6) is a Fe (II)- and 2-oxoglutarate (2OG)-dependent oxygenase that catalyses arginine demethylation and lysine hydroxylation of histone and non-histone peptides. JMJD6 has been implicated in embryonic development, cellular proliferation and migration, self-tolerance induction in the thymus, and adipocyte differentiation. In this review we present JMJD6's structure and activity, as well as its role in angiogenesis, oxygen sensing, and adverse pregnancy outcomes related to placental development. Understanding the interaction between JMJD6 and other placental factors may identify potential therapeutic targets for correcting abnormal placental angiogenesis and function. [ABSTRACT FROM AUTHOR]

The objective of this prospective cohort study was to investigate whether cryopreservation of cleavage or blastocyst stage embryos improves in vitro fertilization outcomes in recurrent implantation failure (RIF) patients. The study comprised 575 patients who were allocated to receive either single frozen/thawed blastocyst-stage transfer (SBT) or frozen/thawed double-cleavage-stage embryo transfer (DET). The clinical pregnancy rate, implantation rate, and ongoing pregnancy rate were higher in the SBT group compared with the DET group (41.15% vs. 27.11%, p < 0.001; 41.15% vs. 19.28%, p < 0.001; 40.03% vs. 25.9%, p < 0.001), but the miscarriage rate did not differ between the two groups. It was concluded that frozen/thawed SBT could be a preferred strategy for RIF patients. [ABSTRACT FROM AUTHOR]

Background: Using re-vitrified human embryos for frozen-warmed embryo transfer (FET) is a valuable option when there are no other cryopreserved embryos to use, however, except for the PGT cases, no published data are available for FET with human embryos that were re-vitrified at different developmental stages. Objective: To evaluate the effect of re-vitrification of embryos at different stages on embryonic developmental potential. Method: This study included clinical retrospective and mouse experimental studies. For the retrospective study, a total of 25 FET cycles with re-vitrified day 3 embryos (re-vitrification group 1) and 54 FET cycles with re-vitrified day 5 blastocysts (re-vitrification group 2) between January 2015 and December 2019 were included in this study. The corresponding FET cycles with once-vitrified embryos were identified using propensity score (PS) matching according to the time of embryo transfer. For the mouse experimental study, we divided embryos into 5 groups: fresh (group 1), vitrified at the 8-cell stage (group 2), vitrified at the early blastocyst stage (group 3), vitrified at the 8-cell stage, and re-vitrified at the 8-cell (group 4) or early blastocyst stage (group 5). The fresh embryos was selected as control group. The primary outcome in this study was delivery outcomes. Results: No significant difference in delivery rate was detected between re-vitrification group 1 (24.00%) and the corresponding control group (28.00%). However, re-vitrification group 2 (46.3%) showed a significant decrease in delivery rate compared with the two corresponding control groups (63.89% and 64.12%) (P < 0.05). Our experiment using mouse embryos also confirmed the clinical data, and showed that re-vitrification at the blastocyst stage following the first round of vitrification at the 8-cell stage reduced the delivery rate. In addition, both re-vitrified groups showed a significantly higher expression level of BAX. However, only re-vitrification at the blastocyst stage increased the expression level of CASPASE3. Conclusions: Re-vitrification at the 8-cell and blastocyst stages has different effects on embryonic developmental potential, as re-vitrification at blastocyst stage following a previous vitrification at 8-cell stage reduced the delivery rate, while vitrification at the 8-cell stage twice achieved comparable pregnancy outcomes to the once-vitrified group. [ABSTRACT FROM AUTHOR]

Background: What are the trends and figures in the treatments involving Assisted Reproductive Technology (ART) in mainland China? Method: The Chinese Society of Reproductive Medicine (CSRM) retrospectively collected and analyzed data from 2013 to 2016 in 28 province of China by CSRM ART Data Reporting System. Results: Among the 327 centers in China by December 2016, 133 centers reported 1,211,303 cycles and 470,725 infants in the 4 year period. Since 2013, the total number of frozen embryo transfer (FET) cycles, PGD/PGS cycle showed an increasing trend year by year. However, the number of donor sperm (DS) and donor egg (DE) cycles remained at a low level. Pregnancy outcomes such as implantation rate, pregnancy rate and delivery rate per embryo transfer cycles were stable in all types of ART, but decreased dramatically with increasing age. However, the average number of transferred embryos gradually decreased from 2013 to 2016, especially in PGD/PGS cycles. Thus, multiple pregnancy rate also decreased, it decreased significantly in PGD/PGS cycles from 30.5% in 2013 to only 1.7% in 2016. Conclusions: The current study gives valuable information for both physicians and patients to know better about the outcome, as well as for administrators for policy development. [ABSTRACT FROM AUTHOR]

Benzo[b]fluoranthene (BbF) is one of the main pollutants of polycyclic aromatic hydrocarbons (PAHs), which are generated from organic materials combustion and diesel exhaust. It has been reported that after maternal exposure, BbF crosses the placental barrier, leading to offspring defects. However, the effect of BbF on the female reproductive system, especially on oocyte maturation has not been studied. To elucidate the effect and precise mechanism of BbF on oocyte maturation, nuclear, and cytoplasm maturation were evaluated after exposing mouse oocytes to different concentrations of BbF. Results showed that BbF exposure shows no effect on the meiotic progression, but it caused defects on nuclear maturation via impairment on chromosome alignment. In addition, the treatment of BbF displayed the defects on the cytoplasmic maturation by leading to the mitochondrial dysfunction, DNA damage accumulation, early apoptosis and the loss of H3K4me3. To investigate the mechanism, we found that BbF impaired the oocyte maturation via the AMPK pathway. BbF exposure caused the phosphorylation of AMPK, which cause the DNA damage accumulation and apoptotic incidence. Taken together, our results demonstrated that BbF exposure impaired the mouse oocyte maturation due to mitochondrial dysfunction and early apoptosis. [ABSTRACT FROM AUTHOR]

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In this prospective cohort study, the effects of a time-lapse monitoring system on embryo quality and clinical pregnancy outcomes were assessed. A total of 608 patients undergoing in vitro fertilization between April 2013 and June 2014 at our institution were recruited for this study and group-matched into a time-lapse monitoring (TLM) (N = 304) or a standard incubator (SI) (N = 304). The patients’ characteristics in the TLM and SI groups were not significantly different. The TLM group showed a significantly higher transferable embryo ratio at Day 3 (61.65% vs. 52.87%; p < 0.0010, RR =1.10 [1.02, 1.19]), a higher number of transferable embryos (4.71 ± 2.38 vs. 4.09 ± 2.35; p = 0.0053, SMD =0.26 [0.06, 0.46]) and number of good-quality embryos cryopreserved at Day 3 (2.72 ± 2.35 vs. 2.11 ± 2.33; p = 0.0056, SMD =0.26 [0.06, 0.46]). In addition, the implantation and clinical pregnancy rates were not statistically significant between the TLM and SI groups. However, the TLM group had a higher ongoing pregnancy rate (67.32% vs. 57.22%; p = 0.0410) and live birth rate (65.37% vs. 55%; p = 0.0380) compared with the SI group. The observed beneficial effects could be the result of a more stable environment provided by the TLM system. [ABSTRACT FROM AUTHOR]