Spermatozoa centriolar defects can result in abnormal zygote functions. Recently, a method to quantify spermatozoa centriolar defects was developed named Fluorescence-Based Ratiometric Analysis of Sperm Centrioles (FRAC). However, whether spermatozoa centriolar defects identified by FRAC can result in abnormal zygote functions was not tested. Here, we quantified spermatozoa centriolar defects using FRAC, and zygote centriole function was assessed by imaging Nucleolus Precursor Body (NPB) polarization which was based on the pattern of NPB polarization. Data was analyzed at couple and embryo levels. Subjects were divided into two groups: seven couples and 62 embryos with normal spermatozoa centrioles versus eight couples and 78 embryos with abnormal spermatozoa centrioles (140 embryos from 15 couples in total). Patterned NPB polarization was statistically significant in both couple- and embryo-level analyses (p < 0.0001 and p = 0.0024). These results suggest that the abnormal spermatozoa centrioles identified by FRAC may correlate with abnormal zygote centrosome function via NPB polarization scoring. This study provides a foundation for more extensive studies to test for FRAC's utility in assessing spermatozoa centriole quality.
Abstract Objectives CD8 + T cells play a critical role in the immune dysfunction associated with liver cirrhosis. CD38 + HLA‐DR + CD8 + T cells, or bystander‐activated CD8 + T cells, are involved in tissue injury but their specific contribution to liver cirrhosis remains unclear. This study sought to identify the mechanism for CD38 + HLA‐DR + CD8 + T cell‐mediated pathogenesis during liver cirrhosis. Methods The immunophenotype, antigen specificity, cytokine secretion and cytotoxicity‐related indicators of CD38 + HLA‐DR + CD8 + T cells were determined using flow cytometry. The functional properties of these cells were assessed using transcriptome analysis. CD38 + HLA‐DR + CD8 + T‐cell killing was detected using cytotoxicity and antibody‐blocking assays. Results The proportion of CD38 + HLA‐DR + CD8 + T cells was significantly elevated in liver cirrhosis patients and correlated with tissue damage. Transcriptome analysis revealed that these cells had innate‐like functional characteristics. This CD8 + T‐cell population primarily consisted of effector memory T cells and produced a high level of cytotoxicity‐related cytokines, granzyme B and perforin. IL‐15 promoted CD38 + HLA‐DR + CD8 + T‐cell activation and proliferation, inducing significant TCR‐independent cytotoxicity mediated through NKG2D. Conclusions CD38 + HLA‐DR + CD8 + T cells correlated with cirrhosis‐related liver injury and contributed to liver damage by signalling through NKG2D in a TCR‐independent manner.
The female reproductive lifespan is highly dependent on egg quality, especially the presence of a normal number of chromosomes in an egg, known as euploidy. Mistakes in meiosis leading to egg aneuploidy are frequent in humans. Yet, knowledge of the precise genetic landscape that causes egg aneuploidy in women is limited, as phenotypic data on the frequency of human egg aneuploidy are difficult to obtain and therefore absent in public genetic datasets. Here, we identify genetic determinants of reproductive aging via egg aneuploidy in women using a biobank of individual maternal exomes linked with maternal age and embryonic aneuploidy data. Using the exome data, we identified 404 genes bearing variants enriched in individuals with pathologically elevated egg aneuploidy rates. Analysis of the gene ontology and protein-protein interaction network implicated genes encoding the kinesin protein family in egg aneuploidy. We interrogate the causal relationship of the human variants within candidate kinesin genes via experimental perturbations and demonstrate that motor domain variants increase aneuploidy in mouse oocytes. Finally, using a knock-in mouse model, we validate that a specific variant in kinesin KIF18A accelerates reproductive aging and diminishes fertility. These findings reveal additional functional mechanisms of reproductive aging and shed light on how genetic variation underlies individual heterogeneity in the female reproductive lifespan, which might be leveraged to predict reproductive longevity. Together, these results lay the groundwork for the noninvasive biomarkers for egg quality, a first step toward personalized fertility medicine.
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Abstract The female reproductive lifespan depends on egg quality, particularly euploidy. Mistakes in meiosis leading to egg aneuploidy are common, but the genetic landscape causing this is not well understood due to limited phenotypic data. We identify genetic determinants of reproductive aging via egg aneuploidy using a biobank of maternal exomes linked with maternal age and embryonic aneuploidy data. We found 404 genes with variants enriched in individuals with high egg aneuploidy rates and implicate kinesin protein family genes in aneuploidy risk. Experimental perturbations showed that motor domain variants in these genes increase aneuploidy in mouse oocytes. A knock-in mouse model validated that a specific variant in kinesin KIF18A accelerates reproductive aging and diminishes fertility. These findings suggest potential non-invasive biomarkers for egg quality, aiding personalized fertility medicine. One sentence summary The study identifies novel genetic determinants of reproductive aging linked to egg aneuploidy by analyzing maternal exomes and demonstrates that variants in kinesin genes, specifically KIF18A , contribute to increased aneuploidy and accelerated reproductive aging, offering potential for personalized fertility medicine.
Abstract Background: Liver cirrhosis could lead to immune dysfunction. During the pathogenesis of liver cirrhosis, CD8 + T cells play a critical role. While CD38 + HLA-DR + CD8 + T cells, also called bystander activation CD8 + T cells, had been shown to be involved in host injury, its specific contribution to liver cirrhosis had remained not unclear. The aim of this study was to understand how these CD38 + HLA-DR + CD8 + T cells exerted a pathogenic role in liver cirrhosis. Methods: Flow cytometry was performed to detect the immunophenotype, antigen-specific T cells, cytokines secretion, and cytotoxicity related indicators of CD38 + HLA-DR + CD8 + T cells. Transcriptome analysis was utilized to analyze the functional properties of these cells. The cytotoxicity of CD38 + HLA-DR + CD8 + T cells was detected by cytotoxicity assay and antibody blocking assay. Results: The percentage of CD38 + HLA-DR + CD8 + T cells in patients with liver cirrhosis significantly increased and was correlated with liver injury. These CD8 + T cells contained largely non-HBV specific T cells. Transcriptome analysis revealed that these CD8 + T cells subsets exhibited innate-like functional characteristic. In addition, these cells mainly consisted of effector memory T cells and displayed high expression levels of cytotoxicity-related cytokines, especially granzyme B and perforin. Stimulation experiments with cytokines shown that IL-15 could promote the activation and proliferation of these CD8 + T cells. Lastly, blocking assays indicated that CD38 + HLA-DR + CD8 + T cells had strong cytotoxic effects in a TCR-independent manner, mediated by NKG2D. Conclusion: CD38 + HLA-DR + CD8 + T cells were correlated with the liver injury in liver cirrhosis, and these cells exerted liver damaging effects through NKG2D in a TCR-independent manner.
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