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1. Sex-biased Transcriptome in in vitro Produced Bovine Early Embryos

   https://doi.org/10.1101/2025.03.04.641446  

   Shi, Meihong; Li, Guangsheng; Araujo, Hannah Marie; Lee, Angie S; Zhang, Jingzhi; Lee, Yoke Lee; Cheong, Soon Hon; Duan, Jingyue Ellie (March 2025, bioRxiv)

   Abstract BackgroundMorphologic sex differences between males and females typically emerge after the primordial germ cell migration and gonad formation, although sex is determined at fertilization based on chromosome composition. A key debated sexual difference is the embryonic developmental rate, within vitroproduced male embryos often developing faster. However, the molecular mechanisms driving early embryonic sex differences remain unclear. ResultsTo investigate the transcriptional sex difference during early development,in vitroproduced bovine blastocysts were collected and sexed by PCR. A significant male-biased development was observed in expanded blastocysts. Ultra-low input RNA-seq analysis identified 837 DEGs, with 231 upregulated and 606 downregulated in males. Functional enrichment analysis revealed male-biased DEGs were associated with metabolic regulation, whereas female-biased DEGs were related to female gonad development, sex differentiation, inflammatory pathways, and TGF-beta signaling. Comparing X chromosome and autosome expression ratio, we found that female-biased DEGs contributed to the higher X-linked gene dosage, a phenomenon not observed in male embryos. Moreover, we identified the sex-biased transcription factors and RNA-bind proteins, including pluripotent factors such asSOX21andPRDM14, and splicing factorsFMR1andHNRNPH2. Additionally, we revealed 1,555 significantly sex-biased differential alternative splicing (AS), predominantly skipped exons, mapped to 906 genes, with 59 overlapping with DEGs enriched in metabolic and autophagy pathways. By incorporating novel isoforms from long reads sequencing, we identified 1,151 sex-biased differentially expressed isoforms (DEIs) associated with 1,017 genes. Functional analysis showed that female-biased DEIs were involved in the negative regulation of transcriptional activity, while male-biased DEIs were related to energy metabolism. Furthermore, we identified sex-biased differential exon usage inDENND1B, DIS3L2, DOCK11, IL1RAPL2,andZRSR2Y,indicating their sex-specific regulation in early embryo development. ConclusionThis study provided a comprehensive analysis of transcriptome differences between male and female bovine blastocysts, integrating sex-biased gene expression, alternative splicing, and isoform dynamics. Our findings indicate that enriched metabolism processes in male embryos may contribute to the faster developmental pace, providing insights into sex-specific regulatory mechanisms during early embryogenesis. Plain English summaryMale and female early embryos develop at different speeds, with male embryos often developing faster than female embryos. However, the reasons behind these early differences remain unclear. In this study, we examined gene activity in bovine embryos to uncover the biological factors regulating these early sex differences. We collected in vitro-produced bovine blastocysts, examined their sex, and confirmed that male embryos develop faster. By analyzing global gene activity, including alternative splicing, which allows one gene to code for multiple RNA isoforms and proteins, we found distinct gene expression profiles between male and female embryos. Male embryos showed higher activity in genes related to metabolism and cellular functions, while female embryos had increased activity in genes associated with female-specific gonad development and gene expression regulation. We also examined differences in how genes on the X chromosome were expressed. Female embryos had higher X-linked gene expression, which may contribute to sex-specific developmental regulation. Additionally, we identified sex-specific transcription factors and RNA-binding proteins that regulate early embryo development, some of which are known to control pluripotency and gene splicing. Overall, our study provides new insights into how gene activity shapes early sex differences, suggesting that enhanced metabolism in male embryos may be a key driver of their faster developmental rate. HighlightsMale embryos develop faster due to increased gene expression in metabolism pathwaysFemale embryos exhibit higher X-linked gene expression, suggesting X-dosage compensation plays a role in early developmentSex-biased alternative splicing events contribute to embryonic metabolism, autophagy, and transcriptional regulation in embryosSex-biased isoform diversity contributes to distinct developmental regulation in male and female embryosKey pluripotency factors (SOX21, PRDM14) and splicing regulators (FMR1, HNRNPH2) drive sex-specific gene expression 

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2. Meta Data Analysis of Sex Distribution of Study Samples Reported in Summer Biomechanics, Bioengineering, and Biotransport Annual Conference Abstracts

   https://doi.org/10.1115/1.4064032  

   Sebastian, Frederick; Vargas, Ana I.; Clarin, Julia; Hurgoi, Anthony; Amini, Rouzbeh (June 2024, Journal of Biomechanical Engineering)

   Abstract The biased use of male subjects in biomedical research has created limitations, underscoring the importance of including women to enhance the outcomes of evidence-based medicine and to promote human health. While federal policies (e.g., the 1993 Revitalization Act and the 2016 Sex as a Biological Variable Act) have aimed to improve sex balance in studies funded by the National Institutes of Health (NIH), data on sex inclusivity in non-NIH funded research remain limited. The objective of this study was to analyze the trend of sex inclusion in abstracts submitted to the Summer Biomechanics, Bioengineering, & Biotransport Conference (SB3C) over 7 years. We scored every abstract accepted to SB3C, and the findings revealed that approximately 20% of total abstracts included sex-related information, and this trend remained stable. Surprisingly, there was no significant increase in abstracts, including both sexes and those with balanced female and male samples. The proportion of abstracts with balanced sexes was notably lower than those including both sexes. Additionally, we examined whether the exclusion of one sex from the corresponding studies was justified by the research questions. Female-only studies had a 50% justification rate, while male-only studies had only 2% justification. Disparity in sex inclusion in SB3C abstracts was apparent, prompting us to encourage scientists to be more mindful of the sex of the research samples. Addressing sex inclusivity in biomechanics and mechanobiology research is essential for advancing medical knowledge and for promoting better healthcare outcomes for everyone. 

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3. A test of Haldane’s rule in Neodiprion sawflies and implications for the evolution of postzygotic isolation in haplodiploids

   https://doi.org/10.1086/724820  

   Bendall, Emily E.; Mattingly, Kayla M.; Moehring, Amanda J.; Linnen, Catherine R. (January 2023, The American Naturalist)

   Haldane’s rule—a pattern in which hybrid sterility or inviability is observed in the heterogametic sex of an interspecific cross—is one of the most widely obeyed rules in nature. Because inheritance patterns are similar for sex chromosomes and haplodiploid genomes, Haldane’s rule may apply to haplodiploid taxa, predicting that haploid male hybrids will evolve sterility or inviability before diploid female hybrids. However, there are several genetic and evolutionary mechanisms that may reduce the tendency of haplodiploids to obey Haldane’s rule. Currently, there are insufficient data from haplodiploids to determine how frequently they adhere to Haldane’s rule. To help fill this gap, we crossed a pair of haplodiploid hymenopteran species (Neodiprion lecontei and Neodiprion pinetum) and evaluated the viability and fertility of female and male hybrids. Despite considerable divergence, we found no evidence of reduced fertility in hybrids of either sex, consistent with the hypothesis that hybrid sterility evolves slowly in haplodiploids. For viability, we found a pattern opposite of Haldane’s rule: hybrid females, but not males, had reduced viability. This reduction was most pronounced in one direction of the cross, possibly due to a cytoplasmic-nuclear incompatibility. We also found evidence of extrinsic postzygotic isolation in hybrids of both sexes, raising the possibility that this form or reproductive isolation tends to emerge early in speciation in host-specialized insects. Our work emphasizes the need for more studies on reproductive isolation in haplodiploids, which are abundant in nature, but under-represented in the speciation literature. 

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4. Plasticity of sex-biased aggression in response to the sex of territory intruders in an African cichlid fish, Julidochromis marlieri

   https://doi.org/10.1101/2024.05.22.595328  

   Dennis, Ry; Wood, Kelsey J; Renn, Suzy CP; Anderson, Andrew P (May 2024, bioRxiv)

   Behavior is often linked to gonadal sex; however, ecological or social environments can induce plasticity in sex-biased behaviors. In biparental species, pairs may divide offspring care into two parental roles, in which one parent specializes in territory defense and the other in nest care. The African cichlid fish Julidochromis marlieri displays plasticity in sex-biased behaviors. In Lake Tanganyika, J. marlieri form female-larger pairs in which the female is more aggressive than the male who performs more nest care, but under laboratory conditions, male-larger pairs can be formed in which these sex-biased behaviors are reversed. We investigated the influence of social environment on behavior by observing how individuals in both pair-types respond to conspecific intruders of either sex. We examined behavioral responses to three factors: sex of the subject, relative size of the subject, and the sex of the intruder. We confirm that relative size is a factor in behavior. The larger fish in the pair is more aggressive than the smaller fish is towards an intruder. While neither fish in the female-larger pairs varied their behaviors in response to the sex of the intruder, both members of the male-larger pairs were sensitive to intruder sex. Both individuals in the male-larger pairs engaged in more biting behaviors towards the intruder. Intruder biting behaviors strongly correlated with the biting behavior of the larger individual in the pair and occurred more frequently when encountering pairs with same sex as the larger fish when compared to pairs with the same sex as the smaller fish. Our results support the role of the social environment as a contributor in the expression of sex-biased behavior. 

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5. Sex and the Riddle of Variability

   https://doi.org/10.3998/ptpbio.5492  

   Richardson, Sarah S (June 2025, Philosophy, Theory, and Practice in Biology)

   Scientific research associations, funders, and publishers have recently introduced sex inclusion mandates requiring the use of male and female specimens in preclinical research designs and the analysis and reporting of data disaggregated by sex. However, it is not necessarily a simple matter to incorporate males and females in the same study design with the aim of detecting differences between them while following best practices for rigorous inference in laboratory science using model organisms. For example, if there are ways in which male and female variability might differ for the trait or procedure of interest, principles of sound experimental design may require larger numbers of organisms and observations to make valid inferences about the presence of a sex difference. This paper analyzes a current scientific debate over differences in variability between male and female laboratory rodents, and specifically over whether potential sources of sex-specific variability such as the estrous cycle, group housing, and body size constitute components of sex that should be measured. The variability debate surfaces the trade-offs between constructs of sex difference and similarity that face scientific researchers attempting to meet mandates to include both males and females in research design and report sex-specific results. This riddle of variability illuminates how laboratory researchers using model organisms must make contextual choices (Richardson 2022) at multiple decision points in order to stabilize sex as a biological variable in a particular research design. These judgments are informed by social and epistemic values and carry consequences for the validity, precision, and generalizability of claims of biological sex differences derived from preclinical research models. 

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