Biology of Sex Differences最新文献

Background: While it is clear that inflammation contributes to Parkinson's disease (PD) and prevalence is higher in males, sex remains an underexplored determinant of immune responses in PD.

Methods: Using the 3KL transgenic mouse model, which expresses three E to K α-synuclein mutations, we investigated how sex and age shape peripheral and central immunity and behavior in synucleinopathy. Male and female 3KL mice were aged to 8- and 14-months. At these ages animals underwent motor and cognitive assessment, followed by assessment of the peripheral immune response using flow cytometry and analysis of microglial transcriptional profiles by bulk RNA sequencing.

Results: Male 3KL mice exhibited earlier onset and greater severity of motor and cognitive impairments, which was linked to a pro-inflammatory peripheral immune profile marked by increased cytotoxic CD8⁺ T cells and IFNγ-producing CD4 Th1 cells. In contrast, female mice displayed delayed symptom onset, preserved cognition, along with early elevations in regulatory IL-10⁺ CD4 and γδ T cells. RNA sequencing of microglia revealed broad sex differences at 8 months. Males demonstrated early upregulation of microglia neurodegenerative signatures, MHC class I/II signaling, ceramide signaling, and pronounced lipid dysregulation, while females showed upregulation of microglial pathways related to protein, metabolic, and neuronal maintenance, including phagosome formation, docosahexaenoic acid signaling, and synaptogenesis pathways. Microglial transcriptional differences were nearly absent by 14 months, suggesting sex-specific trajectories converge during late-stage disease, which is concurrent with a decrease in estrogen in aged female mice.

Conclusions: Together, these findings reveal distinct immune signaling in male and female 3KL mice and identify coordinated changes in T cell and microglial responses that may contribute to sex differences in PD vulnerability and progression. This work underscores the importance of incorporating sex as a biological variable in neurodegeneration research and provides mechanistic insight into immune-mediated modulation of synucleinopathy.

Background: Polycystic ovary syndrome (PCOS) impairs endometrial receptivity, contributing to reproductive dysfunction. Our previous work identified ferroptosis-related dipeptidyl Peptidase 4 (DPP4) as a key regulator of endometrial receptivity in PCOS, though its mechanism remained unclear.

Objective: We aimed to explore the regulatory mechanism of DPP4 in the occurrence and tolerance of endometrial ferroptosis in PCOS.

Methods: Using high dose (HD) DHEA-induced rats and hormone-treated (E2 and HD DHEA) telomerase-immortalized human endometrial stromal cells (T-HESCs), we investigated DPP4's role in endometrial ferroptosis and receptivity. We evaluated the correlation of specific endometrial marker expression levels with reproductive outcomes.

Results: Phenotypic assessments revealed elevated endometrial Fe²⁺ accumulation, antioxidant dysfunction, mitochondrial damage, and enhanced estrogen/androgen receptor expression in PCOS models. DPP4 inhibition via sitagliptin improved decidualization responses and receptivity markers in rats prior to pregnancy. In T-HESCs, downregulated DPP4 could suppress hormone receptor expression and ferroptosis markers. Functional validation using BeWo spheroid implantation assays demonstrated restored endometrial receptivity following DPP4 intervention. Mechanistically, DPP4-driven ferroptosis exacerbated PCOS-associated endometrial dysfunction, while its suppression would enhance stromal cell decidualization capacity and implantation potential. Consistent with these findings, evaluation of endometrial specimens from PCOS patients confirmed a marked reversal of ferroptosis-related markers following sitagliptin intervention, which was further associated with significantly improved reproductive outcomes, including higher clinical pregnancy and live birth rates.

Conclusion: Reducing DPP4 expression not only inhibited ferroptosis but also improved the PCOS phenotype of the endometrium, ultimately influencing changes in endometrial receptivity, and indicating the ferroptosis-related protein DPP4 as a promising therapeutic target.

Debates about the nature of sex are prominent in scientific, scholarly and public discourses. Scientific as well as societal debates largely focus on whether sex is appropriately conceptualized as a binary, a spectrum, or some other form. These have taken on particular urgency because of highly contested, polarizing, and consequential developments in the global landscape in which the political weaponization of binary sex has escalated. Here we propose three frameworks useful for retaining focus on why sex might be conceptualized in a certain way to address the aims of a given project to help avoid pitting binary versus non-binary approaches against one another in a continued impasse. These three frameworks are (a) sex as a system of classification, (b) sex as a trait, and (c) sex as a dynamic system. We also provide a series of questions and considerations to guide a critical read of scholarship and scientific engagement of sex in ways that might help mitigate the isolating effects of disciplinary silos and advance cross-disciplinary dialogue and collaboration. Thus, rather than recapitulating discussions of how sex should be conceptualized or trying to establish a universally applicable definition of sex, these three frameworks and guiding questions can be drawn on to consider why certain projects might employ particular definitions and methods of operationalization of sex over others, and outline the merits and drawbacks of each. By refocusing our scholarly attention on what sex is empirically being employed to do and why, and providing these frameworks to think with, we hope to bring some essential bridging between those for and those against binary thinking about sex and foster a diversity of approaches that might more effectively build on one another rather than exist in opposition. We can then continue to try to nimbly engage what it is sex is being leveraged to do and why in order to ask how a given conceptualization will help us to learn about a given phenomenon.

Background: Women are nearly twice as likely to be diagnosed with Alzheimer's Disease (AD) over their lifetime. However, historically, preclinical studies utilizing AD rodent models to define new therapeutic targets in AD treatment have neglected to consider the confounding influence of subject sex leading to a lack of mechanistic insight into the biological underpinnings of sex bias in AD.

Methods: Here, we tracked choice of subject sex over the twenty-year history of the 5xFAD mouse, one of the most frequently cited pre-clinical AD models. We analyzed 1,330 primary research articles indexed on PubMed and recorded information provided regarding subject sex and/or as a rationale for not including datasets separated by sex, if noted. Trends were then plotted as a function of time ending in December 2024.

Results: In the last 15 years, the number of published manuscripts on the 5xFAD model omitting information on subject sex has progressively declined. However, the proportion of studies utilizing either males only (29%) or combining data from both sexes (24%) far surpasses studies acknowledging sex as a biological variable (SABV) (< 12%) with no significant changes noted over time. On average, the ratio of male only: female only studies of 5xFAD mice hovered around 2:1. The most frequently cited reason for omitting sex-based analyses was either a lack of sex differences found (29%), accelerated development of plaque burden in 5xFAD females (17%), or the possibility of within- or between-sex variability (15%). Mention of SABV has steadily increased in studies utilizing 5xFAD mice peaking at ~ 30% of manuscripts published in 2024. However, two key confounds in the 5xFAD model, including the potential impact of an estrogen response element (ERE) and parental imprinting in the Thy1 promoter driving transgene expression, have been largely ignored.

Conclusions: The 5xFAD model represents a compelling example of how neglecting to recognize the impact of biological sex on neural function can compromise study design and data interpretation. Given sex-dependent Thy1 promoter regulation may skew phenotypic outcomes, investigators should judiciously interpret sex differences observed in any AD mouse utilizing the Thy1 promoter to drive transgene expression.

Objectives: A scoping review was conducted to investigate knowledge gaps in the informatics research literature regarding sex differences in cognitive decline and impairment, identifying existing studies and areas requiring further exploration.

Methods and materials: Our scoping review follows the Preferred Reporting Items for Systematic reviews and Meta-Analysis Extension for Scoping Reviews (PRISMA - ScR) guidelines. We searched Ovid and other databases (APA PsychInfo, EMB Reviews, and Embase) for studies on sex differences in cognitive decline and impairment, focusing on peer-reviewed informatics journals and conference proceedings from 2000 to 2025. The selected manuscripts were analyzed based on metadata statistics, study attributes, and thematic content.

Results: A total of 17 full articles met the inclusion criteria. Most studies were conducted in North America (n = 7) and the European Union (n = 5). More than half of the studies were published after 2020 (n = 10). Our analyses highlight key aspects of selected studies, including bibliometric metadata, study attributes (e.g., study types, methods, and data sources), and thematic findings. Statistical modeling (n = 8) and machine learning (n = 4) are the most widely used study methods. Majority (n = 11) of the publications are single-site studies, while the other multi-site collaborations (n = 6) have emerged among hospitals, academic institutions, and research institutions.

Discussion: Sex-specific disparities in cognitive decline and impairment remain a critical issue in healthcare. Most informatics research has primarily concentrated on identifying generic sex differences in cognitive decline and impairment progression, rather than exploring the complex underlying mechanisms such as observational studies with causal analysis. While these studies are valuable, they lack a holistic approach to understanding sex-specific disparities.

Conclusion: There is a significant gap in using informatics to understand how biological, social, and behavioral factors contribute to sex-specific disparities in cognitive decline and impairment. This limitation underscores the need for more comprehensive informatics research that goes beyond mere identification to find the root cause of these disparities in healthcare.

Background: Memory impairments are highly prevalent in patients with epilepsy, yet important gaps remain in the understanding of potential sex and gender differences. This systematic review and meta-analysis aim to synthesize the available evidence on sex and gender differences in memory functioning in adults and children with epilepsy, and to explore the relevance of the epilepsy type, the side of seizure focus, the hemispheric dominance for language, the educational level and the age group in these differences.

Methods: The study followed PRISMA guidelines and was registered in PROSPERO (CRD420251006928). Studies were retrieved from Web of Science, PubMed/MEDLINE, Embase, and Scopus.

Results: The systematic search yielded 1,261 records, from which 32 studies were selected. Women scored higher than men in immediate verbal memory, both at baseline (g = 0.34; 95% CI = 0.23, 0.44; p < 0.0001) and after epilepsy surgery (g = 0.30; 95% CI = 0.15, 0.44; p < 0.0001). This advantage was also observed in delayed verbal memory, at baseline (g = 0.30; 95% CI = 0.19, 0.41; p < 0.0001) and after surgery (g = 0.25; 95% CI = 0.09, 0.41; p = 0.0018). In contrast, men outperformed women in immediate visual memory, both before (g = -0.13; 95% CI = -0.22, -0.03; p = 0.01) and after surgery (g = -0.17; 95% CI = -0.33, -0.01; p = 0.04). No significant differences were observed in working memory or delayed visual memory. Effect sizes favoring women in verbal memory were significantly smaller in studies including only patients with temporal lobe epilepsy compared to mixed epilepsy types. The effect size for postsurgical delayed verbal memory was moderated by the side of seizure focus: studies including a greater proportion of patients with left-hemisphere epilepsy showed poorer postsurgical delayed verbal memory. Hemispheric dominance for language, age, and educational level did not moderate sex-gender differences in memory.

Conclusions: These findings underscore the importance of incorporating sex and gender variables in neuropsychological assessment and intervention planning, offering evidence-based recommendations.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease. An increasing body of evidence indicates that hormones, particularly estrogen, play a significant role in RA. To date, no bibliometric studies have been conducted specifically on the role of estrogen in RA. This study seeks to perform a bibliometric analysis to elucidate research trends concerning estrogen in the context of RA from a comprehensive and systematic viewpoint.

Methods: We extracted literature pertaining to estrogen in RA from the Web of Science Core Collection (WOSCC) database, up to April 22, 2025. Research trends in this domain were analyzed utilizing bibliometric software tools, VOSviewer and Bibliometricx.

Results: A total of 1,009 literatures were included in this study. Articles in this field were first published in 1951 and have shown an overall upward trend since 1982. The United States and China were the countries that contributed the most articles, while the University of Genoa was the most contributing affiliation. CUTOLO M is the most prolific and most cited author. Arthritis and Rheumatology is the most published and cited journal in this field in the world. The primary focus of research in this area encompasses the evidence, mechanisms, and practical applications of estrogen's involvement in RA. In addition, the key words such as "cytokines", "inflammation", "immune response", "oxidative stress", and "endometriosis" appear most frequently, which indicates that the mechanism research of estrogen's participation in RA has been a research hotspot in recent years.

Conclusion: This study reflects the degree of academic interest in the potential link between estrogen and RA. This also lays a foundation for continuous research in this field and provides certain insights for future research directions.

Background: Bone morphogenetic proteins (BMPs) have been reported in many studies to be related to adult neurogenesis. Neurogenic impairment is a hallmark of Alzheimer's disease (AD), while the involvement of BMPs remains unclear.

Methods: AD models were established using APP^NL-G-F transgenic mice and C57BL/6 mice subjected to intracerebral injection of Aβ_(25-35) peptide. Female APP^NL-G-F mice received pharmacological inhibitor treatment, whereas Neuro2a cells were exposed to estrogen stimulation in vitro. Immunofluorescence staining was conducted to evaluate hippocampal neural stem cell proliferation. The hippocampus and cellular pellets were isolated, and quantitative PCR (qPCR) was employed to determine mRNA expression levels.

Results: Our study revealed that APP^NL-G-F mice and Aβ-injected mice exhibited impaired neurogenesis in the brain, with a clear sex-dependent difference only in APP mice. Several BMPs were markedly upregulated in the hippocampus of AD model mice, with significantly higher expression in females than in males. BMP inhibitor attenuated neural stem cell proliferation deficits in female APP^NL-G-F mice. Estrogen stimulation robustly enhanced BMP6 expression in Neuro2a cells.

Conclusions: Our findings reveal a sex-dependent impairment of neurogenesis in APP^NL-G-F mice driven by BMP signaling. Blocking BMP signaling enhances adult neural stem cell proliferation in female APP^NL-G-F mice, providing a potential therapeutic target for AD.

Background: The ventral premammillary nucleus (PMv), situated within the ventrobasal hypothalamus, is sensitive to steroid hormones and is involved in pheromone-responsive circuits. It maintains robust connections with sexually dimorphic nuclei both within and beyond the hypothalamus. Investigations over the past 15 years have suggested the role of the PMv in integrating environmental cues from conspecifics with internal states, thereby facilitating appropriate physiological and behavioral responses during reproductive and agonistic interactions. Neurochemical evidence indicates sexual dimorphism in the PMv of rats; however, comprehensive structural analyses are lacking.

Methods: After perfusing and processing the brains of male and female rats during the estrus and diestrus phases, we applied stereological methodology in the PMv.

Results: Males presented significantly greater neuronal volume and quantity than females did across both cycling phases. Neuronal volume in females was notably greater during estrus than during diestrus. However, no dimorphism was detected in overall volume, neuronal density, volume occupied by neurons, or neuropils.

Conclusions: Given its role as a nexus between nutritional status and reproductive physiology, as well as its involvement in modulating agonistic behavior, including maternal aggression, structural disparities in the PMv between males and females may reflect divergent functional roles, contributing to sex-specific strategies in reproduction and aggression.