搜索结果：Biology of sex differences

Despite longstanding recognition of sex as a biological variable, its integration into biomedical research remains inconsistent. Numerous publishers have introduced policies to improve reporting and inclusion of sex and gender, including Nature, which requires authors to complete a Life Science Reporting Summary documenting sex inclusion. Here, we evaluated the effectiveness of these policies by examining sex inclusion and reporting practices in all original research articles involving humans, vertebrates, or cell lines published in Nature in 2025 (N = 513). Nearly two-thirds of articles included both sexes (62.7%); however, inclusion was often nominal. Of these articles reporting inclusion of both sexes, 33% did not maintain inclusion across experiments, used markedly unbalanced sex ratios (≥ 2:1), or alternated between male- and female-only experiments. Another 45.5% of these articles reporting inclusion of both sexes did not report sample size by sex, so it cannot be ascertained whether sex inclusion was maintained across experiments or balanced by sex. Single-sex studies accounted for approximately one-fifth of articles. While male-only and female-only studies occurred at similar overall rates, male-only studies were more than four times more likely to address conditions affecting both sexes while female-only studies were more likely to address sex-specific conditions (e.g., ovarian cancer). Notably, the policies aimed at improving reporting and inclusion also did not increase analysis by sex; only 7% of articles explicitly analyzed sex as a discovery variable for at least some analyses. These findings suggest that transparency-focused reporting summaries alone are insufficient to ensure sex inclusion and/or meaningful analytical integration of sex (i.e., direct comparison of sexes, rather than using sex as a covariate). As a leading biomedical journal, Nature plays a central role in shaping research norms; without stronger editorial expectations, reporting requirements risk reinforcing male-default assumptions rather than advancing rigor and generalizability. Biological sex can influence how diseases develop and how treatments work. For this reason, researchers are increasingly encouraged to include both males and females in their studies. Many scientific journals now have policies to improve how sex is considered and reported. In this study, we looked at whether these policies are working by reviewing all research articles published in Nature in 2025. We found that nearly two-thirds of studies said they included males and females. However, this inclusion was often incomplete or unclear. In many cases, researchers did not consistently include both sexes throughout all experiments, used uneven numbers of males and females, or switched between studying only males or only females. Nearly half of the studies that claimed to include both sexes did not provide enough detail to confirm how many males and females were used. About one in five studies used only one sex. Studies using only males were much more likely to focus on conditions that affect everyone, while studies using only females were more likely to focus on female-specific conditions. Importantly, very few studies (7%) compared results between males and females to see if there were meaningful differences. Overall, our findings suggest that current reporting requirements are not enough to ensure that sex is properly included, reported, and analyzed in research. Stronger expectations are needed to improve the quality and usefulness of scientific findings for everyone.

Women have a greater lifetime risk of developing dementia. Despite clear sex differences, studies investigating modifiable dementia risk factors often overlook differences between sexes and age. This study examined sex and age differences in the prevalence of modifiable dementia risk factors and their associations with cognition. Participants were from the Health and Retirement Study, a nationally representative cohort study. Thirteen risk factors were examined, including education, hearing loss, cholesterol, depression, physical inactivity, diabetes, smoking, hypertension, obesity, excessive alcohol use, social isolation, poor vision, and poor sleep. A global cognitive summary score was also examined. Chi-square and t-tests examined sex and age differences in prevalence; linear regression examined interactions between sex, age, and risk factors on cognition. This study included 17,182 participants with a mean age of 69.2 ± 10.6 years, 59.2% of which were women. Ten out of 13 risk factors had sex differences in prevalence. Women had higher prevalence of elevated cholesterol, depression, physical inactivity, smoking, poor vision, and poor sleep. Women also had fewer years of education. Men had a higher prevalence of hearing loss, diabetes, and excessive alcohol use. Hearing loss, diabetes, and hypertension were associated with greater effects on cognitive performance in woman than men. BMI was negatively associated with cognitive performance in women compared to men in their 50s and 60s, but not at older ages. Education and cholesterol had stronger, positive associations with cognitive performance in women compared to men. These data suggest that women's greater risk of dementia may be due to a higher prevalence of multiple risk factors and stronger cognitive effects of risk factors. Results may inform future personalized prevention strategies for dementia risk reduction, particularly in women. Women are more likely than men to develop dementia over their lifetime, but many studies do not examine how dementia risk factors differ by sex or age. This study investigated whether modifiable dementia risk factors are more common in women or men and whether these risk factors differentially impact cognition by sex. Thirteen risk factors linked to dementia were examined: education, hearing loss, cholesterol, depression, physical inactivity, diabetes, smoking, high blood pressure, obesity, alcohol use, social isolation, poor vision, and poor sleep. Women had a higher prevalence of more risk factors than men, including poor sleep, poor vision, physical inactivity, cholesterol, depression, smoking, and fewer years of education. Men were more likely to have hearing loss, diabetes, and high alcohol use. Several risk factors were linked to worse cognitive performance in women than men, including hearing loss, diabetes, hypertension, and obesity. However, more years of education was associated with better cognition in women compared to men. These findings suggest that women’s higher dementia risk may reflect both greater exposure to risk factors and stronger negative effects of these risk factors on cognition.

Small differences between females and males in cognitive abilities have been consistently reported, but the factors underlying these sex differences remain unclear. Social and cultural factors are thought to play a key role, but studies on this topic have been inconclusive. Examination of genetic factors may shed some light on the mechanisms underlying cognitive sex differences. Using data from the Philadelphia Neurodevelopmental Cohort, a large, general population sample of individuals aged 8 to 21 years old (N = 4,694), we tested for sex differences in the genetic factors (i.e., Gene × Sex interactions) underlying cognitive ability. Participants completed the Penn Computerized Neurocognitive Battery, which consists of 14 tests designed to capture accuracy and speed in five domains: 1) executive function (abstraction and mental flexibility, attention, working memory), 2) episodic memory (verbal, facial, spatial), 3) complex cognition (verbal reasoning, nonverbal reasoning, spatial processing), 4) social cognition (emotion identification, emotion differentiation, age differentiation), and 5) speed (motor, sensorimotor). Composite domain scores were derived using confirmatory factor analysis, and general accuracy (g) and speed (gs) using principal component analysis. Small sex differences were observed on most cognitive measures (standardized mean difference (SMD) = 0.061-0.182). Males showed significantly higher genetic variance and lower environmental variance in executive (female σ2g = 0.301 v. male σ2g = 0.598, p = 0.001, female σ2e = 0.243 v. male σ2e = 0.024, p = 0.007), and complex (female σ2g = 0.291 v. male σ2g = 0.610, p = 0.001, female σ2e = 0.259 v. male σ2e = 0.023, p = 0.006) accuracy. Females showed significantly higher genetic and lower environmental variance on complex (female σ2g = 0.575 v. male σ2g = 0.135, p = 0.009, female σ2e = 0.222 v. male σ2e = 0.641, p = 0.012) and social (female σ2g = 0.589 v. male σ2g = 0.129, p = 0.009, female σ2e = 0.236 v. male σ2e = 0.672, p = 0.012) speed. Genetic correlations between females and males were not significantly different from 1 on any cognitive measure. Altogether, our results suggest that while the same genetic factors influence cognition in females and males, the magnitude of effect of these genetic factors differs. We observed small differences between females and males on most cognitive measures, as well as sex differences in heritability on some measures. Future studies are needed to delineate how environmental, genetic, and other biological factors jointly influence cognition. Small differences in cognition between females and males have been consistently reported across abilities, cultures, and decades. However, the factors underlying these cognitive sex differences remain unclear. Social and cultural factors are thought to play a key role, but there has been less examination of potential genetic factors. We tested for sex differences in the genetic factors underlying a range of cognitive abilities in a large, general population sample of individuals aged 8 to 21 years old. Small sex differences were observed across most cognitive domains, with female advantages in memory and social cognition, and male advantages in executive and complex cognition. Moreover, differences between females and males in the magnitude of genetic factors underlying cognition were observed for executive, complex, and social cognition, suggesting that some cognitive sex differences are partly driven by sex differences in underlying genetic factors. Most research on the underlying causes of sex differences in cognitive abilities has focused on social and cultural factors, but our findings highlight the importance of considering genetic factors, as well as how these genetic factors act jointly with social and cultural factors to impact cognition. Given the impact of cognition on social, emotional, and health outcomes, further work is needed to delineate the interplay between environmental and genetic factors that underlie cognitive sex differences.

Heart donation after circulatory death (DCD) is a promising strategy to increase graft supply. However, in contrast to conventional heart transplantation, in which organs are retrieved from heart-beating donors, DCD hearts are subjected to damaging conditions before and during functional, warm in-situ ischemia in the donor, leading to ischemia-reperfusion injury (IRI). Although sex differences have been identified in other contexts of cardiac IRI, such as myocardial infarction, they remain underexplored in DCD. Therefore, we aimed to investigate whether sex differences induce changes in the expression of genes in response to cardiac DCD conditions, including IRI, which may contribute to sexual dimorphism in graft quality. 102 animals were included in this study. Male, female, and ovariectomized (OVX) Wistar rats underwent simulated DCD with no or 22 min of functional, warm in-situ ischemia, followed by oxygenated reperfusion with left-ventricular loading. Functional recovery was assessed and left-ventricular tissue was used for RNA-sequencing. Recovery of left ventricular function was decreased by functional, warm in-situ ischemia, but significantly better in females than in males, with OVX resembling the males. Reperfusion induced inflammatory, stress-response and metabolic-related pathways in all groups. Expression of 110 genes correlated with cardiac recovery, many of which were more abundant in females compared to males, consistent with a role in improved post-ischemic ventricular function. Among these genes, Igfbp3, Fam78b, and Galnt10 were differentially expressed in females compared to males and OVX, suggesting an influence of female sex hormones. Compared to male hearts, cardiac recovery is significantly higher in female hearts after exposure to DCD conditions and is accompanied by an increased expression of genes related to quality control programs that positively correlate with ventricular function. Significantly higher expression of genes related to energy metabolism, including fatty acid metabolism, and inflammatory pathways was revealed in males compared to females and is associated with decreased recovery. This study suggests potential new therapeutic targets for optimizing cardiac DCD graft quality, and highlights the importance of underlying sex and sex-hormone differences, e.g. in inflammatory pathways and metabolic adaptations, that should be taken into consideration for the implementation of sex-specific precision therapies. Heart transplantation is currently the only treatment for patients with advanced heart failure to improve quality of life and survival. Nonetheless, the number of newly listed patients needing a transplant continues to increase and outpaces the supply of suitable donors.One promising approach to increase donor availability is using hearts from donors after circulatory death (DCD). In conventional heart donation, the donor is declared brain-dead, but machines keep the heart beating and oxygenated until removal. In DCD, the heart stops beating in the donor and it briefly receives less oxygen and nutrients, which can cause donor organ injury. Although outcomes with DCD hearts are excellent and transplant rates increase, further optimization of the protocol could allow more hearts to be used.In other situations where hearts temporarily lack oxygen, such as myocardial infarction, studies suggest that adult female hearts recover better than male hearts. In the DCD setting, little is known, but it has recently been shown in preclinical studies that female hearts are more tolerant to these conditions.In this study, we simulated the DCD protocol in a rat model. Afterwards, we identified 673 genes that were differentially expressed between male and female hearts. Many of these genes correlated with cardiac recovery; those more abundant in females were linked to better recovery, whereas those more abundant in males were linked to worse recovery. Taken together, our findings may help to identify treatments for the optimization of cardiac graft quality and improve heart transplantation options for both women and men.

Aortic stenosis (AS) presents with distinct sex-related differences in clinical manifestation, pathophysiology, and response to treatment. Women typically present at an older age, with greater frailty, more pronounced symptoms, and paradoxical low-flow AS, often associated with concentric left ventricular remodeling and fibrotic valve changes. In contrast, men show a predominance of calcific AS, eccentric remodeling, and more extensive aortic valve calcification. These differences are not solely anatomical or hemodynamic; they extend to molecular pathways and emerging contributors such as the gut microbiota.Recent evidence suggests that gut microbiota composition and its metabolites, particularly trimethylamine-N-oxide (TMAO) and indoxyl sulfate (IS), play a sex-specific role in AS pathogenesis. Women generally exhibit a more diverse and cardioprotective microbiota profile, shaped by estrogen and dietary habits, that might explain lower levels of pro-calcific metabolites and a fibrotic valve phenotype. Conversely, men tend to have higher TMAO and IS levels, driven by a Firmicutes-enriched microbiota and androgenic modulation, which might promote calcification and inflammatory signaling in the aortic valve.This review integrates current knowledge on sex-related differences in AS, spanning clinical patterns, valvular remodeling, cellular and molecular signaling, and gut-heart interactions, to propose a hypothesis-driven framework on how gut microbiota may contribute to sex-specific differences in AS. Aortic stenosis (AS) affects men and women differently. Women are usually older when the disease is diagnosed, often feel more symptoms, and tend to have a form of the disease with less blood flow and more stiffening of the heart muscle. Their heart valves are more fibrotic (scar-like). Men, on the other hand, more often develop heavily calcified (hardened) valves and a different pattern of heart enlargement.These differences are not just about heart structure or blood flow — they may also be linked to deeper biological processes, including the gut microbiome (the bacteria living in our intestines).Recent research suggests that gut bacteria and the substances they produce can influence how AS develops, and this may differ between men and women. Women tend to have a more diverse and protective gut microbiome, partly influenced by hormones like estrogen and diet. This may lead to lower levels of harmful substances and more fibrotic (less calcified) valve changes. Men, in contrast, often have higher levels of certain metabolites (such as TMAO and indoxyl sulfate) that have been shown in the literature to be linked to inflammation and valve calcification.This review brings together current knowledge on how sex differences, heart changes, biological pathways, and the gut microbiome interact in AS to propose a hypothesis-driven framework linking gut microbiota and its metabolites to sex-specific differences in AS pathophysiology.

Sex differences in aortic dissection (AD) have been consistently reported in epidemiological studies and experimental mouse models, with males showing markedly higher susceptibility. However, the molecular basis underlying these sex-specific differences remains insufficiently understood. Three-week-old male and female C57BL/6J mice were administered 0.4% β-aminopropionitrile (BAPN) in drinking water for 28 d to induce AD. After the induction period, fecal samples, serum, and aortic tissues were collected from all surviving animals. Integrated analyses included strand-specific transcriptomic sequencing of aortic tissues, untargeted serum metabolomics, and full-length 16 S rRNA sequencing of fecal samples to characterize sex-related differences across transcriptomic, metabolic, and microbiome layers. Inter-omics correlations were further assessed using bioinformatic approaches. Furthermore, in vivo experiments were conducted to validate the impact of key metabolites on the progression of AD. Female mice exhibited significantly lower susceptibility to BAPN-induced AD, including reduced rates of aortic rupture, lower incidence of AD or aneurysm (AAD), and attenuated aortic dilation. Transcriptomic analysis revealed that female non-dissected mice (FeNonAD) displayed diminished induction of inflammation-related genes and lower predicted immune cell infiltration. Metabolomic profiling revealed significant elevations of tryptophan-indole pathway metabolites-such as indolepyruvate, indole-3-acetic acid, and indolepropionic acid-in both FeNonAD and AAD groups. Microbiome analysis further revealed a higher relative abundance of tryptophan-metabolizing taxa, particularly key Clostridium species, in the intestinal tract of FeNonAD mice, accompanied by significant upregulation of key functional genes (tyrB and aspC) associated with indolepyruvate synthesis. Weighted gene co-expression network analysis (WGCNA)-based integration identified strong negative correlations between indolepyruvate and indole-3-acetic acid sodium salt levels and aortic gene modules linked to immune-inflammatory activation. Further in vivo experiments demonstrated that treatment with indolepyruvate delayed AD progression in male mice. This study highlights a central "gut microbiota-tryptophan metabolism-aortic inflammation" axis that contributes to sexual dimorphism in BAPN-induced AD. These findings provide new molecular insights into sex-specific disease mechanisms and offer a conceptual basis for developing sex-tailored diagnostic and therapeutic strategies. Aortic dissection is a dangerous condition, in which the wall of the main artery leaving the heart suddenly tears. It leads to internal bleeding and can be fatal. Doctors have long known that men develop this condition more often than women, but the reasons behind this difference have remained unclear.We used a mouse model to investigate why females appear to be better protected against aortic dissection. We examined several layers of biology simultaneously, including gene activity in the aorta, circulating chemicals, and bacteria in the gut. We aimed to understand how the body responds before and during disease.Female mice showed fewer signs of inflammation in the aorta and were less prone to vessel rupture. Their blood also contained higher levels of certain molecules made from the amino acid tryptophan. These molecules, called indole metabolites, are known to modulate immune responses and support healthy cell function. We discovered that female mice produced more of these protective molecules because their gut bacteria were better at converting tryptophan into indole compounds. In further experiments, supplementing male mice with indolepyruvate, an indole metabolite, reduced the incidence of aortic dissection.We found that these indole metabolites were associated with reduced activation of inflammation-related genes in the aorta. This suggests that communication between the gut and the blood vessel wall may help protect females from disease.Our findings highlight a gut–body pathway that may explain why females are less vulnerable to aortic dissection and point to new possibilities for prevention or treatment.

The amygdala is involved in the emotional expression, memory processing and managing stimulatory input. Although amygdala atrophy is early evidenced in Alzheimer's Disease (AD), the molecular mechanisms disrupted in initial neuropathological stages are still unknown. In the present study, we investigated the proteomic impairment of the amygdaloid region from AD-Braak stage I-II and III-IV subjects to better understand the neuropathological processes occurred early in this area and to identify potential targets that may face AD from the beginning of the disease. Label-free quantitative proteomics was applied using an Orbitrap Exploris 480 mass-spectrometer in 24 postmortem amygdala specimens derived from non-demented (n&#x2009;=&#x2009;3F/5M), AD-Braak stage I-II (n&#x2009;=&#x2009;4F/4M) and AD-Braak stage III-IV (n&#x2009;=&#x2009;4F/4M). Data analysis was performed using MaxQuant and Perseus software (two-way Student T-test; p&#x2009;<&#x2009;0.05). Metascape and Ingenuity Pathway Analysis softwares were considered for biological interpretation. Connectivity map platform was used for drug repurposing analyses. Transcriptomic/proteomic data of other brain regions were obtained from AlzData, Neuropro, and Agora repositories. Amygdaloid proteome of AD-Braak stage I-II and III-IV subjects compared to controls revealed a progressive proteomic impairment with a minimal overlap across Braak stages. Some of the amygdaloid DEPs were known interactors of human A&#x3b2; plaques, APP, or Tau proteins or were previously identified at transcriptional or translational level in other brain regions affected by AD. Interestingly, amygdaloid proteome was more severely affected in women than in men with a particular protein expression profile associated to each AD stage. Comparing our sex-dependent differential proteome datasets with transcriptomic data of different brain regions, we identified potential sex-specific proteins related to cognitive decline and neurodegeneration. Finally, data-driven drug repositioning using amygdaloid omics profiles unveiled that most of the small molecule candidates were neuropathological stage and/or sex-specific. Early and sex-specific amygdaloid proteome dysregulation in AD highlights the consideration of a deliberate stratification by sex in future research and clinical trials to develop effective therapeutic strategies in AD for both sexes. The amygdala is a brain region involved in the expression of emotions, memory processing and managing incoming stimulus. Atrophy of this area is evidenced at the first stages of Alzheimer's Disease (AD), pointing out a potential involvement of amygdala in the pathology of this disease. However, the molecular changes occurred early in this area are not fully understood. To this end, we interrogated the proteome of amygdala postmortem samples came from subjects of early AD stages. By applying data and functional analyses, we observed a stage-dependent and progressive proteomic impairment in this area. We detected proteins differentially expressed that were already known to interact with well-stablished neuropathological proteins or were altered in other brain areas. Importantly, data stratification by sex revealed that protein expression changes of amygdala were more abundant in women than men across AD progression. After comparing our results with published data in different brain regions affected by AD, we identified sex-specific proteins that could be used as biomarkers of cognitive decline and neurodegeneration. Finally, a drug repositioning-based approach proposed candidates with the potential to reverse amygdaloid malignant AD signature more effectively in one sex than in other or just in one sex. These observations highlight the consideration to include sex differences in future research to develop more precise and effective treatments in AD.

Sex differences are observed in the immune system in innate and adaptive immune responses. These sex differences can be pronounced during periods of significant hormonal change for women, such as puberty, pregnancy, and menopause. Despite evidence of these immunological sex differences shifting and changing during the life course, some research imprecisely conceptualizes sex differences as simply comparative. The dynamic nature of sex differences in the immune system requires moving beyond static male-female comparisons that ignore life-stage transitions and instead adopting a life-course lens that recognizes how immune function-particularly in women-is continuously reshaped across biological transitions. Evidence demonstrates meaningful sex differences across immune-mediated conditions, infection outcomes, and reactogenicity, yet critical gaps remain in the understanding of mechanism and life-course variation in these immune responses. To meaningfully advance research on sex differences in immunity, studies must explicitly and intentionally account for life-stage transitions, moving beyond static male-female comparisons that do not account for life-stage transitions. This shift requires the use of research designs that appropriately consider sex differences and life stage and that studies are powered for life-stage immune questions. Sex differences in immunity are continuously reshaped by and across the lifespan due to aging, hormonal changes, and social and environmental exposures. The field of immunology and immunology research&#xa0;must&#xa0;reconsider life stage as a&#xa0;core&#xa0;principle&#xa0;of sex differences.&#xa0;Failure to intentionally study sex differences across the life course&#xa0;in immunology leaves major gaps in our understanding of immune function in women across the life course and drive disparities, inefficiencies, and&#xa0;inaccuracies in research, treatment, and clinical care.

Liver metabolism is under tight control of the circadian system. Disruption of key clock gene expression (desynchronosis) leads to the misalignment of metabolic pathways. However, the relationship between circadian dysregulation and hepatic protein-synthetic function, as well as its sexual dimorphism, remains poorly understood. To evaluate the effect of chronic photoperiod disruption on hepatic protein-synthetic function (total protein, albumin) and to establish its relationship with the expression of key circadian proteins (BMAL1, CLOCK, PER2) in male and female rats, as well as to assess the efficacy of exogenous melatonin in correcting the identified disturbances. The study was performed on 240 adult Wistar rats (120 males, 120 females). Animals were divided into 3 groups: control (light: dark 10:14&#xa0;h), dark deprivation (LL, constant light for 21 days), and LL&#x2009;+&#x2009;melatonin (12&#xa0;mg/L drinking water). Plasma levels of total protein and albumin were measured. Immunohistochemistry was used to assess the percentage of positively stained hepatocytes for BMAL1, CLOCK, and PER2. Statistical analysis included two-way ANOVA, Pearson correlation analysis, ANCOVA, and ROC analysis. Dark deprivation reduced albumin levels by 15.7% in males and by 15.9% in females compared to controls. Two-way ANOVA revealed significant effects of "lighting conditions" (F&#x2009;=&#x2009;145.3, p&#x2009;<&#x2009;0.0001), "sex" (F&#x2009;=&#x2009;18.7, p&#x2009;<&#x2009;0.01), and their interaction (F&#x2009;=&#x2009;7.2, p&#x2009;<&#x2009;0.05). BMAL1 and CLOCK expression decreased by more than 70% in both sexes, whereas PER2 expression paradoxically increased by 28.9-35.0%. Strong correlations were found between albumin levels and expression of BMAL1 (r&#x2009;=&#x2009;0.79-0.81, p&#x2009;<&#x2009;0.001), CLOCK (r&#x2009;=&#x2009;0.69-0.74, p&#x2009;<&#x2009;0.001), and PER2 (r= -&#x2009;0.68 to -&#x2009;0.71, p&#x2009;<&#x2009;0.001). ANCOVA (R&#xb2;=0.71, p&#x2009;<&#x2009;0.0001) identified BMAL1 expression as the most significant independent predictor of albumin levels (&#x3b2;&#x2009;=&#x2009;0.52, p&#x2009;<&#x2009;0.0001), with sex retaining independent significance (p&#x2009;=&#x2009;0.02). ROC analysis demonstrated high predictive performance of BMAL1 expression for hypoalbuminemia (AUC&#x2009;=&#x2009;0.87-0.89, p&#x2009;<&#x2009;0.0001). Melatonin treatment fully restored the expression of all examined circadian proteins and normalized protein synthetic parameters to control levels in both sexes. Chronic photoperiod disruption induces profound hepatic desynchronosis characterized by suppression of BMAL1/CLOCK and accumulation of PER2, which is associated with decreased protein synthetic function. A pronounced sexual dimorphism in susceptibility to desynchronosis was identified. BMAL1 expression is a highly informative predictor of hypoalbuminemia. Exogenous melatonin fully restores the impaired parameters, supporting its use as an effective chronobiotic. The liver works on a daily (circadian) rhythm. When this rhythm is disrupted&#x2014;for example, by constant light exposure&#x2014;it can harm liver function. However, scientists did not know exactly how rhythm disruption affects the liver&#x2019;s ability to make proteins (like albumin), or whether males and females respond differently. This study tested whether constant light harms liver protein production, and whether the sleep hormone melatonin could fix it. They used 240 adult rats (120 males, 120 females). The rats were split into three groups:1. Normal light-dark cycle (control).2. Constant light for 21 days (to disrupt their body clock).3. Constant light plus melatonin in their drinking water.They measured blood levels of total protein and albumin (a key protein made by the liver). They also measured three key clock proteins (BMAL1, CLOCK, PER2) in the liver cells. Constant light lowered albumin levels by about 16% in both male and female rats. It also caused major changes in the liver&#x2019;s clock proteins: BMAL1 and CLOCK dropped by over 70%, while PER2 increased. These changes were strongly linked to lower albumin levels. The study also found that sex mattered&#x2014;males and females responded differently to rhythm disruption. Using a statistical model, BMAL1 was the best predictor of low albumin. Importantly, melatonin treatment fully restored all clock proteins and normalised protein production in both sexes. Disrupting the body&#x2019;s daily rhythms harms the liver&#x2019;s ability to make essential proteins. The clock protein BMAL1 may serve as a useful marker for liver problems. Melatonin&#x2014;a natural hormone already used for sleep disorders&#x2014;could potentially help protect liver function when circadian rhythms are disturbed (e.g., in shift workers, people with chronic jet lag, or those living under abnormal light cycles).

Consistent with differences in behaviors between sexes, studies reveal sex differences in the organization of neural circuits, synaptic function, and neuronal excitability, as well as sex-dependent recruitment of specific neuronal subtypes during behavior. These studies demonstrate sex differences in cell numbers, brain region volumes, cellular composition of brain areas, and density and strength of synapses in many brain regions, innervation of neuronal subtypes, receptor-mediated transduction mechanisms, neurotransmitter and neuropeptide release, and the influence of neuronal growth factors. Beyond insights into the mechanisms of sex differences in behaviors, understanding sex-typical circuit, cellular, and synaptic processes is crucial for identifying the causes of sex-typical vulnerabilities to nervous system disorders, such as the high prevalence of autism spectrum disorders and attention deficit hyperactivity disorder in males, and the higher incidence of affective, anxiety, and trauma-related disorders in females. Because these disorders often emerge during various developmental stages, it is essential to understand how development interacts with genetic, epigenetic, metabolic, hormonal, and environmental factors to affect the nervous system across sexes. Consequently, future research that examines the interaction between the nervous system and these critical factors is expected to elucidate the mechanisms underlying nervous system disorders. Additionally, targeting sex-specific mechanisms involved in these disorders could open new opportunities for more effective treatments in both sexes.

This study aimed to systematically map the sex-specific clinical and proteomic risk profiles of aortic aneurysm (AA), elucidate its molecular mechanisms, and develop a sex-specific protein risk prediction score. Based on the UK Biobank, we adopted a sex-stratified strategy to assess associations between traditional clinical factors and AA in 471,660 participants, and performed proteomics analysis on 49,887 participants with plasma protein data. Mediation analysis was used to explore the molecular mechanisms by which clinical risks drive AA. Finally, sex-specific protein risk scores were developed via LASSO regression, and their predictive performance was evaluated in an independent validation cohort. Smoking (HR: Male: 2.82; Female: 4.42) and valvular disease (HR: Male: 2.01; Female: 4.62) were the strongest shared risk factors, with women exhibiting significantly higher susceptibility. Incident AA was primarily attributed to smoking (Male: 15.3%; Female: 19.8%) and hypertension (Male: 11.2%; Female: 10.2%). Smoking was associated with AA potentially through the ECM degradation pathway in both sexes. Hypertension may also influence AA risk through this pathway in men, whereas in women, it may primarily operate through metabolic and growth factor regulation pathways. Among LASSO-selected proteins, 4 were shared, 10 were male-specific, and 9 were female-specific. Ultimately, the model integrating traditional risk factors and sex-specific protein scores demonstrated superior predictive performance in an independent cohort (C-statistic: Male: 0.809; Female: 0.832). Smoking and hypertension are primary risk factors for AA. Men may be predisposed to structural destruction potentially mediated by ECM degradation, whereas women may be predisposed to intrinsic failure potentially involving metabolic dysregulation and cell apoptosis. The model integrating age, clinical factors, and protein scores better captures residual risk, significantly improving AA prediction. Aortic aneurysm (AA) refers to a dangerous dilation of the aorta, the body&#x2019;s largest blood vessel. It often presents no obvious symptoms before a rupture occurs, an event that carries an extremely high fatality rate. Although previous research has explored traditional clinical risk factors, the existence of significant sex differences has remained largely unexamined. Utilizing large-scale real-world data from nearly 500,000 individuals, this study provides an in-depth investigation into the impact of sex differences on AA. We found that smoking and valvular heart disease are the top risks shared by both sexes; however, women exhibit a far higher sensitivity to these risks than men.Based on proteomics, the research reveals distinct biological mechanisms underlying the disease&#x2019;s onset in men versus women: For men, smoking and hypertension primarily lead to the destruction of the vascular wall&#x2019;s &#x201c;structural scaffold&#x201d; resulting in physical damage akin to &#x201c;old pipes.&#x201d; In contrast, for women, the disease is more frequently triggered by interferences with cellular repair and energy metabolism, resembling an &#x201c;internal system failure.&#x201d;Accounting for these sex differences, we constructed unique protein risk scores for both males and females. The results demonstrate that among the 23 proteins associated with AA, only 4 are common to both sexes. Combining these protein scores with traditional risk factors enables a more accurate prediction of high-risk populations. This study serves as a critical reminder that cardiovascular health should prioritize sex differences. Furthermore, through such sex-specific blood tests, doctors may be able to identify high-risk individuals much earlier in the future, achieving true personalized prevention.

Lipid traits are known to be sex-differential, but the underlying molecular players are largely unknown. Herein, we aim to highlight differential molecular signatures in lipid metabolism between males and females by identifying proteins that are causally linked to lipids in a sex-specific or sex-differentiated manner. Since protein levels are downstream products of gene expression, proteomics data can be crucial to understand etiology of sex-differences in lipids metabolism.We used sex-specific pQTL summary statistics for 2,923 circulating proteins measured in the UK Biobank Pharma Proteomics Project, along with sex-specific summary statistics of lipids from the Global Lipids Genetics Consortium. We combined these using two-sample Mendelian Randomization analyses and applied stringent multiple testing p-values correction and sensitivity analyses.We identified several sex-specific significant causal links between protein levels and lipid phenotypes: 83 were exclusive to females and 82 to males, 46% of which would not have been identified using combined-sex GWASs. The estimated causal effect was instead significant in both sexes but substantially different in size for 39 causal relationships (p&#x2009;<&#x2009;0.05). Intriguingly, several of these proteins were previously shown to be involved in inflammation and cardiometabolic diseases, such as Apolipoprotein(a) and lipoprotein lipase. Furthermore, two sex-specific proteins - LEPR and LPA - are molecular targets of emerging cardiometabolic therapies, highlighting the need for future investigations to determine whether these protein-level differences translate into sex-specific efficacy or safety in clinical trials and routine treatments.The discovery of these sex-differences can provide important etiological insights into the management of lipid metabolism. Such knowledge may in turn improve the predictive use of sex-specific pQTLs and point to new therapeutic gender specific strategies to prevent cardiovascular disease.

There is a gap in understanding the predominance of males with idiopathic pulmonary fibrosis (IPF). While gonadal hormones contribute to fibrosis susceptibility, evidence suggests a role for sex chromosomes. We used The Four Core Genotypes (FCG) mouse model, which uncouples gonadal sex from sex chromosomes, in aged mice before and after bleomycin (BLM)-induced lung injury. Fibrosis severity was assessed by histology, collagen content, and profibrotic gene expression, along with analysis of estrogen receptor (ER)&#x3b1; and ER&#x3b2; signaling, matrix metalloproteinase activity, insulin-like growth factor-1 (IGF-1), and microRNAs. Data were analyzed using two-way ANOVA to test effects of gonadal sex, sex chromosome complement, and their interaction; gonadectomy experiments used three-way ANOVA including gonadal status. BLM-induced lung injury resulted in the greatest fibrosis in XY mice with ovaries, which was associated with elevated ER&#x3b1; expression and increased ER&#x3b1;:ER&#x3b2; ratio. In contrast, ER&#x3b2; expression was highest in XX mice with testes and associated with attenuated fibrosis. Multiple fibrotic pathways were regulated by gonadal sex, sex chromosome complement, or their interaction. Gonadectomy revealed organizational and activational effects of sex hormones and uncovers interactions between gonadal sex, sex chromosomes, and hormone status. Sex chromosome-dependent regulation of let-7d and miR-29a linked chromosomal dosage to ER&#x3b1;-IGF-1 mediated remodeling. These findings identify hormonal and chromosomal mechanisms contributing to sex bias in pulmonary fibrosis and suggest sex-informed therapeutic targets for IPF. IPF is a progressive, incurable lung disease characterized by excessive lung scarring and a strong male predominance. The biological reasons for these sex differences are not well understood. Most studies compare males and females as whole groups, which makes it difficult to determine whether these differences are driven by sex hormones, sex chromosomes, or both.In this study, we used a specialized mouse model that allows us to separate the effects of sex chromosomes (XX or XY) from the effects of male or female hormones. This approach made it possible to test how each factor contributes to lung injury.We found that both sex chromosomes and sex hormones influence lung injury. Mice with XY chromosomes developed more severe lung injury under certain conditions, even when they did not have male hormones. Removing sex hormones changed the severity of lung injury in ways that depended on the animal&#x2019;s chromosome makeup. We also identified changes in key molecular pathways that help explain how these biological differences affect lung injury and repair.Together, these findings show that sex differences in pulmonary fibrosis are not explained by hormones alone. Instead, sex chromosomes and hormones work together to shape disease risk and severity. Understanding these mechanisms may help guide future research toward preventing or treating lung fibrosis in men and women.

Chronic pain-depression comorbidity is characterized by sensory hypersensitivity and emotional dysregulation, and has been linked to alterations in prefrontal network connectivity. It represents a major therapeutic challenge due to its pronounced sex differences in symptom manifestation and increased treatment resistance. Nitrous oxide (N&#x2082;O), an inhalational anesthetic traditionally used for its analgesic properties, has recently emerged as a potential rapid-acting antidepressant, with evidence suggesting both rapid and sustained antidepressant effects. Here, we evaluated the behavioral and electrophysiological effects of N&#x2082;O (50%, 1&#xa0;h) in adult male and female mice subjected to the chronic constriction injury (CCI) model of neuropathic pain, assessing its potential to simultaneously target nociceptive and affective symptoms, as well as locomotor behavior. N&#x2082;O reduced locomotor activity in both sexes, with longer-lasting effects in males. EEG recordings revealed decreased low-frequency spectral power in both sham and CCI animals, with more widespread effects in females. In the acetone test, N&#x2082;O produced analgesia in CCI males but no significant effect in females, while stimulus application increased oscillatory EEG activity across groups and sexes. Notably, CCI females showed an attenuated electrophysiological response compared with Sham-Air controls. In sham animals, N&#x2082;O reduced post-stimulus power, whereas in CCI mice it restored prefrontal EEG activity, enhancing the electrophysiological responses in both sexes. In the tail suspension test, only CCI males exhibited a prodepressive phenotype, while no antidepressant-like effects were observed in either sex 24&#xa0;h post-treatment. These findings demonstrate sex-specific behavioral and neurophysiological responses to N&#x2082;O, highlighting the importance of incorporating sex as a biological variable in NMDA receptor-targeted interventions. Chronic pain and depression often occur together and can severely affect quality of life. People living with both conditions frequently experience increased pain sensitivity, low mood, reduced motivation, and poor response to treatment. Importantly, men and women can experience these symptoms differently, yet many studies do not adequately investigate these sex differences. Nitrous oxide (N&#x2082;O), commonly known as &#x201c;laughing gas,&#x201d; is used in clinical practice for pain relief and has recently attracted interest as a potential fast-acting antidepressant. However, its effects in chronic pain&#x2013;related depression, as well as potential differences between males and females, have not been explored. In this study, we investigated how N&#x2082;O affects pain- and mood-related behaviors and brain activity in male and female mice with nerve injury&#x2013;induced chronic pain. After N&#x2082;O exposure, we evaluated movement activity, pain sensitivity, depressive-like behavior, and electroencephalographic (EEG) activity. Our findings reveal that N&#x2082;O produced distinct behavioral and EEG responses in male and female mice. Particularly, N&#x2082;O similarly reduced movement activity and altered EEG activity in both sexes, although the timing and magnitude of these effects differed between sexes. N&#x2082;O reduced pain sensitivity in male mice with chronic pain, but not in females, and did not produce clear antidepressant-like effects 24&#xa0;h after treatment in either sex. Overall, our findings show that males and females respond differently to N&#x2082;O treatment and highlight the importance of considering sex differences when developing new treatments for chronic pain and depression.

As algorithm-based decision support tools become increasingly integrated into clinical workflows, particularly with the popularization of artificial intelligence, the conceptualization and operationalization of demographic variables such as sex and gender have implications for how these variables are measured and interpreted. Misalignment between variable labels, response categories, and underlying data sources may introduce measurement error or ambiguity in algorithm inputs, potentially affecting clinical interpretation and downstream decision-making. This concern reflects issues of variable specification rather than terminology alone. The objective of this study is to evaluate how sex and gender are labeled, operationalized, and aligned with underlying source data in clinical decision-support tools. In May 2025, we conducted a cross-sectional review of clinical tools available on MDCalc, a widely-used online repository of clinical decision-support tools derived from biomedical research and clinical guidelines. We assessed tools with a demographic input labeled as sex, gender, or both. Main measures were the presence and operationalization of sex or gender variables within tool interfaces and corresponding primary references. Variable labeling (sex or gender), response categories (e.g., male/female or man/woman), reported data collection methods in primary references, and concordance between tool interfaces and source literature. Tools were also qualitatively categorized by potential clinical impact (high, medium, low). Among 821 tools screened, 84 (10.2%) included a sex or gender variable. Of these, 69 (82.1%) labeled the variable as sex and 15 (17.9%) as gender. Binary response categories were used in 83 tools (98.8%). Sex-gender conflation occurred in 16 tools (19.0%), reflecting inconsistencies between variable labels and response categories used as inputs. Primary references were available for 76 tools (90.5%); among those that explicitly reported sex or gender collection, 18 (25.7%) demonstrated sex-gender conflation. Most tools were classified as having medium (51.2%) or high (33.3%) potential clinical impact. Sex and gender are inconsistently labeled and operationalized in clinical decision-support tools. One in five tools demonstrated misalignment between variable labels, response categories, and underlying source data. Greater conceptual clarity and transparency of sex and gender variables may reduce ambiguity and strengthen the validity, interpretability, and equity of algorithm-based clinical decision tools.

The 2023 iteration of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimated prevalence, incidence, and health burden for 375 diseases and injuries, including 12 mental disorders. We assess past, current, and emerging trends in the prevalence and burden of mental disorders across sexes and age groups, for 21 regions, 204 countries and territories, and by Socio-demographic Index (SDI) quintile, from 1990 to 2023. Mental disorders included in GBD 2023 were anxiety disorders, major depressive disorder, dysthymia, bipolar disorder, schizophrenia, autism spectrum disorders, conduct disorder, attention-deficit hyperactivity disorder, anorexia nervosa, bulimia nervosa, idiopathic developmental intellectual disability, and a residual category of other mental disorders. A literature review identified epidemiological data for each disorder. These were analysed via a Bayesian meta-regression to estimate prevalence by disorder, sex, age, location, and year. Disorder-specific prevalence was multiplied by disability weights representing the severity of health loss associated with each disorder to estimate years lived with disability (YLDs). Deaths due to anorexia nervosa were assessed with a Cause of Death Ensemble modelling strategy to estimate deaths by sex, age, location, and year, and then multiplied by the standard life expectancy at age of death to estimate years of life lost (YLLs). YLDs equalled disability-adjusted life-years (DALYs) for all mental disorders except anorexia nervosa (the only mental disorder considered as an underlying cause of death in GBD), for which DALYs represented the sum of YLDs and YLLs. We presented prevalence, deaths, YLDs, YLLs, and DALYs as counts, age-specific rates per 100&#x2008;000 population, and age-standardised rates per 100&#x2008;000 population. We estimated 1&#xb7;17 billion (95% uncertainty interval 1&#xb7;06-1&#xb7;31) prevalent cases of mental disorders globally in 2023, equivalent to an age-standardised prevalence rate of 14&#x2008;210&#xb7;7 cases (12&#x2008;849&#xb7;5-15&#x2008;940&#xb7;1) per 100&#x2008;000 population. These estimates represented a 95&#xb7;5% (75&#xb7;0-121&#xb7;2) increase in prevalent cases and 24&#xb7;2% (11&#xb7;4-41&#xb7;4) increase in age-standardised prevalence rate between 1990 and 2023. All mental disorders showed increases in prevalent cases between 1990 and 2023, while notable increases were seen in age-standardised prevalence rates for anxiety disorders, major depressive disorder, dysthymia, anorexia nervosa, bulimia nervosa, schizophrenia, and conduct disorder. There were an estimated 171 million (127-228) DALYs due to mental disorders globally across sex and age in 2023, equivalent to an age-standardised DALY rate of 2070&#xb7;5 DALYs (1519&#xb7;1-2750&#xb7;5) per 100&#x2008;000 population. Mental disorders contributed to 6&#xb7;1% (4&#xb7;8-7&#xb7;6) of all-cause DALYs in 2023, making them the fifth leading cause of global DALYs (up from 12th in 1990). DALYs were almost entirely composed of YLDs. Mental disorders were the leading cause of YLDs in 2023 (up from second in 1990), explaining 17&#xb7;3% (14&#xb7;8-20&#xb7;6) of all-cause global YLDs. Leading causes of mental disorder DALYs were anxiety disorders (ranked 11th among the 304 diseases and injuries at Level 4 of the GBD cause hierarchy), major depressive disorder (15th), and schizophrenia (41st). Globally in 2023, mental disorder age-standardised DALY rates were higher among females (2239&#xb7;6 [1643&#xb7;7-3014&#xb7;1] per 100&#x2008;000) than among males (1900&#xb7;2 [1399&#xb7;8-2510&#xb7;8] per 100&#x2008;000), and peaked in the 15-19 years age group (2617&#xb7;3 [1850&#xb7;6-3696&#xb7;8] per 100&#x2008;000). All locations showed increased mental disorder DALY rates in 2023 compared with 1990, ranging across countries and territories from 1302&#xb7;4 (952&#xb7;7-1683&#xb7;7) per 100&#x2008;000 in Viet Nam to 3555&#xb7;8 (2661&#xb7;9-4715&#xb7;0) per 100&#x2008;000 in the Netherlands. Across SDI quintiles, DALY rates ranged from 1853&#xb7;0 (1352&#xb7;1-2469&#xb7;3) per 100&#x2008;000 for middle SDI to 2184&#xb7;1 (1606&#xb7;1-2890&#xb7;3) per 100&#x2008;000 for high SDI. A significant health burden was imposed by mental disorders in all countries and territories in 2023, irrespective of the health resources available. In some instances, this burden has increased over time and is unevenly distributed across populations. Stronger surveillance systems, particularly in low-income and middle-income countries, are required. Additionally, we need more coordinated and inclusive policies to reduce the burden through early treatment and prevention, tailored to sex and age differences across locations. Responding to the mental health needs of our global population, especially those most vulnerable, is an obligation, not a choice. Gates Foundation, Queensland Health, and University of Queensland.

The health and environmental risks associated with using 17-methyltestosterone hormone (MT) to produce all-male tilapia stocks limit the sustainability of aquaculture. As such, plant-based products with the potential to induce masculinisation in tilapia are gaining considerable attention as potentially safe, nature-based alternatives. However, the underlying mechanism for sex change induction by plant products remains unknown. The present study used pine pollen (PP) to study the processes modulating female-to-male sex change in three-day-old all-female Nile tilapia (Oreochromis niloticus). Experimental fish were fed either a basal diet supplemented with 1,280&#xa0;mg PP kg-&#x2009;1 from 3 to 30 days post-hatch (dph), or the same basal diet incorporated with 60&#xa0;mg MT kg-&#x2009;1 (MT treatment), or the basal diet only (CT treatment. After 30 dph, fish in all treatments were fed only a basal diet up to 120 dph. Histological observations showed that female-to-male sex change occurred between 21 and 45 dph in MT and PP treatments. During this period, gonadal tissue in PP-treated fish progressively shifted from undifferentiated germ cells toward testes dominated by spermatogonia and spermatocytes. In contrast, MT treatment accelerated spermatogenic progression, with gonads exhibiting advanced germ cells, including spermatids and spermatozoa, reflecting complete masculinisation. Conversely, fish in the CT group underwent normal ovarian differentiation between 21 and 30 dph, characterised by ovarian cavity formation and oocyte-like germ cells. These gonadal histological changes were closely related to temporal changes in sex-biased gene expression and steroid hormone profiles. The PP and MT treatments significantly up-regulated male sex gene expression (dmrt1 and amh) and down-regulated female transcripts (cyp19a1a and foxl2), whereas an opposite pattern was observed in the CT group. Correspondingly, sex steroid concentrations (testosterone and 11-ketotestosterone) were also significantly elevated in both PP- and MT-treated fish, consistent with higher proportions of male individuals (PP: 77.8&#x2009;&#xb1;&#x2009;2.9% and MT: 97.8&#x2009;&#xb1;&#x2009;1.1%), unlike the CT group, where fish remained all-female with significantly higher 17&#x3b2;-estradiol levels. These findings imply that PP induces female-to-male sex change in Nile tilapia by disrupting the expression of sex-biased genes and, consequently, the androgen-to-estrogen balance. However, further studies are required to enhance the androgenic potency of PP. Nile tilapia mature early and spawn prolifically, leading to overcrowding in aquaculture systems, which causes resource competition and stress, resulting in stunted growth. All-male tilapia stocks are preferred as they grow faster and larger than females. However, producing all-male tilapia typically involves the synthetic chemical 17&#x3b1;-methyltestosterone (MT), which poses health and environmental risks. Recent studies suggest that plant-based alternatives, such as pine pollen (PP), could safely and affordably masculinize tilapia. This study tested PP as a natural alternative to MT by feeding all-female tilapia three diets: one with PP, one with MT, and one control (no PP or MT). The fish were fed these diets from 3 to 30 days old, then switched to a control diet until 120 days. Results showed that both PP and MT successfully converted females into males between 21 and 45 days, whereas the control group remained all-female. This masculinization was linked to the increased expression of male sex genes and the reduced expression of female sex genes in both the PP and MT groups. Consequently, male sex steroids were elevated, promoting female to male sex change. Up to 78% of the PP group and 98% of the MT group became males, while all fish in the control group remained females. The study suggests PP could be a natural method for sex control in tilapia farming.

Bipolar disorder (BD) exhibits significant sex differences in its frequency, symptom presentation, and treatment response, suggesting distinct underlying neurobiological mechanisms. However, transcriptomic studies investigating these sex-specific pathways have been fragmented and underpowered. We conducted the first meta-analysis of post-mortem brain RNA-seq data to delineate sex-related transcriptomic landscapes in BD. We integrated data from four public datasets (GSE80336, GSE80655, GSE202537, GSE42546) from GEO and Array Express, comprising an aggregate of 173 individuals (66 BD cases and 117 controls). After preprocessing and correcting for batch effects, sex-stratified expression analysis was performed using DESeq2. A meta-analysis was conducted with the metafor package to identify differentially expressed genes (DEGs) at an FDR&#x2009;<&#x2009;0.05. We also performed functional enrichment, protein-protein interaction (PPI) network analysis, hub gene identification, regulatory network reconstruction, and supplementary quantitative analyses of sex-specific interaction effects. Our results reveal striking differences in transcriptomic signatures between men and women with bipolar disorder, with the most pronounced changes occurring in the brain. A meta-analysis across brain regions identified 34 significantly dysregulated genes. In females, upregulated genes were enriched for hormonal signaling (FSHR pathway, G-protein signaling) and transcriptional/epigenetic regulation (GLIS1, neural plasticity). In males, upregulated genes were involved in synaptic calcium signaling (PDLIM5, dendritic spine regulation) and DNA mismatch repair pathways (PMS1). Analysis of the striatum identified 289 differentially expressed genes. The most significantly upregulated genes in females were implicated in immunity and synaptic plasticity, while the male-specific pattern pointed to alterations in basic cellular functions like structure, internal communication, and genetic regulation. A quantitative interaction analysis revealed a negligible correlation (r = -0.122) between disease effect sizes in females and males and identified one gene with opposing, sex-dependent dysregulation (MEF2C). This study provides robust evidence that bipolar disorder engages fundamentally distinct molecular pathways in males and females, underscoring the necessity of integrating sex as a biological variable in psychiatric research and advancing toward personalized therapeutic strategies. Bipolar disorder is a mental health condition that affects mood, energy, and activity levels. It is well known that the disorder affects men and women differently. However, the biological reasons for these differences are not well understood.In this study, we investigated these differences by analyzing gene activity in brain tissue from people with and without bipolar disorder. By combining data from several existing studies, we created a large dataset to see how the disorder&#x2019;s biology differs between sexes.We found that the biological basis of bipolar disorder is fundamentally different in men and women. The most striking differences were in a brain region called the striatum, which is involved in reward and motivation. In men, gene changes were related to basic cell functions like energy production. In women, the changes involved genes for brain cell communication and immune response.This means the illness process differs between males and females. These findings help explain why symptoms vary by sex. Ultimately, this research suggests that doctors should consider sex as a crucial factor. Understanding these separate biological pathways could lead to better, more personalized treatments for everyone living with bipolar disorder.

The prevalence, timing and disease course of mental and neurological disorders vary according to sex, yet the neurogenetic mechanisms underlying sex differences in brain disorders remain poorly understood. While sex chromosomes and hormones contribute to sex differences in brain biology, previous studies suggest a role for autosomal genetic variation as well. We investigated autosomal genetic associations with brain volumes in 15,740 females and 15,740 males from the UK Biobank, matched for age and scan site, using sex-stratified genome-wide association analyses. We applied a multivariate genome-wide approach (MOSTest) across 257 brain regions and complemented these analyses with region-specific univariate genome-wide association studies. Heritability estimates and genetic correlations were highly similar between females and males in late adulthood, indicating largely shared genetic influences on brain volumes. Many loci reaching genome-wide significance in one sex also showed signal in the other. Gene mapping in these loci yielded a greater total number of brain-volumes associated genes in females than in males. Variability in the number of mapped genes was particularly pronounced in limbic regions such as the insula, cingulate cortex, hippocampus and amygdala. Overall, our findings contribute to a better understanding of autosomal genetic influences on brain volumes in males and females and may inform future studies examining sex variability in neurobiological mechanisms relevant to brain disorders. Mental and neurobiological disorders often differ between females and males. Some disorders are more common in one sex than the other, and symptoms can present or evolve differently. Variation in brain biology, partly shaped by genetic factors, may contribute to these patterns. In this study, we investigated genetic factors linked to brain structure in females and males separately. We focused on the volumes of 257 brain regions and analyzed genetic data from more than 30,000 adults from the UK Biobank. Overall, we found that the genetic influences on brain volumes are largely similar between females and males in late adulthood. At the same time, we observed that the number of genes associated with brain volumes was higher in females than in males. These variations in number of genes were marked in brain regions involved in the limbic system. Together, our findings improve our understanding of how genetics contribute to brain structure in females and males and may inform future studies examining sex-related variation in brain disorders.