搜索结果：Sex roles

The overlap between experiencing and perpetrating sexual harm remains understudied within the sexual violence literature. Nonconsensual sexual experiences (NSEs) are associated with increased post-traumatic stress (PTS), depressive symptomatology, and greater risk for perpetration of nonconsensual sexual experiences (PNSEs). The current study examined differences between people with NSE-only histories and those with dual-role histories involving both victimization and perpetration (dual nonconsensual sexual experiences [DNSEs]). Guided by victim-offender overlap, social learning, and cognitive distortion frameworks, theory-informed comparisons across cumulative victimization exposure, perpetration tactics, acknowledgment of NSEs, beliefs about sexual aggression, psychological distress, and demographic characteristics. Cross-sectional data were collected from 1,177 participants recruited through Prolific, a university research pool, and snowball sampling. The final sample included 417 participants in the NSE-only group (57.8%) and 305 in the DNSE group (42.2%). Participants with DNSE histories reported significantly greater NSE frequency, higher acceptance of myths about sexual aggression, and greater experiences involving intoxication and enticement tactics. DNSE histories were also associated with being older, more highly educated, and more likely to identify as cisgender men. No significant group differences emerged for PTS symptoms, depressive symptoms, or NSE acknowledgment. Findings suggest that dual-role histories may be associated with cumulative exposure to sexual harm, greater endorsement of beliefs that normalize sexual aggression, and differential exposure to coercive tactics. Implications for theory development, prevention, and trauma-informed intervention are discussed.

The word sex can refer to at least seven distinct, evolutionarily related biological phenomena (0-6 below). Bacteria and archaea use mechanisms for horizontal gene transfer (0) broadly and promiscuously, even without cell contact. Their endosymbiotic merger led to eukaryotes and a new form of gene exchange, using syngamy and meiosis (1) to mix and recombine similar genomes. This innovation altered the course of evolution. The requirement for chromosome homology in meiosis separated evolving lineages. Mating types evolved within them, differentiating roles of the cells pairing in syngamy, and gamete size dimorphisms (2) evolved many times. Organisms evolved diverse gamete-production strategies (3) and a plethora of traits associated with those strategies (4). They also evolved many ways to facilitate gamete encounters (5). Some of these were expressed in other contexts and gained new functions (6). These phenomena include cellular genetic processes (0, 1), alternative states of cells and organisms (2-4), and things organisms do (5, 6) that have diversified over billions of years. Sex is neither biologically simple nor conceptually singular, but the word is often used without qualifiers, assuming shared understanding that may not exist. We present a framework for multiple sex concepts that serve as anchor points to discuss the relationships among these phenomena and the diversity and complexity of each, including the biologically fuzzy edges generated by developmental variation and evolutionary change. We highlight several communication challenges that may limit biological understanding and/or facilitate the deployment of biology to justify social harms. For instance, sex is used for three alternative-state concepts (2-4 above) whose distinctions are sometimes collapsed, fostering overgeneralization based on the supposed simplicity of anisogamy, but even gamete sex is evolutionarily complex and subject to shifting definitional criteria. Attempts to narrowly bound "biological sex" minimize this complexity and what we can learn from it, while facilitating the misuse of biology in anti-diversity social projects. Another challenge is that using accessible language that works for organisms like ourselves may misrepresent or obscure the biology of other life forms, but specialized language can create information silos; these limit the broad comparisons that are necessary both for perspective on our own biology and a more expansive understanding of life. The multiple sex concepts framework is a way to acknowledge the scope and discuss the complexity of sex in biology, offering a scaffold to facilitate broader thinking, better communication, and discovery.

Personality traits play an important role in shaping how individuals approach their sexual goals and regulate their sexual behavior. The present study (819 participants from Colombia) examined the association between different Dark Triad traits (i.e., Machiavellianism, narcissism, and psychopathy) and sexual regulatory focus, defined as a motivational orientation toward the pursuit of pleasure and rewards in sex (i.e., predominant focus on pleasure promotion) or the maintenance of safety and avoidance of negative health outcomes (i.e., predominant focus on disease prevention). We also explored whether these associations were moderated by gender. Results showed that all three Dark Triad traits were positively associated with promotion focus scores, and only psychopathy was negatively associated with prevention focus scores. Despite a priori gender differences in Dark Triad traits and promotion focus scores, we found no evidence of moderation by gender in any of the tested associations. Our findings suggest that Dark Triad traits shape individuals' motives to pursue sexual pleasure or avoid sexual health threats, thus contributing to the literature on personality and sexuality. Theoretical and applied implications are discussed.

Bystander intervention programs have grown in popularity as prevention strategies to respond to high levels of sexual and relationship violence (SRV) on college campuses. Although the benefits and efficacy of bystander intervention programs have been well-studied, existing programs insufficiently attend to the experiences of LGBTQIA2S+ (e.g., lesbian, gay, bisexual, trans, queer, intersex, asexual, Two-Spirit) students. Moreover, bystander research rarely focuses on survivors' experiences, and no previous studies have specifically examined LGBTQIA2S+ survivors' experiences of bystander intervention. To address this gap, we conducted interviews with 29 LGBTQIA2S+ survivors of SRV to explore their experiences of bystander intervention before, during, and after SRV and how these experiences were shaped by cisheteronormative assumptions about gender, sexuality, and vulnerability. Using reflexive thematic analysis, we identified four themes: (1) "Was This Assault or Was It Not?" (2) "My Identity is Distracting," (3) "Not Built for Us," and (4) "Queer Community Was Key." Our findings highlight the central role of recognition in bystander intervention processes and clarify how harm is recognized, how vulnerability to harm is assigned, and when intervention is perceived as warranted, shaping survivors' access to timely intervention and responses to disclosure. Participants described barriers to engaging with formal university services and emphasized the importance of informal support from LGBTQIA2S+ peers in filling gaps left by institutional responses. These findings demonstrate how commonly observed bystander processes are structured by broader social assumptions about gender and sexuality, influencing how SRV is interpreted and responded to in ways that shape access to help and care. These findings extend bystander intervention research by centering LGBTQIA2S+ survivors' perspectives and have implications for the development of LGBTQIA2S+-specific and -affirming bystander education, survivor support services, and campus policy.

Diabetes mellitus encompasses disorders characterized by hyperglycemia due to pancreatic β-cell dysfunction. Type 2 diabetes (T2D) constitutes over 90% of cases, with a background of genetic, metabolic, and environmental risk factors. Knowing that sex differences impact insulin resistance and glycemic control, this review aims to identify differences in adherence to dietary patterns between women and men with T2D. This systematic review aims to evaluate sex differences in dietary pattern adherence among individuals with T2D and the implications of these differences for glycemic control. The protocol was developed using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Studies published until July 2026 will be identified by searching the following electronic databases: MEDLINE, Scopus, Cochrane Library, and Web of Science. Three investigators will independently screen articles based on titles and abstracts followed by a thorough analysis of selected full-text articles of interest. Articles on T2D and dietary pattern scores that include biological sex data will be included. The estimation of risk of bias will be performed using the Standard Quality Assessment Criteria for Evaluating Primary Research Papers From a Variety of Fields. To synthesize the results, a narrative analysis will be performed based on the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework. The search strategy was developed and refined between July 2025 and July 2026 through scoping and pilot searches. The comprehensive database search will be conducted in August 2026, covering records from database inception to July 2026. Study selection and data extraction are expected to be completed by December 2026, with publication anticipated in late 2027. This systematic review will provide a comprehensive overview of the role of sex in dietary adherence among individuals with T2D. Identifying sex-specific and gender differences may inform the development of tailored nutritional strategies and interventions aimed at improving glycemic outcomes. Ultimately, this work highlights the importance of incorporating sex-based approaches in the management of T2D to optimize long-term health outcomes. PROSPERO CRD42024340213; https://www.crd.york.ac.uk/PROSPERO/view/CRD42024340213. DERR1-10.2196/98958.

Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) and associated dyslipidemia is a growing health issue that gives rise to cardiovascular risk. Men are more prone to development of MASLD than women. Understanding mechanisms underlying sex differences in MASLD may lead to improved prevention and treatment approaches. Cholesteryl ester transfer protein (CETP) is a lipid transfer protein that shuttles triglycerides and cholesteryl esters between blood lipoproteins and tissues. In this study investigate the impact of hepatic CETP expression on MASLD. Hepatic CETP expression (L-HuCETP) was achieved by injecting liver-targeted CETP-expressing adeno-associated virus into C57BL/6J mice. In females, L-HuCETP improved glucose tolerance, consistent with our prior clamp results in global human CETP transgenic mice. Whereas in males, L-HuCETP worsened glucose metabolism and impaired insulin signaling. Correspondingly, L-HuCETP expression reduced the expression of gluconeogenic pathway genes in females but upregulated these genes in males. In males, L-HuCETP mice exhibited increased hepatic lipid droplet accumulation, lipogenesis proteins and these changes were not observed in females. L-HuCETP expression resulted in sex-specific hepatic responses, with increased expression of inflammation and fibrosis related genes in male, but decreased expression of these genes in females. Mechanistic studies indicate that L-HuCETP had sex specific effects on transcription factors ChREBP and HNF4α, which are important for glucose and lipid metabolism. Our studies suggest that sex-specific roles of L-HuCETP with regard to liver metabolic adaptation and MASLD risk in obesity, highlighting CETP-mediated pathways as potential targets for sex-specific precision medicine approaches to improve MASLD.

Harassment, including sexual harassment, in the workplace poses a significant threat to workers' wellbeing and contributes to social inequities. Organizations play a pivotal role in both enabling and preventing workplace harassment. We use a grounded theory approach to understand how workers experience workplace sexual harassment. Drawing on semi-structured interviews with thirty U.S. workers, most from the service industry in the San Francisco Bay Area, who have experienced sexual harassment at work, we describe organizational practices that workers believe effectively prevent and respond to harassment. Findings demonstrate that workplaces may better support workers by (1) setting clear expectations that harassment will not be tolerated and (2) responding effectively to incidents of harassment by establishing an independent entity to whom victims can report incidents, providing verbal support, and taking appropriate actions to support and protect victims.

The role of environmental factors in college students' learning adaptation has been widely examined. However, few studies have adopted a more micro-level perspective by focusing on the dormitory context to investigate the relationship between dormitory exclusion and learning adaptation, and its underlying mechanisms. This study investigates the chain mediating roles of loneliness and psychological distress in the relationship between dormitory exclusion and college students' learning adaptation, as well as the gender differences in these mediating pathways based on the Temporal Need-threat Model of Social Exclusion, Social Support Theory and Gender Role Theory. Using a convenience sampling method, 940 college students were surveyed using the dormitory exclusion scale, the loneliness scale, the depression-anxiety-stress scale, and the learning adaptation scale. The results showed that: (1) Dormitory exclusion significantly negatively predicted learning adaptation; (2) Dormitory exclusion predicted college students' learning adaptation through the single and chain mediation of loneliness and psychological distress; and (3) The chain mediation model exhibits gender differences. Specifically, for males, loneliness mediated the relationship between dormitory exclusion and learning adaptation; for females, loneliness and psychological distress serve as both independent mediators and sequential mediators in the relationship between dormitory exclusion and learning adaptation. The findings revealed the underlying mechanism of college students' dormitory exclusion and learning adaptation, providing valuable insights for interventions.

While exposure to individual non-essential metals (NEMs) links to abdominal obesity (AOB), the NEM mixture effects and mechanisms remain unclear, particularly in vulnerable aging populations. We included 3795 community-dwelling Chinese older adults (age ≥ 60 years), measured 6 urine NEMs [gallium (Ga), arsenic (As), cesium (Cs), barium (Ba), thallium (Tl), and uranium (U)] via ICP-MS, defined AOB by sex-specific waist circumference, assessed insulin resistance (IR) via triglyceride-glucose (TyG) index, and determined vitamin D status by serum 25-hydroxyvitamin D [25(OH)D]. Multivariable logistic regression, mixture models [weighted quantile sum (WQS), quantile g-computation (QGC), and Bayesian kernel machine regression (BKMR)], mediation and moderation analyses, and network toxicology analyses were performed. Multivariable logistic regression showed a positive association between urinary Tl and AOB (OR = 1.18, 95% CI: 1.05-1.32). Mixture analyses consistently revealed a significant overall effect of NEMs on AOB, with Tl identified as the primary contributor (WQS weight = 0.481; QGC weight = 0.428; conditional PIP = 0.918). The TyG index was identified as a potential mediator, accounting for 10.18-7.84% of the associations between Tl and AOB and the NEM mixture and AOB, respectively. Vitamin D sufficiency [serum 25(OH)D ≥ 75 nmol/L] significantly attenuated TyG index-AOB association. Network toxicology identified the AGE-RAGE signaling pathway and several hub genes as candidate biological pathways for future investigation of the association between NEM exposure and AOB. These findings highlight the metabolic implications of NEMs, particularly Tl, and suggest that Vitamin D sufficiency may influence metabolic responses associated with AOB, offering novel insights into AOB prevention in the context of NEMs exposure.

Acid-sensing ion channels (ASICs) are proton-gated members of the degenerin/epithelial sodium channel family that are emerging as multifaceted regulators of cardiovascular function. ASICs expressed in baroreceptor, cardiac, and skeletal muscle afferents contribute to reflex control of blood pressure, cardiac function, and sympathetic outflow. In vascular smooth muscle and endothelial cells, ASICs integrate mechanical, metabolic, and humoral signals to regulate vascular tone. In the systemic circulation, ASIC2 contributes to pressure-dependent vasoconstriction of renal and cerebral arteries, supporting blood flow autoregulation and protection against organ injury. In contrast, ASIC1a promotes vasodilation, contributing to nitric oxide-dependent dilation in the cerebral arteries and to endothelium-dependent hyperpolarization and vasodilation in mesenteric arteries. In the pulmonary vascular smooth muscle cells, ASIC1a plays a central role in acute hypoxic- and receptor-mediated vasoconstriction, a role that becomes increasingly important in chronic hypoxia-induced pulmonary hypertension. Under these conditions, metabolic reprogramming drives extracellular acidification and enhances ASIC1a trafficking to the plasma membrane, promoting sustained depolarization, augmented store-operated calcium entry, and a hyperproliferative, apoptosis-resistant smooth muscle phenotype. ASIC1a additionally regulates mitochondrial homeostasis by modulating mitochondrial membrane potential, redox balance, and apoptotic susceptibility. Chronic hypoxia redistributes ASIC1a from mitochondria to the plasma membrane, leading to mitochondrial dysfunction and cell survival signaling, key features of pulmonary vascular disease. This review summarizes current understanding of ASIC function in the systemic and pulmonary vasculature and highlights non-proton-mediated signaling mechanisms, emerging mitochondria-specific mechanisms, sex-related differences, and therapeutic opportunities and challenges in targeting ASIC-dependent signaling pathways in vascular disease.

Dating violence is an important public health and psychosocial concern among young adults. Gender role attitudes may be associated with whether violent behaviors within intimate relationships are recognized, tolerated, or normalized. Evidence regarding gender differences and subscale-level associations between attitudes toward dating violence and gender role attitudes among university students remains limited. This study aimed to examine university students' attitudes toward dating violence and gender roles, compare total and subscale scores by gender, and investigate associations between the two constructs. This cross-sectional study included 1,866 students at a state university. Data were collected using a sociodemographic form, the Dating Violence Attitude Scale, and the Gender Roles Attitude Scale. Gender comparisons were performed using parametric or non-parametric tests as appropriate. Associations between attitudes toward dating violence, gender role attitudes, and age were analyzed using Spearman correlation coefficients. The observed Dating Violence Attitude Scale scores suggested relatively low reported acceptance of dating violence; however, this interpretation was descriptive because the scale has no established categorical cut-off point. Male students had higher total Dating Violence Attitude Scale scores than female students, indicating lower reported acceptance, although the effect was very small and was the only gender difference on this scale that remained significant after Bonferroni correction (r&#x2009;=&#x2009;0.06, p&#x2009;=&#x2009;0.006). Differences in physical and economic violence subscales did not remain significant after correction. Male students had higher total Gender Roles Attitude Scale scores and higher female, marital, traditional, and male gender role subscale scores, whereas female students had higher egalitarian gender role subscale scores. Total Dating Violence Attitude Scale and Gender Roles Attitude Scale scores were moderately and positively correlated (r&#x2009;=&#x2009;0.35, p&#x2009;<&#x2009;0.001). Gender role attitudes were associated with attitudes toward dating violence. Because of the cross-sectional and correlational design, these findings do not establish causal, predictive, or behavioral effects. Future longitudinal and experimental studies are needed to clarify the direction and practical relevance of these associations.

Insects utilize a sophisticated olfactory system for host and mate location. This process depends on antennal olfactory proteins that facilitate chemical recognition and subsequent signal transduction. The moth Hyblaea puera is a major polyphagous defoliator, yet its underlying olfactory mechanisms remain poorly understood. To elucidate this process, we profiled the complete antennal transcriptomes of adults of both sexes, identified key chemosensory gene families, and reconstructed phylogenetic trees. The tissue-specific expression profiles of key OBP and OR genes were analyzed using quantitative real-time PCR (qPCR). A repertoire of chemosensory genes was identified through antennal transcriptome analysis of H. puera, comprising 22 odorant-binding proteins (OBPs), 7 chemosensory proteins (CSPs), 46 odorant receptors (ORs), 20 ionotropic receptors (IRs), 9 gustatory receptors (GRs) and 4 sensory neuron membrane proteins (SNMPs). qPCR-based expression profiling revealed a striking female antennae-biased expression pattern for HpueOBP6, HpueOR2, HpueOR7, HpueOR11, HpueOR12, HpueOR13, HpueOR21, HpueOR29 and HpueOR47. On the other hand, a cluster of genes, including HpueOBP3, HpueOBP10, HpueOBP16, HpueOBP19, HpueOBP20, HpueOBP21, HpueORco, HpueOR5, HpueOR33, HpueOR35 and HpueOR43 were predominantly expressed in male antennae. In addition to its significantly high expression in male antennae, HpueOR43 also showed moderate expression in male legs. Notably, HpueOBP12 showed exclusive and high expression in male abdominal tips, and HpueOBP14 was notably abundant in the legs of both sexes. This study identified 108 key chemosensory genes in H. puera. Phylogenetic analysis enabled their classification into distinct chemosensory gene families. Analysis by qPCR also showed a localized expression pattern in specific tissues for important HpueOBPs and HpueORs, suggesting that several may be putatively involved in recognizing sex pheromones and host plant volatile organic compounds (VOCs); however, these inferred roles require functional validation. Together, these results offer a platform for characterizing the functions of these key proteins and for designing novel control measures that disrupt the pest's olfactory sensing.

Sexing the skeletal remains of young individuals is crucial yet notoriously difficult in archaeology. Children, who cannot be reliably sexed morphologically, are often excluded from gender-related research, limiting our understanding of past childhood. This issue is compounded in contexts lacking grave goods, such as early Christian burials. We conducted genomic screening of 142 individuals from Sweden dating from the late Viking Age to the Medieval period, including 68 subadults and 74 adults from 27 single and 50 multiple burials. To investigate the treatment of children in death and the role of collective graves, we applied genomic sexing and kinship analyses to individuals from three sites. Contrary to the assumption that collective burials reflect close kinship, our results show that children interred with adults rarely shared close biological ties. Burial patterns indicate that gender roles were established early, with both boys and most girls mirroring adult spatial patterns. However, flexibility existed, and extended kinship likely played a central role in structuring these communities.

Early mathematical skills are robust predictors of later academic achievement. However, few studies have examined the indirect roles of cognitive factors in the association between executive function (EF) and early mathematics. The present study investigated whether preschoolers' patterning and spatial skills play indirect roles in the association between EF and subsequent mathematical skills. A sample of 281 Chinese preschool children (Mage&#xa0;=&#xa0;4.53&#xa0;years, SD&#xa0;=&#xa0;0.76; 48.8% boys) was assessed at two time points approximately seven months apart. Hierarchical regression analyses indicated that EF, patterning, and spatial skills at Time 1 significantly predicted mathematical skills at Time 2 after controlling for age, gender, family socioeconomic status, and baseline mathematical skills. The structural equation model further showed that patterning and spatial skills played partial indirect roles in the association between EF and mathematical skills through both parallel and serial indirect effects. These findings extend prior research by simultaneously examining multiple indirect associations within a longitudinal framework and highlight the interrelated roles of EF, patterning, and spatial skills in early mathematical development. The results suggest that these cognitive skills may be important correlates of early mathematics learning.

PVT is involved in stress responses, fear, anxiety, arousal, aversion and reward. Anterior and posterior PVT (aPVT and pPVT) have different neuronal connections, molecular contents, and functional roles. PVT expressed a high level of KOR. Herein we mapped the projection targets of aPVT KOR(+) neurons and explored the behavioral significance of aPVT KOR. Using KOR-iCre mice and Cre-dependent anterograde tracer, we found that KOR(+) glutamatergic neurons in aPVT primarily projected to NAc, CeA, BNST, PFC, and reticular nucleus of the thalamus (RT). 3-D images showed the pathway emanating from aPVT to the ventral RT, through NAc, and out to the other regions, indicating widespread axonal collateralization. We conditionally knock-downed KOR (KOR cKD) in aPVT by injection of AAV-eGFP-Cre or AAV-eGFP (control) into aPVT of Oprk1 lox/lox mice. [ 3 H]U69,593 receptor autoradiography revealed substantial KOR cKD in aPVT. In both male and female mice, the KOR cKD in aPVT significantly reduced anxiety-like behaviors in the elevated plus-maze test, cue-induced freezing after fear conditioning and naloxone-precipitated morphine withdrawal-associated jumps. KOR cKD attenuated U50,488H-induced conditioned place aversion in males only, while having no effect on forced swim immobility or the U50,488H-induced visceral analgesic and antipruritic effects in either sex. Thus, our results reveal for the first time that KOR-mediated inhibition of aPVT neurons may mediate morphine withdrawal, anxiety, and cue-induced fear in both sexes but contribute to KOR agonist-induced aversion only in males. Notably, our findings reveal a previously unrecognized role for aPVT in regulating morphine withdrawal, acting in a manner distinct from pPVT.

Women exhibit sex-specific differences in their responses to nicotine, with sex hormones like estrogen and progesterone playing key roles in nicotine addiction among women. Nicotine disrupts neuronal firing in the brain's reward system, an effect regulated by estrogen. In this study, we hypothesized that exposing human female neurons to both nicotine and estrogen would activate distinct signaling pathways. We treated human female SH-SY5Y neurons with nicotine and estrogen, and compared these to treatments with each substance alone or vehicle control. Using PamGene PamStation technology, we created an atlas of over 500 kinase activities per sample. We found that nicotine modulates MAP kinase pathways in a dichotomous manner. Estrogen showed unique kinase effects, and in combination with nicotine, elicited diverse pathway responses-some kinases becoming hyperactive and others hypoactive. Bioinformatics analysis highlighted several kinases as central to this combined signaling, including PKC&#x269; and TAO, which showed higher kinase activity only with combined treatment and have known links to behavior in rodent models. Conversely, kinases such as the insulin receptor (INSR), HER2, FAK1, and ABL1 exhibited decreased activity under combined treatment. These findings reveal nicotine-specific kinase mechanisms and suggest potential targets for pharmacotherapy aimed particularly at females with high estrogen levels and nicotine use disorder.

While dopamine is a monoamine neurotransmitter best known for its roles in reward, motivation, and motor function in the central nervous system, its actions extend beyond neurons and can influence non-neuronal cells via epigenetic mechanisms. An increasing body of literature demonstrates that dopamine signaling is important in immune cells, which express dopamine receptors (DRD1-DRD5) as well as the molecular machinery for dopamine synthesis and metabolism. Dopamine can regulate inflammatory activity, cell trafficking, and disease pathology, yet the epigenetic mechanisms underlying these effects remain poorly understood. Primary human monocyte-derived macrophages were treated with dopamine, and DNA methylation at the IL-1&#x3b2; proximal promoter was evaluated alongside IL-1&#x3b2; and epigenetic enzyme gene expression. Associations between donor characteristics, dopamine receptor expression, and dopamine-induced epigenetic responses were also examined. Dopamine increased DNA methylation at the IL-1&#x3b2; proximal promoter in a DNMT-dependent manner while concurrently increasing IL-1&#x3b2; gene expression. Dopamine treatment also upregulated the expression of several key epigenetic regulators, including TET2, HDAC2, and HDAC6, suggesting coordinated regulation of both DNA methylation and histone modifications that shape inflammatory transcription. Furthermore, baseline dopamine receptor expression and donor demographics, including sex and age, influence the magnitude of these epigenetic responses, highlighting inter-individual variability in macrophage sensitivity to dopaminergic signaling. These findings establish dopamine as a modulator of macrophage inflammation via epigenetic remodeling and provide a mechanistic framework for understanding how peripheral immune cells respond to dopaminergic cues. By linking dopamine signaling, epigenetic regulation, and innate immunity, this work identifies potential targets for therapeutic intervention and supports the use of accessible human immune cells to investigate dopaminergic dysregulation in neuroimmunological disorders.

Nearly all individuals with Down syndrome (DS) develop Alzheimer's disease (AD) dementia, primarily due to overexpression of the APP gene. Although specific cerebrospinal fluid (CSF) and plasma tau biomarkers have been investigated in DS-AD, how different tau species change in the DS-AD continuum in comparison to sporadic AD remains uncertain. In this cross-sectional study, we analysed CSF and plasma tau biomarkers in 461 samples from the DABNI and SPIN cohorts, including individuals with DS, cognitively normal euploid participants, and patients with sporadic AD. Biomarker differences were assessed using linear regression with Tukey post hoc comparisons. LOESS modelling was applied to estimate the age at which tau biomarkers became abnormal. We analysed 461 participants from the DABNI and SPIN cohorts. Both CSF and plasma tau biomarkers increased during the asymptomatic stages of DS and in euploid controls, coinciding with A&#x3b2; positivity; across the DS clinical spectrum the largest increases were observed for CSF NTA-tau (fold-change [fc] = 6.46-6.94), CSF p-tau217 (fc = 6.43-6.74) and plasma p-tau217 (fc = 4.63-6.54) (linear regression adjusted for age, sex and APOE-&#x3b5;4 with Tukey post-hoc tests; all p < 0.001). During the dementia stages, CSF tau biomarkers showed only modest further increases (no CSF biomarker differed between pDS and dDS; all p &#x2265; 0.268), whereas plasma tau biomarkers retained a broader dynamic range across symptomatic phases (pDS vs dDS: plasma p-tau217 p = 0.001, p-tau181 p = 0.002, p-tau231 p = 0.004). Plasma p-tau217 showed the highest diagnostic accuracy, with areas under the curve (AUC) of 0.91-0.97 for biological categorisations and numerically higher values than CSF in symptomatic stages (pDS vs dDS: plasma p-tau217 AUC = 0.69 [95% CI 0.58-0.80] vs CSF p-tau217 AUC = 0.53 [95% CI 0.41-0.65]; DeLong test p = 0.019). In LOESS analyses, tau biomarkers diverged from age-matched controls in the late 30s to early 40s (e.g., plasma p-tau217 &#x2248; 37.3 years, CSF p-tau181 &#x2248; 38.1 years) and reached abnormality (+2 SD) over an approximately 20-year span between the fourth and sixth decades, outlining differential but temporally compressed increases. Finally, during symptomatic stages, tau biomarker levels remained stable in DS-AD, in contrast to sporadic AD, where levels declined with advancing age. These findings highlight the complementary roles of CSF and plasma tau biomarkers in tracking disease progression: CSF biomarkers capture early pathological changes, whereas plasma biomarkers more effectively reflect disease progression within symptomatic stages. Furthermore, tau biomarkers might support disease staging and monitor clinical progression in DS-AD, but with the need to adapt biomarker frameworks to this specific population. La Caixa Foundation, Instituto de Salud Carlos III, Generalitat de Catalunya, National Institute on Ageing, Wellcome Trust, J&#xe9;r&#xf4;me Lejeune Foundation, Medical Research Council, Alzheimer's Association, National Institute for Health Research, EU Joint Programme-Neurodegenerative Disease Research, Alzheimer's Society.

Depressive disorders and obesity are highly comorbid conditions sharing genetic, metabolic, and immunological substrates. In a cross-sectional analysis of 53 participants across the obesity spectrum (lean n = 12; overweight n = 9; obese n = 32), a depression genetic risk score (d-GRS) correlated positively with BMI (&#x3c1; = 0.379, p = 0.005) and with serum CRP (&#x3c1; = 0.322, p = 0.031), consistent with the known genetic coarchitecture between depression and inflammatory traits. The d-GRS was tested against 116 flow-cytometry-derived immune parameters using Spearman rank correlation. The most consistent immune association at nominal significance (p < 0.05, uncorrected) involved the immunoregulatory CD56brightCD16- natural killer (NK) cell subset across two independent gate representations (&#x3c1; = 0.444, p = 0.004), remaining significant after sequential adjustment for BMI, sex, age, and physical activity (adjusted &#x3c1; range: 0.439-0.469), with no equivalent association for a genetically independent obesity GRS. In silico analysis of d-GRS SNP-tagged genes identified several with documented roles in NK cell trafficking, activation, and cytokine production, providing a putative mechanistic basis for this association. These findings nominate the CD56brightCD16- NK cell subset as a candidate immunological link between depression genetic susceptibility and neuroimmune mechanisms, warranting independent replication and functional characterisation in prospective cohorts.