Mediate Sex Differences Research Articles

Sex differences in mitochondrial gene expression during viral myocarditis

BackgroundMyocarditis is an inflammation of the heart muscle most often caused by viral infections. Sex differences in the immune response during myocarditis have been well described but upstream mechanisms in the heart that might influence sex differences in disease are not completely understood.MethodsMale and female BALB/c wild type mice received an intraperitoneal injection of heart-passaged coxsackievirus B3 (CVB3) or vehicle control. Bulk-tissue RNA-sequencing was conducted to better understand sex differences in CVB3 myocarditis. We performed enrichment analysis and functional validation to understand sex differences in the transcriptional landscape of myocarditis and identify factors that might drive sex differences in myocarditis.ResultsAs expected, the hearts of male and female mice with myocarditis were significantly enriched for pathways related to an innate and adaptive immune response compared to uninfected controls. Unique to this study, we found that males were enriched for inflammatory pathways and gene changes that suggested worse mitochondrial electron transport function while females were enriched for pathways related to mitochondrial homeostasis. Mitochondria isolated from the heart of males were confirmed to have worse mitochondrial respiration than females during myocarditis. Unbiased TRANSFAC analysis identified estrogen-related receptor alpha (ERRα) as a transcription factor that may mediate sex differences in mitochondrial function during myocarditis. Transcript and protein levels of ERRα were confirmed as elevated in females with myocarditis compared to males. Differential binding analysis from chromatin immunoprecipitation (ChIP) sequencing confirmed that ERRα bound highly to select predicted respiratory chain genes in females more than males during myocarditis.ConclusionsFemales with viral myocarditis regulate mitochondrial homeostasis by upregulating master regulators of mitochondrial transcription including ERRα.

Sex hormone-binding globulin may explain sex differences for glucose homeostasis and incidence of type 2 diabetes: the KORA study

Research has indicated that sex hormone-binding globulin (SHBG) is associated with glucose homeostasis and may play a role in the etiology of type 2 diabetes (T2D). While it is unclear whether SHBG may mediate sex differences in glucose control and subsequently, incidence of T2D. We used observational data from the German population-based KORA F4 study (n = 1937, mean age: 54 years, 41% women) and its follow-up examination KORA FF4 (median follow-up 6.5 years, n = 1387). T2D was initially assessed by self-report and validated by contacting the physicians and/ or reviewing the medical charts. Mediation analyses were performed to assess the role of SHBG in mediating the association between sex (women vs. men) and glucose- and insulin-related traits (cross-sectional analysis) and incidence of T2D (longitudinal analysis). After adjustment for confounders, (model 1: adjusted for age; model 2: model 1 + smoking + alcohol consumption + physical activity), women had lower fasting glucose levels compared to men (β = -4.94 (mg/dl), 95% CI: -5.77, -4.11). SHBG levels were significantly higher in women than in men (β = 0.47 (nmol/l), 95% CI:0.42, 0.51). Serum SHBG may mediate the association between sex and fasting glucose levels with a proportion mediated (PM) of 30% (CI: 22–41%). Also, a potential mediatory role of SHBG was observed for sex differences in incidence of T2D (PM = 95% and 63% in models 1 and 2, respectively). Our novel findings suggest that SHBG may partially explain sex-differences in glucose control and T2D incidence.

Sex differences in response to rehabilitation treatment for musculoskeletal pain: the mediating role of post-traumatic stress symptoms

Aim: Numerous investigations have revealed sex differences in recovery outcomes in individuals who have sustained work-related musculoskeletal injuries (WRMIs). Previous research has also revealed significant sex differences in the prevalence and severity of post-traumatic stress symptoms (PTSS) following musculoskeletal injury. This study investigated whether PTSS mediated sex differences in recovery outcomes in individuals receiving treatment for a work-related musculoskeletal injury. The recovery outcomes of interest in the present study were pain severity and pain-related disability. Methods: The study sample included 137 individuals (68 men; 69 women) with WRMIs who were enrolled in a 7-week physical rehabilitation program. Participants completed measures of pain severity, pain disability and PTSS at admission and termination of the physical rehabilitation program. Results: Consistent with previous research, independent samples t-tests revealed that women obtained significantly higher baseline scores on measures of pain severity (P < 0.01), number of pain sites (P < 0.001), depression (P < 0.001) and PTSS (P < 0.001) compared to men. Also consistent with previous research, the measure of PTSS, assessed at baseline, was prospectively associated with treatment-related disability reduction (P < 0.01), and return to work (P < 0.01). Bootstrap regression analyses revealed that PTSS partially mediated the relation between sex and pain-related disability. Conclusions: The results of the present study suggest that the experience of PTSS might be one of the factors that explain sex differences in recovery outcomes following a WRMI. The results call for greater attention to the assessment and intervention of PTSS in individuals who have sustained WRMIs.

STIM1-dependent store-operated calcium entry mediates sex differences in macrophage chemotaxis and monocyte recruitment

Infiltration of monocyte-derived cells to sites of infection and injury is greater in males than in females, due in part, to increased chemotaxis, the process of directed cell movement toward a chemical signal. The mechanisms governing sexual dimorphism in chemotaxis are not known. We hypothesized a role for the store-operated calcium entry (SOCE) pathway in regulating chemotaxis by modulating leading and trailing edge membrane dynamics. We measured the chemotactic response of bone marrow derived macrophages (BMDMs) migrating towards complement component 5a (C5a). Chemotactic ability was dependent on sex and inflammatory phenotype (M0, M1, M2), and correlated with SOCE. Notably, females exhibited a significantly lower magnitude of SOCE than males. When we knocked out the SOCE gene, stromal interaction molecule 1 (STIM1), it eliminated SOCE and equalized chemotaxis across both sexes. Analysis of membrane dynamics at the leading and trailing edges showed that STIM1 influences chemotaxis by facilitating retraction of the trailing edge. Using BTP2 to pharmacologically inhibit SOCE mirrored the effects of STIM1 knockout, demonstrating a central role of STIM/Orai-mediated calcium signaling. Importantly, by monitoring the recruitment of adoptively transferred monocytes in an in vivo model of peritonitis, we show that increased infiltration of male monocytes during infection is dependent on STIM1. These data support a model in which STIM1-dependent SOCE is necessary and sufficient for mediating the sex difference in monocyte recruitment and macrophage chemotactic ability by regulating trailing edge dynamics.

Neurogenesis and Its Downstream Synaptic Targets Mediate Sex Differences in Contextual Fear Discrimination in Advanced Aged Mice

Neurogenesis and Its Downstream Synaptic Targets Mediate Sex Differences in Contextual Fear Discrimination in Advanced Aged Mice

An evolutionarily conserved olfactory receptor is required for sex differences in blood pressure.

Sex differences in blood pressure are well-established, with premenopausal women having lower blood pressure than men by ~10 millimeters of mercury; however, the underlying mechanisms are not fully understood. We report here that sex differences in blood pressure are absent in olfactory receptor 558 knockout (KO) mice. Olfr558 localizes to renin-positive cells in the kidney and to vascular smooth muscle cells. Female KOs exhibit increased blood pressure and increased pulse wave velocity. In contrast, male KO mice have decreased renin expression and activity, altered vascular reactivity, and decreased diastolic pressure. A rare OR51E1 (human ortholog) missense variant has a statistically significant sex interaction effect with diastolic blood pressure, increasing diastolic blood pressure in women but decreasing it in men. In summary, our findings demonstrate an evolutionarily conserved role for OLFR558/OR51E1 to mediate sex differences in blood pressure.

Associations among early life adversity, sleep disturbances, and depressive symptoms in adolescent females and males: a longitudinal investigation.

Exposure to adversity early in life (ELA) has been associated with elevated risk for depression during adolescence, particularly for females; the mechanisms underlying this association, however, are poorly understood. One potential mechanism linking ELA and sex differences in depressive symptoms is sleep disturbances, which increase during adolescence and are more common in females. Here, we examined whether sleep disturbances mediate the association between ELA and increases in depressive symptoms during adolescence and whether this mediation differs by sex. 224 (N = 132 females) youth were recruited at age 9-13 years and assessed every 2 years across three timepoints. At the first timepoint, we conducted extensive interviews about stressful events participants experienced; participants provided subjective severity ratings of events and we objectively scored the severity of each event. Self-reported sleep disturbances and depressive symptoms were assessed at all timepoints. We conducted linear mixed models to estimate both initial levels and changes in sleep disturbances and depressive symptoms, and moderated mediation analyses to test whether initial levels and/or changes in sleep disturbances mediated the association of ELA (objective and subjective) with increases in depressive symptoms across adolescence and whether the mediations differed by sex. While higher initial levels and increases in sleep problems were uniquely associated with increases in depressive symptoms for males and females, they were related to ELA differently by sex. For females, greater ELA (both objectively and subjectively rated) was associated with higher initial levels of sleep problems, which in turn were associated with increases in depressive symptoms from early to late adolescence. In contrast, for males, ELA exposure was not associated with either initial levels of, or increases in, sleep problems. These findings highlight the role of sleep disturbances during the transition to adolescence in mediating sex differences in the effects of ELA on depressive symptoms.

Lung proinflammatory microRNA and cytokine expression in a mouse model of allergic inflammation: role of sex chromosome complement and gonadal hormones.

Epigenetic alterations such as dysregulation of miRNAs have been reported to play important roles in interactions between genetic and environmental factors. In this study, we tested the hypothesis that induction of lung inflammation by inhaled allergens triggers a sex-specific miRNA regulation that is dependent on chromosome complement and hormonal milieu. We challenged the four core genotypes (FCGs) model through intranasal sensitization with a house dust mite (HDM) solution (or PBS as a control) for 5 wk. The FCG model allows four combinations of gonads and sex chromosomes: 1) XX mice with ovaries (XXF), 2) XY mice with testes (XYM), 3) XX mice with testes (XXM), and 4) XY mice with ovaries (XYF). Following the challenge (n = 5-7/group), we assessed the expression of 84 inflammatory miRNAs in lung tissue using a PCR array and cytokine levels in bronchoalveolar lavage fluid (BAL) by a multiplex protein assay (n = 4-7 animals/group). Our results showed higher levels of the chemokine KC (an Il-8 homolog) and IL-7 in BAL from XYF mice challenged with HDM. In addition, IL-17A was significantly higher in BAL from both XXF and XYF mice. A three-way interaction among treatment, gonads, and sex chromosome revealed 60 of 64 miRNAs that differed in expression depending on genotype; XXF, XXM, XYF, and XYM mice had 45, 32, 4, and 52 differentially expressed miRNAs, respectively. Regulatory networks of miRNAs identified in this study were implicated in pathways associated with asthma. Female gonadal hormonal effects may alter miRNA expression and contribute to the higher susceptibility of females to asthma.NEW & NOTEWORTHY miRNAs play important roles in regulating gene and environmental interactions. However, their role in mediating sex differences in allergic responses and lung diseases has not been elucidated. Our study used a targeted omics approach to characterize the contributions of gonadal hormones and chromosomal components to lung responses to an allergen challenge. Our results point to the influence of sex hormones in miRNA expression and proinflammatory markers in allergic airway inflammation.

Sustained activation of 12/15 lipoxygenase (12/15 LOX) contributes to impaired renal recovery post ischemic injury in male SHR compared to females

BackgroundAcute kidney injury (AKI) due to ischemia-reperfusion (IR) is a serious and frequent complication in clinical settings, and mortality rates remain high. There are well established sex differences in renal IR, with males exhibiting greater injury following an ischemic insult compared to females. We recently reported that males have impaired renal recovery from ischemic injury vs. females. However, the mechanisms mediating sex differences in renal recovery from IR injury remain poorly understood. Elevated 12/15 lipoxygenase (LOX) activity has been reported to contribute to the progression of numerous kidney diseases. The goal of the current study was to test the hypothesis that enhanced activation of 12/15 LOX contributes to impaired recovery post-IR in males vs. females.Methods13-week-old male and female spontaneously hypertensive rats (SHR) were randomized to sham or 30-minute warm bilateral IR surgery. Additional male and female SHR were randomized to treatment with vehicle or the specific 12/15 LOX inhibitor ML355 1 h prior to sham/IR surgery, and every other day following up to 7-days post-IR. Blood was collected from all rats 1-and 7-days post-IR. Kidneys were harvested 7-days post-IR and processed for biochemical, histological, and Western blot analysis. 12/15 LOX metabolites 12 and 15 HETE were measured in kidney samples by liquid chromatography–mass spectrometry (LC/MS).ResultsMale SHR exhibited delayed recovery of renal function post-IR vs. male sham and female IR rats. Delayed recovery in males was associated with activation of renal 12/15 LOX, increased renal 12-HETE, enhanced endoplasmic reticulum (ER) stress, lipid peroxidation, renal cell death and inflammation compared to females 7-days post-IR. Treatment of male SHR with ML355 lowered levels of 12-HETE and resulted in reduced renal lipid peroxidation, ER stress, tubular cell death and inflammation 7-days post-IR with enhanced recovery of renal function compared to vehicle-treated IR male rats. ML355 treatment did not alter IR-induced increases in plasma creatinine in females, however, tubular injury and cell death were attenuated in ML355 treated females compared to vehicle-treated rats 7 days post-IR.ConclusionOur data demonstrate that sustained activation 12/15 LOX contributes to impaired renal recovery post ischemic injury in male and female SHR, although males are more susceptible on this mechanism than females.

Are sex differences in verbal memory related to sex differences in cognitive reserve?

AbstractBackgroundCognitive reserve (CR) is the capacity to maintain cognitive performances despite underlying brain pathology and a concept used in Alzheimer’s disease (AD) studies to explain clinical heterogeneity. Evidence for a female‐specific verbal memory reserve may contribute to sex disparities in AD incidence, via delayed diagnosis. However, whether sex differences in verbal memory relate to sex differences in CR, is unclear. The current study examined whether multiple measures of CR differed by sex and whether they mediated sex differences in verbal memory.MethodCross‐sectional data from 59 older adults (mean age = 68.1; SD = 10.7; Female = 62%; White = 70%), without a prior diagnosis of cognitive impairment, were included. Total recall from the immediate and delayed recall trials of the scores Hopkins Verbal Learning Test (HVLT) were used to assess verbal learning and memory. Years of education, self‐reported leisure activities, physical activity, mindfulness, and the MIND diet were used to assess CR. Sex differences in HVLT scores were tested with ANCOVAs, controlling for age and reran adjusting for education. A MANCOVA was used to assess sex differences on CR measures. A mediation analyses was used to test whether sex differences in CR measures mediated the association between sex differences and verbal memory.ResultWomen had higher scores on HVLT learning (M = 23.1, SD = 5.2; p<.01), delayed recall (M = 8.2; SD = 2.6; p<.01) and leisure activities (M = 35.93; SD = 7.9; p<.01) compared to men (learning: M = 19.5; SD = 5.2; delayed recall: M = 6.2; SD = 2.5; leisure: M = 28.5; SD = 10.9; p<.01). No other sex differences in CR measures were revealed. Leisure activities fully mediated sex and HVLT associations, such that women’s higher scores on leisure explained 39% and 35% of the variance between sex and HVLT learning and delayed recall, respectively.ConclusionWomen’s overall higher engagement in leisure activities accounted for their higher scores on HVLT learning and delayed recall relative to men. Increasing men’s engagement in leisure activities could attenuate sex differences in verbal learning/memory but warrants further investigation. Larger and more diverse samples are needed for follow‐up data analyses.

Abstract 17513: Decreased Sensory Neurotransmission Due to Neuronal Mitochondrial Dysfunction Mediates Sex Differences in Vagal Remodeling After Myocardial Infarction

Background: Vagal dysfunction after chronic myocardial infarction (MI) exacerbates heart failure and predisposes to ventricular tachyarrhythmias (VT/VF). VT/VF after MI is more common in males than females. The mechanisms behind these sex differences are unknown. Hypothesis: We hypothesized that differences in autonomic remodeling in the vagal ganglia, which in a healthy state, provide beat-to-beat sensory neurotransmission and modulate efferent cardiac vagal tone, may serve as the mechanisms behind the sex differences in the incidence of VT/VF. Methods: MI was created (left anterior descending artery ligation) in male and female mice expressing channel rhodopsin in glutamatergic vagal neurons (VGlut2-ChR2-EYFP mice). Sham animals underwent thoracotomy only. Two weeks post-MI, heart rate (HR) responses were assessed following in vivo vagal afferent nerve activation via optogenetic stimulation (5 sec duration, 20 Hz, 10 ms and 20 ms stimulations). Ventricular fibrosis was quantified. Mitochondrial oxygen consumption rates (OCR), glutamate levels, and the levels of oxidative stress marker, 4-hydroxy nonenal (4HNE), were measured in the vagal ganglia. Results: Male MI animals demonstrated significantly reduced HR responses to optogenetic stimulation than female MI animals. No sex differences in the degree of ventricular fibrosis was observed. A decrease in glutamate content accompanied by decreased mitochondrial OCR and increased 4HNE levels was observed in the vagal ganglia of male infarcted vs. female infarcted mice, figure. There were no differences in the HR responses, glutamate content, mitochondrial OCR, and 4HNE levels between sham males vs. sham females. Conclusion: This study demonstrates significant sex differences in vagal remodeling post-MI, with decreased efferent vagal tone in males mediated at least in part by reduced vagal afferent glutamatergic signaling associated with impaired neuronal mitochondrial function.

Estradiol mediates sex differences in aversion-resistant alcohol intake.

Alcohol consumption despite negative consequences is a core symptom of alcohol use disorder. This can be modeled in mice by pairing aversive stimuli with alcohol consumption, such as adding the bitter tastant quinine to the alcohol solution. If an animal continues to drink alcohol despite such negative stimuli, this is typically considered aversion-resistant, or inflexible, drinking behavior. Previous studies in our lab have found that females are more aversion-resistant than males in that they tolerate higher concentrations of quinine before they suppress their alcohol intake. Interestingly, we did not observe any differences in intake across the estrous cycle. In regards to neuronal activation patterns during quinine-alcohol intake, we have found that male mice show higher levels of activation in the ventromedial prefrontal cortex and posterior insular cortex, while females show higher levels of activation in the ventral tegmental area. In the experiments presented here, we conducted ovariectomies to further examine the role of circulating sex hormones in aversion-resistant alcohol intake and neuronal activation patterns. Furthermore, we used hormonal addback of estradiol or progesterone to determine which ovarian sex hormone mediates aversion-resistant consumption. We found that ovariectomy reduced quinine-adulterated alcohol intake, demonstrating that circulating sex hormones play a role in this behavior. We also observed reduced neuronal activation in the VTA of ovariectomized mice compared to sham females, and that estradiol supplementation reversed the effect of ovariectomy on quinine-alcohol intake. Taken together with our prior data, these findings suggest that circulating estradiol contributes to the expression of aversion-resistant alcohol intake and neuronal activity in the VTA. However, since this behavior is not affected by the estrous cycle, we believe this is due to a threshold level of this hormone, as opposed to fluctuations that occur across the estrous cycle.

Proximal Tubule-Specific Transcriptomic Changes Mediate Sex Differences in Susceptibility to Aristolochic Acid I-Induced AKI in Mice

Proximal Tubule-Specific Transcriptomic Changes Mediate Sex Differences in Susceptibility to Aristolochic Acid I-Induced AKI in Mice

Cardiovascular responses to combined mechanoreflex and metaboreflex activation in healthy adults: effects of sex and low- versus high-hormone phases in females.

Females generally have smaller blood pressure (BP) responses to isolated muscle mechanoreflex and metaboreflex activation compared with males, which may explain sex differences in BP responses to voluntary exercise. The mechanoreflex may be sensitized during exercise, but whether mechanoreflex-metaboreflex interactions differ by sex or variations in sex hormones remains unknown. Thirty-one young healthy subjects (females, n = 16) performed unilateral passive cycling (mechanoreflex), active cycling (40% peak Watts), postexercise circulatory occlusion (PECO; metaboreflex), and passive cycling combined with PECO (combined mechanoreflex and metaboreflex activation). Beat-to-beat BP, heart rate, inactive leg vascular conductance, and active leg muscle oxygenation were measured. Ten females underwent exploratory testing during low- and high-hormone phases of their self-reported menstrual cycle or oral contraceptive use. Systolic BP and heart rate responses did not differ between sexes during active cycling [Δ30 ± 9 vs. 29 ± 11 mmHg (males vs. females), P = 0.9; Δ33 ± 8 vs. 35 ± 6 beats/min, P = 0.4] or passive cycling with PECO (Δ26 ± 11 vs. 21 ± 10 mmHg, P = 0.3; Δ14 ± 7 vs. 18 ± 15 beats/min, P = 0.3). Passive cycling with PECO revealed additive, not synergistic, effects for systolic BP [males: Δ23 ± 14 vs. 26 ± 11 mmHg (sum of isolated passive cycling and PECO vs. combined activation); females: Δ26 ± 11 vs. 21 ± 12 mmHg, interaction P = 0.05]. Results were consistent in subset analyses with sex differences in active cycling BP (P > 0.1) and exploratory analyses of hormone phase (P > 0.4). Despite a lack of statistical equivalence, no differences in cardiovascular responses were found during combined mechanoreflex-metaboreflex activation between sexes or hormone levels. These results provide preliminary data regarding the involvement of muscle mechanoreflex-metaboreflex interactions in mediating sex differences in voluntary exercise BP responses.NEW & NOTEWORTHY The muscle mechanoreflex may be sensitized by metabolites during exercise. We show that cardiovascular responses to combined mechanoreflex (passive cycling) and metaboreflex (postexercise circulatory occlusion) activation are primarily additive and do not differ between males and females, or across variations in sex hormones in females. Our findings provide new insight into the contributions of muscle mechanoreflex-metaboreflex interactions as a cause for prior reports that females have smaller blood pressure responses to voluntary exercise.

Sex differences in microglia function in aged rats underlie vulnerability to cognitive decline

Aging is associated with a significant shift in immune system reactivity (“inflammaging”), as basal inflammation increases but protective responses to infection are compromised. The immune system exhibits considerable sex differences, which may influence the process of inflammaging, including immune cell activation and behavioral consequences of immune signaling (i.e., impaired memory). Here, we test the hypothesis that sex differences in immune aging may mediate sex differences in cognitive decline. Aged male and female rats received peripheral immune stimulation using lipopolysaccharide (LPS), then molecular, cellular, and behavioral outcomes were assessed. We observed that LPS-treated aged male rats showed cognitive impairment and increased neuroinflammatory responses relative to adult males. In contrast, aged female rats did not display these aging-related deficits. Using transcriptomic and flow cytometry analyses, we further observed significant age- and sex- dependent changes in immune cell populations in the brain parenchyma and meninges, indicating a broad shift in the neuroinflammatory environment that may potentiate these behavioral effects. Ovariectomized aged female rats were also resistant to inflammation-induced memory deficits, indicating that ovarian hormones are not required for the attenuated neuroinflammation in aged females. Overall, our results indicate that males have amplified inflammatory priming with age, which contributes to age-associated cognitive decline. Our findings highlight sexual dimorphism in mechanisms of aging, and suggest that sex is a crucial consideration for identifying therapies for aging and neuroinflammation.

Cocaine and amphetamine regulated transcript (CART) mediates sex differences in binge drinking through central taste circuits

The neuropeptide cocaine- and amphetamine-regulated transcript (CART) has been implicated in alcohol consumption and reward behaviours, yet mechanisms mediating these effects have yet to be identified. Using a transgenic CART knockout (KO) mouse line we uncovered a sexually dimorphic effect of CART in binge drinking, with male CART KO mice increasing intake, whilst female CART KO mice decreased their alcohol intake compared to controls. Female CART KO mice show greater sensitivity to bitter solutions that can be overshadowed through addition of a sweetener, implicating taste as a factor. Further we identify that this is not driven through peripherally circulating sex hormones, but the central nucleus of the amygdala (CeA) is a locus where CART contributes to the regulation of alcohol consumption, with CeA CART neutralisation specifically reducing plain alcohol, but not sweetened alcohol consumption in female mice. These findings may have implications for the development of sex-specific treatment options for alcohol use disorders through targeting the CART system.

Sex differences in cognition and structural covariance-based morphometric connectivity: evidence from 28,000+ UK Biobank participants.

There is robust evidence for sex differences in domain-specific cognition, where females typically show an advantage for verbal memory, whereas males tend to perform better in spatial memory. Sex differences in brain connectivity are well documented and may provide insight into these differences. In this study, we examined sex differences in cognition and structural covariance, as an index of morphometric connectivity, of a large healthy sample (n = 28,821) from the UK Biobank. Using T1-weighted magnetic resonance imaging scans and regional cortical thickness values, we applied jackknife bias estimation and graph theory to obtain subject-specific measures of structural covariance, hypothesizing that sex-related differences in brain network global efficiency, or overall covariance, would underlie cognitive differences. As predicted, females demonstrated better verbal memory and males showed a spatial memory advantage. Females also demonstrated faster processing speed, with no observed sex difference in executive functioning. Males showed higher global efficiency, as well as higher regional covariance (nodal strengths) in both hemispheres relative to females. Furthermore, higher global efficiency in males mediated sex differences in verbal memory and processing speed. Findings contribute to an improved understanding of how biological sex and differences in cognition are related to morphometric connectivity as derived from graph-theoretic methods.

Stereotypes, same-sex struggles, and sustainable shopping: intrasexual competition mediates sex differences in green consumption values

PurposeThe present study aimed to investigate whether male consumers report weaker green consumption values than their female counterparts, and whether such a presumed sex difference, at least in part, can be explained by different levels of intrasexual competition. In other words, the study tested the notion that intrasexual competition acts as a psychological mechanism explaining why male (vs female) consumers are sometimes less prone to prefer and purchase sustainable goods, with their higher tendency to compete with same-sex rivals making them less likely to engage in green consumption.Design/methodology/approachThe study was based on a large cross-sectional survey, in which a final sample of 1,382 participants (823 female and 559 male) provided complete responses on well-validated scales measuring intrasexual competition and green consumption values. The large sample size implies that even small effect sizes could be detected with high statistical power. The data were analyzed using a series of Mann–Whitney U tests to compare the responses made by male and female participants. Subsequently, multiple linear regressions as well as regression-based mediation and moderation analyses were performed with control variables added to show robustness of the results, test the proposed chain of events, and demonstrate generalizability.FindingsMale (vs female) participants expressed significantly higher levels of intrasexual competition both generally and on the two subdimensions corresponding to superiority striving and inferiority irritation. Further, they were slightly less inclined to express green consumption values. Importantly, the sex difference in green consumption values was mediated by inferiority irritation as well as the entire intrasexual competition scale but not by superiority striving. Thus, men's inferiority irritation, in particular, and their more pronounced propensity to compete with same-sex rivals, in general, drove them away from green consumption, whereas women's weaker willingness to compete with same-sex rivals instead increased their inclination of “going green.”Originality/valueDrawing on findings from the domains of competitiveness and gender stereotypes, the current research demonstrates a novel mechanism through which green consumption responses can be understood. Specifically, this study provides empirical evidence for the mediating role of intrasexual competition, especially regarding the more negatively charged subdimension of inferiority irritation, in explaining why male and female consumers may differ in terms of their green consumption values. The present research also contributes to the literature by questioning the unidimensional structure of the intrasexual competition scale and showing that the negative (vs positive) subdimension of this scale is more influential in explaining sex-differentiated patterns in consumers' green consumption values, thereby supporting the notion that “bad is stronger than good.”

Sex specific molecular networks and key drivers of Alzheimer’s disease

BackgroundAlzheimer’s disease (AD) is a progressive and age-associated neurodegenerative disorder that affects women disproportionally. However, the underlying mechanisms are poorly characterized. Moreover, while the interplay between sex and ApoE genotype in AD has been investigated, multi-omics studies to understand this interaction are limited. Therefore, we applied systems biology approaches to investigate sex-specific molecular networks of AD.MethodsWe integrated large-scale human postmortem brain transcriptomic data of AD from two cohorts (MSBB and ROSMAP) via multiscale network analysis and identified key drivers with sexually dimorphic expression patterns and/or different responses to APOE genotypes between sexes. The expression patterns and functional relevance of the top sex-specific network driver of AD were further investigated using postmortem human brain samples and gene perturbation experiments in AD mouse models.ResultsGene expression changes in AD versus control were identified for each sex. Gene co-expression networks were constructed for each sex to identify AD-associated co-expressed gene modules shared by males and females or specific to each sex. Key network regulators were further identified as potential drivers of sex differences in AD development. LRP10 was identified as a top driver of the sex differences in AD pathogenesis and manifestation. Changes of LRP10 expression at the mRNA and protein levels were further validated in human AD brain samples. Gene perturbation experiments in EFAD mouse models demonstrated that LRP10 differentially affected cognitive function and AD pathology in sex- and APOE genotype-specific manners. A comprehensive mapping of brain cells in LRP10 over-expressed (OE) female E4FAD mice suggested neurons and microglia as the most affected cell populations. The female-specific targets of LRP10 identified from the single cell RNA-sequencing (scRNA-seq) data of the LRP10 OE E4FAD mouse brains were significantly enriched in the LRP10-centered subnetworks in female AD subjects, validating LRP10 as a key network regulator of AD in females. Eight LRP10 binding partners were identified by the yeast two-hybrid system screening, and LRP10 over-expression reduced the association of LRP10 with one binding partner CD34.ConclusionsThese findings provide insights into key mechanisms mediating sex differences in AD pathogenesis and will facilitate the development of sex- and APOE genotype-specific therapies for AD.

Specific health beliefs mediate sex differences in food choice.

Although sex differences in dietary habits are well documented, the etiology of those differences is still a focus of research. The present study examines the role of specific health beliefs regarding healthy amounts of food for food choice and its relation to sex, more specifically, the assumption that sex differences in food choices are mediated by differentiating health beliefs. 212 German participants (44.3% female) aged 18-70 answered an online self-report questionnaire on their dietary habits and health beliefs, based on the recommendations of the German Nutrition Society. Most of the anticipated sex differences in food choice and some differences in health beliefs were found. The mediation hypothesis was partly supported, as the relationship between sex and fruit, vegetable, and fish consumption was mediated by the respective health beliefs. However, no mediation effects were found for meat, egg, cereal, and milk product consumption. The support for the mediation hypothesis aligns with previous findings and indicates that health beliefs might be an important pathway to fostering healthier food choices, especially for men. Nonetheless, sex differences in food choice were only partially mediated by sex differences in specific health beliefs, indicating that future studies might benefit from parallel mediation analyses to reveal the impact of other relevant factors influencing sex differences in food choice.