Sex Differences Research Articles

Chronic kidney disease and sex dimorphism.

This review highlights studies published in the last 18 months focusing on sex dimorphism in clinical and preclinical areas related to chronic kidney disease (CKD). Hypertension, cardiorenal disease, hormone exposure, heat stress and dietary intake are all risk factors with sexually dimorphic effects thus contributing differentially to the development of chronic kidney disease. In CKD, GFR decline and cardiovascular mortality are more pronounced in males. Females have higher STEMI related in hospital mortality. When on dialysis, females have higher cardiovascular events rate. Males develop anemia and hyperparathyroidism earlier. Hyperphosphatemia is more prevalent in males. Vitamin D deficiency is associated with CKD in males only. Males are more likely to develop severe sarcopenia. The renoprotective effects of estrogen or estrogen agonists are mediated in part through GPER. ET-1 dual antagonism offset the action of GPER. ET-1 dual antagonism abolished the sex differences in acclimation to high salt. Sodium transport and oxygen consumption across the different renal segments is sexually dimorphic. Sexually dimorphic gene expression is mostly seen in the proximal tubules and is under androgen control. The above findings emphasize the need to systematically include female models in preclinical and clinical research which will improve clinical management and allow for development and implementation of precision medicine tailored to sex.

Brain morphology in the peracarid crustacean Neomysis integer (Leach, 1814) with an emphasis on sexual dimorphism of the olfactory pathway.

Our current understanding of brain organization in malacostracan crustaceans is strongly biased towards representatives of the Decapoda ("ten legged" crustaceans) such as crayfish, crabs, clawed lobsters and spiny lobsters. However, to understand aspects of brain evolution in crustaceans, a broader taxonomic sampling is essential. The peracarid crustaceans are a species-rich group that embraces representatives of, e.g. the Isopoda, Amphipoda and Mysida ("opossum shrimps"), taxa whose neuroanatomy has not been carefully examined. The current study sets out to analyze brain morphology of the mysid Neomysis integer (Leach, 1814; Peracarida, Mysida) using immunohistochemistry against the presynaptic protein synapsin and the neuropeptides RFamide, SIFamide and allatostatin combined with three-dimensional reconstruction of elements of the central olfactory pathway. Furthermore, we studied the inventory of sensilla on the first pair of antennae using cuticular autofluorescence. Anterograde fillingwith neuronal tracers allowed visualisation the central projections of the sensilla on the first pair of antennae. This species is known to display a sexual dimorphism in both the peripheral and central olfactory pathway. We focussed our analysis on this aspect because in contrast to Hexapoda, reports on a sexual dimorphism of the olfactory system are extremely rare in malacostracan crustaceans. We provide a detailed description of the sensilla associated with a male-specific structure on the pair of first antenna the "lobus masculinus". Furthermore, we analyzed the projection patterns of theses sensilla into the "male-specific neuropil" in the deutocerebrum and critically discussour results in comparison to examples of sexual dimorphism in the chemosensory pathways in other malacostracan crustaceans and hexapods.

Sexual dimorphism of lung immune-regulatory units imprintbiased pulmonary fibrosis.

Pulmonary fibrosis (PF) is sexually dimorphic, with a relatively high prevalence and severity in males; however, the mechanism remains unclear. Our study revealed pronounced sexual dimorphism of immune cell genes in the lung, among which grancalcin (GCA) showed profound sex differences. GCA was produced by lung-infiltrating bone marrow macrophages triggered by heightened inflammation in the lung. However, a unique HTR2C+ alveolar macrophage population enriched in female lungs metabolically reprogramed bone marrow-derived macrophages and constrained local GCA amplification. As a novel chemokine, GCA bound to protein tyrosine phosphatase receptor type T (PTPRT) in Th17 cells and facilitated pathogenic lung infiltration by activating the ROCK1-MLC pathway, thus aggravating lung fibrosis. Notably, both GCA and Th17 cells abundantly accumulated in lung biopsies from male PF patients but not in those from female patients. GCA-neutralizing antibodies in combination with pirfenidone, a prescribed medication for treating fibrosis, provided superior effectiveness and survival rates against PF compared with treatment with pirfenidone alone. Overall, our findings reveal that sex-biased lung fibrosis is shaped by lung immune-regulatory units, which could be targeted to limit lung fibrosis.

Prenatal Antidepressant Exposure and the Developing Brain: A Review of Neuroimaging Findings.

Antenatal mood disturbances are experienced by as many as 20% of pregnant mothers and are commonly treated with serotonin reuptake inhibitor (SRI) antidepressants. Both maternal depression and SRIs during pregnancy are associated with low birth weight and infant neurobehavioral disturbances, as well as longer-term impacts on child neurodevelopment, behavior, and mental health. As maternal depression and its pharmacotherapy are inherently interrelated prenatal exposures, distinguishing how these early life factors uniquely impact child development remains methodologically challenging. Over the past several years, however, advanced neuroimaging has been successfully used to identify neural correlates of prenatal depression and SRI antidepressant exposure on the developing brain, extending from the early newborn period through adolescence. In this review, we examine the use of magnetic resonance imaging and electroencephalography to study child brain structure or function, with a specific focus on prenatal antidepressants as the primary exposure in relation to either typical development or exposure to maternal depressed mood alone. We include both cross-sectional and longitudinal neuroimaging studies, as well as those that link early brain findings with cognitive or behavioral outcome in childhood. We also discuss factors that may shape neurodevelopmental risk (e.g., maternal mental illness severity, sex differences, genetic variability) and present suggestions for future research that will advance our understanding of child brain development in the context of maternal mood disturbances during pregnancy.

Post-acute sequelae SARS-CoV-2 infection and neuropathic pain: a narrative review of the literature and future directions.

Neuropathic pain is a recognized and debilitating symptom of SARS-CoV-2 infection across acute, post-acute, and long-COVID phases. Initially emerging as acute or subacute symptoms, these neuropathic manifestations can evolve into chronic conditions, with approximately 10% of all SARS-CoV-2 cases (estimated 65 million individuals globally) developing post-acute SARS-CoV-2 (PASC) neuropathic sequalae. Given the limited literature specifically addressing neuropathic pain related to PASC, a deeper understanding is needed to improve management and reduce patient burden. PASC symptoms are associated with disease severity, elevated body mass indexes, preexisting psychological conditions, and addiction history. Sex differences appear to influence prevalence, and the multisystem nature of PASC complicates symptom presentation, with mood disorders, fatigue, and cognitive dysfunction contributing to altered pain perception. Proposed mechanisms include immune dysregulation, persistent viral protein effects, and neuroanatomical changes. Management typically involves a multimodal approach. This review examines SARS-CoV-2 neuropathic pain across the illness trajectory, examining its pathophysiology, prevalence, and treatment. It highlights the potential for subacute neuropathic symptoms to become chronic and calls for future research to refine long-term management strategies and assess broader healthcare implications.

Persistent articular infection and host reactive response contribute to Brucella-induced spondyloarthritis in SKG mice.

Brucellosis, one of the most prevalent zoonotic diseases worldwide, often results in osteoarticular complications including large joint and axial arthritis mimicking spondyloarthritis. To model this chronic manifestation, we infected autoimmunity-prone SKG mice containing a mutation in the T cell adaptor ZAP-70 with Brucella species. B. melitensis infection resulted in a fully penetrant, readily scoreable disease involving large joint wrist and foot arthritis, peri-ocular inflammation, and less frequent scaly paw rash. Infection with B. abortus resulted in similar manifestations, although with delayed arthritis onset, and B. neotomae revealed sex differences, with a more severe disease in females. Heat-killed Brucella did not induce arthritis, evincing a requirement for viable infection. Across species, splenic CFU correlated well with final clinical score at 12 weeks (ρ = 0.79 and P < 0.001). Moreover, viable Brucella was recovered from the paws at 12 weeks, consistent with persistent articular infection. Mice infected with a BrucellaΔtcpB mutant lacking a Type IV secretion system-dependent mediator displayed an intermediate phenotype without significant differences in splenic CFU. Thus, the degree of arthritis did not strictly correlate with the degree of systemic infection, but it suggested an additional reactive component. Together, these data suggest that Brucella-induced spondyloarthritis reflects both persistent colonization and excess host reactivity. Moreover, the sensitivity of the SKG model to different species and mutants will provide new opportunities for dissecting correlates of Brucella virulence and host immunity.IMPORTANCEBrucellosis, a bacterial infection acquired from herd animals, remains one of the most common zoonotic diseases worldwide. Chronic infection often results in spondyloarthritis-like complications. Investigation into pathogenesis has been limited by the lack of overt disease in standard laboratory mice. We addressed this issue using spondyloarthritis-susceptible SKG mice. Upon infection with B. melitensis, SKG mice develop robust, fully penetrant large joint arthritis. Arthritis development required viable bacteria, and live Brucella persisted in paw tissue out to 12 weeks. Disease onset, severity, and manifestations varied upon infection with different Brucella species and mutants, suggesting an additional immune reactive component. Together, these results suggest that this new model will be very useful to the scientific community for determining correlates of bacterial virulence leading to clinical disease.

Sex differences in the genetic regulation of the human plasma proteome

Mechanisms underlying sex differences in the development and prognosis of many diseases remain largely elusive. Here, we systematically investigated sex differences in the genetic regulation of plasma proteome (>5800 protein targets) across two cohorts (30,307 females; 26,058 males). Plasma levels of two-thirds of protein targets differ significantly by sex. In contrast, genetic effects on protein targets are remarkably similar across sexes, with only 103 sex-differential protein quantitative loci (sd-pQTLs; for 2.9% and 0.3% of protein targets from antibody- and aptamer-based platforms, respectively). A third of those show evidence of sexual discordance, i.e., effects observed in one sex only (n = 30) or opposite effect directions (n = 1 for CDH15). Phenome-wide analyses of 365 outcomes in UK Biobank did not provide evidence that the identified sd-pQTLs accounted for sex-differential disease risk. Our results demonstrate similarities in the genetic regulation of protein levels by sex with important implications for genetically-guided drug target discovery and validation.

Parallel gene expression changes in ventral midbrain dopamine and GABA neurons during normal aging.

The consequences of aging can vary dramatically between different brain regions and cell types. In the ventral midbrain, dopaminergic neurons develop physiological deficits with normal aging that likely convey susceptibility to neurodegeneration. While nearby GABAergic neurons are thought to be more resilient, decreased GABA signaling in other areas nonetheless correlates with age-related cognitive decline and the development of degenerative diseases. Here, we used two novel cell type-specific Translating Ribosome Affinity Purification models to elucidate the impact of healthy brain aging on the molecular profiles of dopamine and GABA neurons in the ventral midbrain. By analyzing differential gene expression from young adult (7-10 month) and old (21-24 month) mice, we detected commonalities in the aging process in both neuronal types, including increased inflammatory responses and upregulation of pro-survival pathways. Both cell types also showed downregulation of genes involved in synaptic connectivity and plasticity. Intriguingly, genes involved in serotonergic synthesis were upregulated with age in GABA neurons and not dopamine-releasing cells. In contrast, dopaminergic neurons showed alterations in genes connected with mitochondrial function and calcium signaling, which were markedly downregulated in male mice. Sex differences were detected in both neuron types, but in general were more prominent in dopamine neurons. Multiple sex effects correlated with the differential prevalence for neurodegenerative diseases such as Parkinson's and Alzheimer's seen in humans. In summary, these results provide insight into the connection between non-pathological aging and susceptibility to neurodegenerative diseases involving the ventral midbrain, and identify molecular phenotypes that could underlie homeostatic maintenance during normal aging.Significance statement This work describes altered gene expression profiles in ventral midbrain dopamine and GABA neurons with aging. Experiments used two novel cell type-specific reporter models to enable translatome analysis. Common age-driven alterations included increased inflammatory and pro-survival cell signaling, and downregulation of synaptic transmission and plasticity genes. In individual cell types, we observed upregulation of serotonergic synthesis in GABA neurons and downregulation of mitochondrial function genes in dopamine neurons. Sex differences were detected in both neuronal types, but were more prominent in dopamine neurons. These results reinforce aging as a risk factor for neurodegeneration in these neuronal populations while providing insight into potential mechanisms of homeostatic regulation during healthy aging and into genetic adaptations that are sex or neuron type specific.

Amyloid and Tau Pathology in Cognitively Unimpaired Individuals With a Parental History of Alzheimer Disease: Role of Sex and Parent's Sex.

Female sex and a parental history of Alzheimer disease (AD), especially maternal, confer increased risk of AD. Associations between sex, or affected AD parent's sex, and biomarkers of AD are less clear. We examined whether sex or affected AD parent's sex influences (1) β-amyloid (Aβ) and tau burden/accumulation, (2) the association between Aβ and tau burden, and (3) brain and cognitive resilience to Aβ and tau burden. The sample included 243 participants from the Presymptomatic Evaluation of Experimental or Novel Treatments for AD cohort in Canada. All participants with [18F]-NAV4694 and [18F]-AV1451 PET and MRI were included. We examined (1) sex or affected AD parent's sex differences on regional Aβ and tau burden/accumulation; (2) 2-way interactions between sex, or affected AD parent's sex, and Aβ on tau burden; and (3) 3-way interactions between time, sex or affected AD parent's sex, and Aβ or tau deposition on hippocampal volume (brain resilience) and cognition (cognitive resilience) over time. Participants (69.4% female) were aged 68.3 ± 5.1 years at their first PET scans. All were cognitively unimpaired at baseline. Longitudinal cognitive data were available for 242 participants (follow-up, 6.72 ± 2.38 years), including 238 (6.53 ± 2.48 years of follow-up) with MRI follow-ups and 115 (4.4 ± 0.6 years of follow-up) with PET follow-ups, and 71 developed mild cognitive impairment. Women showed greater tau deposition (standardized β = 0.13 ± 0.3) and showed a stronger association between global Aβ and tau deposition than men (standardized β = 0.79 ± 0.1). Individuals with an affected AD father showed stronger association between global Aβ and tau deposition than those with an affected AD mother (standardized β = 0.65 ± 0.1). Women showed less Aβ-associated hippocampal atrophy over time (standardized β = 0.24 ± 0.1). Women and, surprisingly, individuals with a paternal history of AD seemed more vulnerable to the Aβ-related spread of tau, whereas women showed greater brain resilience to Aβ. Understanding sex-specific risk and resilience could allow more clinical trial precision and personalization. A major limitation included the reduced sample for the affected AD parent's sex analyses.

Sex difference in the relationship between 24-h sodium–potassium ratio and prevalence of metabolic syndromes: a cross-sectional study

Maintaining a balanced ratio between sodium and potassium intake is one of the most important dietary and lifestyle factors in the development of metabolic syndrome (MetS), but available evidence is still limited, particularly when using urine samples to estimate this ratio. We aim to evaluate the associations between the 24-h urinary sodium–potassium ratio (24hUNa/KE) and MetS risk through a large health check-up program in China. This cross-sectional study analyzed health check-up data from 59,292 participants at the Third Xiangya Hospital’s Department of Health Management in Changsha, China, from 2018 to 2021. Each participant gave one fasting urine sample to analyze sodium, potassium, and creatinine levels during the check-up. The Kawasaki formula estimated 24-h urinary sodium (24hUNaE) and potassium excretion (24hUKE), with the 24hUNa/KE ratio calculated by dividing 24hUNaE by 24hUKE. The prevalence of MetS was found to be 19.27%. Notably, the overall MetS prevalence was higher in men (28.08%) than in women (7.83%). In women, MetS prevalence increased from 6.35 to 10.30% across the lowest to highest 24hUNa/KE quartiles. A significant increase in MetS prevalence was associated with each standard deviation increase in 24hUNa/KE (adjusted odds ratio [AOR], 1.03; 95% confidence interval [CI] 1.01–1.06), particularly for central obesity (AOR, 1.04; 95% CI 1.02–1.06) and elevated blood pressure (AOR, 1.20; 95% CI 1.17–1.22). In women, a one standard deviation increase in the 24hUNa/KE ratio raised the risk of MetS by 9% (AOR, 1.09; 95% CI 1.05–1.14), but no significant link was found in men. A strong positive link exists between 24hUNa/KE and MetS and its components, especially central obesity and high blood pressure, with a more significant effect in women.

Sex differences in the associations between prior weight loss and all-cause or cardiovascular mortality in non-elderly individuals with hyperuricemia: a mortality follow-up study

BackgroundHyperuricemia, a common metabolic condition, is strongly associated with obesity and represents as an independent risk factor for elevated risk of mortality. This observational study aimed to examine the sex-specific associations of prior long-term weight loss (LTWL), defined as a sustained reduction in body weight maintained for at least 12 months, with all-cause and cardiovascular disease (CVD) mortality in non-elderly individuals with hyperuricemia.MethodsNon-elderly individuals with hyperuricemia and a historical maximum body mass index ≥ 25 kg/m2 from the 1999–2018 US National Health and Nutrition Examination Survey were included. Sex-specific associations between prior LTWL (< 5%, 5-9.9%, 10-14.9%, and ≥ 15%) with all-cause and CVD mortality were investigated by weighted multivariable Cox proportional hazard regression analysis and stratified analysis.ResultsAmong 5,130 participants included, 505 all-cause (147 from CVD) deaths occurred during a median follow-up of 113 months. Compared with the LTWL < 5% reference group, the hazard ratios and 95% confidence intervals for the LTWL 5-9.9%, 10-14.9% and ≥ 15% groups were 1.11 (0.72–1.71), 1.34 (0.79–2.26) and 1.85 (1.14–2.92), respectively, for all-cause mortality (P for trend = 0.02) and 1.83 (0.76–4.43), 2.15 (0.76–6.10), and 3.76 (1.51–9.36), respectively, for CVD mortality (P for trend = 0.003). Significant associations between LTWL with all-cause and CVD mortality were observed exclusively in female, not male participants.ConclusionsPrior LTWL ≥ 5% was associated with increased all-cause and CVD mortality in US non-elderly female participants with hyperuricemia. Additional prospective and longitudinal randomized clinical trials are necessary to further examine the current findings.

Adverse childhood experiences, inflammation, and depression: evidence of sex- and stressor specific effects in a nationally representative longitudinal sample of U.S. adolescents.

Although adverse childhood experiences (ACEs) are commonly associated with depressive symptoms in adulthood, studies frequently collapse ACEs into a single unitary index, making it difficult to identify specific targets for intervention and prevention. Furthermore, studies rarely explore sex differences in this area despite males and females often differing in the experiences of ACEs, depressive symptoms, and inflammatory activity. To address these issues, we used data from the National Longitudinal Study of Adolescent to Adult Health to model the effects of 10 different ACEs on C-reactive protein (CRP) and depressive symptoms in adulthood. Path modeling was used to measure the effects of ACEs on CRP and depressive symptoms conjointly while also assigning covariances among ACEs to assess their interrelations. Sex-by-ACE interaction terms and sex-disaggregated models were used to test for potential differences. Emotional abuse and parental incarceration were consistently related to both CRP and depressive symptoms for males and females. Childhood maltreatment was associated with depressive symptoms for females, whereas sexual abuse was associated with inflammation for males. Several covariances among ACEs were identified, indicating potential networks through which ACEs are indirectly associated with CRP and depressive symptoms. These data demonstrate that ACEs have differing direct effects on CRP and depressive symptoms - and that they differ with respect to how they cluster - for males versus females. These differences should be considered in theory and clinical workflows aiming to understand, treat, and prevent the long-term impacts of ACEs on depressive symptoms and inflammation-related health conditions in adulthood.

Not all is male biased: sexual dimorphism in carapace size and shape of the kelp crab Taliepus dentatus (Decapoda: Majoidea: Epialtdae)

ABSTRACT Different selection pressures acting on males and females generate biases in the cephalothoracic size and shape of many decapod crustaceans. We assessed such patterns in the carapace components (dorsal cephalothorax, ventral cephalothorax, and pleotelson) of the kelp crab Taliepus dentatus, with morphological variables based on Euclidean and Procrustes coordinates of homologous landmarks, which describe variations in size and shape, respectively. The dorsal and ventral cephalothorax exhibited male-biased sexual size dimorphism, differing from the female-biased sexual size dimorphism expressed by the shape and size of the pleotelson. Size allometry was more restricted in the cephalothorax than in the pleotelson. Shape allometry showed greater restriction in larger females, with robust and parallel limits of variation in males. In contrast, the shape of the pleotelson (female-biased) varied within parallel limits in both sexes. The variations in shape and size of both groups of traits are mainly attributable to adaptive factors that favour population fitness in females through natural selection and individual fitness explained through sexual selection in males. However, the variation in the shape of the dorsal and ventral cephalothorax indicates inherent structural complexity, where developmental modules favour the muscular performance of the chelipeds and the remaining pereiopods. Our results suggest that stabilising selection acting differentially on the shape and size of the caparace components directs the expression of this body plan towards optimality, promoting morphological convergences and taxonomic conflicts for this species, which is consistent with highly integrated complex structures.

DVGLUT Is a Mediator of Sex Differences in Dopamine Neuron Mitochondrial Function Across Aging and in a Parkinson's Disease Model.

Sex differences in Parkinson's disease (PD) offer insights into mechanisms of dopaminergic cell resilience. Female dopamine (DA) neurons are more resilient via mechanisms that remain unclear. Here, we discovered key sex and regional differences in mitochondrial generation of cytotoxic reactive oxygen species (ROS) and their implications for DA neuron resilience using the Drosophila model. While aging raised mitochondrial ROS in DA neurons of both sexes, we observed a sexually dimorphic response in the paraquat (PQ) PD model. DA neuron knockdown of the Drosophila vesicular glutamate transporter (dVGLUT) increased mitochondrial ROS only in males, leaving females protected. Cell depolarization, a physiological stressor, similarly raised mitochondrial ROS in DA neurons selectively in males following dVGLUT knockdown. We also identified dVGLUT-dependent changes in intracellular ATP in both sexes. Overall, we discovered sexually dimorphic relationships between dVGLUT, ATP synthesis, and ROS generation in DA neurons, providing a mechanistic basis for DA neuron resilience.

Molecular insights into region-specific sexual dichromatism: Comparative transcriptome analysis of red cheek pigmentation in zebra finches.

Feathers, the primary skin appendage covering the avian body, undergo dynamic phenotypic changes throughout a bird's life. Males and females of the same species can exhibit sexually dichromatic plumage colors which play a critical role in mating choice, survival, and ecological interactions. In this study, we investigate the molecular mechanisms underlying the changes of color that occur during the transition from juvenile to adult feathers, known as the secondary transition. We focus on sexual dichromatism of craniofacial plumage and use the male cheek domain of the zebra finch (Taeniopygia guttata) as the major model. The transcriptome of the cheek and scalp (crown) domains in males and females of wild-type and genetic color variants were compared. We found that (1) Craniofacial color patterning operates through two regulatory layers. The first layer involves transcription factor (TF) genes that define the cheek domain such as PITX1, PAX1, PAX6. The second layer comprises pigment-related genes responsible for specific colors, including male-biased TFs (SOX10 and DMRT1) and transporters associated with red pigment synthesis. (2) Surprisingly, ASIP, which controls pheomelanin production in other species, was expressed in both male (red) and female (gray) cheeks. Instead, PAX1 in cheek dermal fibroblasts may serve as an upstream regulator, potentially triggering the male-biased color pattern through PAX6 and SOX10. PAX6 and SOX10 in melanocytes potentially enhance the expression of GPR143, SLC45A2, and TMEM163, driving increased pheomelanin production in males. (3) Sexual dichromatism is associated with sex-linked genes on the Z chromosome, notably SLC45A2. In addition, motif analysis comparing the binding strength between regional transcription factors and melanogenesis genes suggests that craniofacial pigmentation may have evolved convergently in passerine birds. These findings provide novel insights into the molecular control of color patterning and lay the groundwork for further studies on avian sexual dichromatism and secondary feather transition.

Sex differences in histamine regulation of striatal dopamine.

Dopamine modulation of the basal ganglia differs in males and females and is implicated in numerous neuropsychiatric conditions, including some, like Tourette Syndrome (TS) and attention deficit hyperactivity disorder (ADHD), that have marked sex differences in prevalence. Genetic studies in TS and subsequent work in animals suggest that a loss of histamine may contribute to dysregulation of dopamine. Motivated by this, we characterized the modulation of striatal dopamine by histamine, using microdialysis, targeted pharmacology, and shRNA knockdown of histamine receptors. Intracerebroventricular (ICV) histamine reduced striatal dopamine in male mice, replicating previous work. In contrast, and unexpectedly, ICV histamine increased striatal dopamine in females. ICV or targeted infusion of agonists revealed that the effect in males depends on H2R receptors in the substantia nigra pars compacta (SNc). Knockdown of H2R in SNc GABAergic neurons abrogated the effect, identifying these cells as a key locus of histamine's regulation of dopamine in males. In females, however, H2R had no discernible role; instead, H3R agonists in the striatum increased striatal dopamine. Strikingly, the effect of histamine on dopamine in females was modulated by the estrous cycle, appearing only in estrus/proestrus, when estrogen levels are high. These findings confirm the regulation of striatal dopamine by histamine but identify marked sexual differences in and estrous modulation of this effect. These findings may shed light on the mechanistic underpinnings of sex differences in the striatal circuitry, and in several neuropsychiatric conditions.Significance Statement Dysregulation of the basal ganglia contributes to the pathophysiology of numerous neuropsychiatric diseases, including several, such as Tourette syndrome (TS), that are characterized by sex differences. Previous genetic studies in humans identified histamine dysregulation as a potential to the development of TS; follow-up work in mice highlighted the role of histamine in regulating striatal dopamine tone. Striatal dopamine dysregulation has been implicated in numerous neuropsychiatric disorders, including TS, schizophrenia, and attention deficit-hyperactivity disorder. Here, we uncover novel and significant sex differences in histamine regulation of dopaminergic modulation of the striatum. A better understanding of these differences may provide insight into the mechanisms underlying sex-dependent outcomes in neuropsychiatric disease.

Variation in adult sex ratios in tetrapods is linked to sex chromosomes through mortality differences between males and females.

Sex chromosomes can determine male and female phenotypes, and the resulting sex differences may have significant impacts on ecology and life history. One manifestation of this link is that ZW/ZZ sex-determination systems are associated with more male-skewed adult sex ratio (ASR, proportion of males in the adult population) than XX/XY systems across tetrapods (amphibians, reptiles, birds, and mammals). Here, we investigate four demographic processes: male and female offspring production, sex differences in juvenile and adult mortalities and in timing of maturation that can contribute to ASR variation between XX/XY and ZW/ZZ systems, using phylogenetic analyses of a large dataset collected from tetrapod species in the wild. We show that sex differences in adult mortality reliably predict ASR that is also more male-biased in XX/XY species than in ZW/ZZ species. Sex differences in juvenile mortality and in maturation time also contribute to ASR skews, but do not differ consistently between XX/XY and ZW/ZZ systems. Phylogenetic path analyses confirm an influence of sex-determination system on ASR through sex-biased adult mortalities. Together these results infer that sex chromosomes can impact, via demographic pathways, frequency-dependent selection emerging from the relative number of males and females. We call for follow-up studies to uncover the potentially complex web of associations between sex determination, population dynamics, and social behavior.

Sex difference in aortic root replacement with a stentless bioprosthesis.

To investigate and quantify differences in survival and reinterventions between sexes after aortic root replacement with a stentless bioprosthesis, stratified for preoperative valve lesion. Elective adults undergoing aortic root replacement with the Freestyle bioprosthesis at six North-Atlantic centers were included. Survival analyses were performed using the Kaplan-Meier method or Aahlen-Johansen with death as competing risk as relevant. Results were quantified using uni- and multivariable Cox regression tested using a log-rank likelihood ratio test. In total, 884 patients were analysed for a median follow-up time of 10 years. Females were 4 years older. Survival was significantly worse in females operated for aortic valve insufficiency (60.7% and 72.2% for females and males at 14 years, respectively (p = 0.001)), but not for the other indications, even after correction for age. There were no differences in early outcomes or need for reoperation between the sexes and between the different aortic valve pathologies. Sex difference in survival outcomes depend on pathology, and females have, compared to males, more symptoms preoperatively regardless of type of valve lesion and worse outcome after aortic root replacement due to aortic insufficiency. Updated surgical risk scores should account for interaction between sex and pathology, and the surgical community must raise awareness on risk of patient's or doctors delay to surgery.

Experimental evidence of pollination by deception in a dioecious palm

BackgroundFlower traits and pollinator activity patterns can vary over the course of a single day. Therefore, the pollination processes occurring over short time scales are crucial to sustain the complex dynamics of plant-pollinator interactions. Here, we characterized the diel patterns of flower opening (e.g. anthesis), scent emission, and insect visits in highly dimorphic male (rewarding) and female (deceptive) inflorescences of the ivory palm (Phytelephas aequatorialis), a thermogenic dioecious species endemic to western Ecuador. We conducted field experiments using artificial scented-baits (designated as artificial flowers) consisting of a heating plate (simulating thermogenesis) and p-methylanisole (the primary odor compound in inflorescences of both sexes) in two different amounts to mimic female and male inflorescences.ResultsWe found that female inflorescences open synchronously at dawn and dusk, while male inflorescences can open at any time throughout the day. Both sexes emitted floral odors consistently throughout the day. Even though male inflorescences emitted greater quantities of p-methylanisole, artificial flowers with different amounts of p-methylanisole attracted a similar diversity and abundance of insects throughout the day. Furthermore, male and female artificial flower attracted an equal abundance of visitors within five minutes of the emission of p-methylanisole.ConclusionsThe findings suggest that, despite sexual dimorphism in opening time, intersexual mimicry in P. aequatorialis is sustained by a consistent odor release, which optimizes the probability of both sexes being visited by the same insect community during the day.

New developments in imaging in ALS

Neuroimaging in ALS has contributed considerable academic insights in recent years demonstrating genotype-specific topological changes decades before phenoconversion and characterising longitudinal propagation patterns in specific phenotypes. It has elucidated the radiological underpinnings of specific clinical phenomena such as pseudobulbar affect, apathy, behavioural change, spasticity, and language deficits. Academic concepts such as sexual dimorphism, motor reserve, cognitive reserve, adaptive changes, connectivity-based propagation, pathological stages, and compensatory mechanisms have also been evaluated by imaging. The underpinnings of extra-motor manifestations such as cerebellar, sensory, extrapyramidal and cognitive symptoms have been studied by purpose-designed imaging protocols. Clustering approaches have been implemented to uncover radiologically distinct disease subtypes and machine-learning models have been piloted to accurately classify individual patients into relevant diagnostic, phenotypic, and prognostic categories. Prediction models have been developed for survival in symptomatic patients and phenoconversion in asymptomatic mutation carriers. A range of novel imaging modalities have been implemented and 7 Tesla MRI platforms are increasingly being used in ALS studies. Non-ALS MND conditions, such as PLS, SBMA, and SMA, are now also being increasingly studied by quantitative neuroimaging approaches. A unifying theme of recent imaging papers is the departure from describing focal brain changes to focusing on dynamic structural and functional connectivity alterations. Progressive cortico-cortical, cortico-basal, cortico-cerebellar, cortico-bulbar, and cortico-spinal disconnection has been consistently demonstrated by recent studies and recognised as the primary driver of clinical decline. These studies have led the reconceptualisation of ALS as a “network” or “circuitry disease”.