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Drosophila prolongata is a member of the melanogaster species group and rhopaloa subgroup native to the subtropical highlands of Southeast Asia. This species exhibits an array of recently evolved male-specific morphological, physiological, and behavioral traits that distinguish it from its closest relatives, making it an attractive model for studying the evolution of sexual dimorphism and testing theories of sexual selection. The lack of genomic resources has impeded the dissection of the molecular basis of sex-specific development and behavior in this species. To address this, we assembled the genome of D. prolongata using long-read sequencing and Hi-C scaffolding, resulting in a highly complete and contiguous (scaffold N50 2.2 Mb) genome assembly of 220 Mb. The repetitive content of the genome is 24.6%, the plurality of which are long terminal repeats retrotransposons (33.2%). Annotations based on RNA-seq data and homology to related species revealed a total of 19,330 genes, of which 16,170 are protein-coding. The assembly includes 98.5% of Diptera BUSCO genes, including 93.8% present as a single copy. Despite some likely regional duplications, the completeness of this genome suggests that it can be readily used for gene expression, genome-wide association studies (GWAS), and other genomic analyses.

Simple Summary: Early life stress (ELS) is a risk factor for neuropsychiatric disorders, and both neuroinflammation and mitochondrial dysfunction are linked to mental health. This study aimed to explore the short-term effects of ELS on neuroinflammation and mitochondrial dynamics using an animal model of maternal deprivation (MD) in male and female Wistar rats. MD led to a temporary increase in pro-inflammatory cytokines in the pre-frontal cortex (PFC) and anti-inflammatory cytokine levels in the hippocampal formation (HCF). It also caused a reduction in mitochondrial density, although respiratory function remained unchanged. The study found that PINK and Parkin may be involved in the MD response, with PINK expression changes observed in the hippocampus, while Parkin's role appeared sex-dependent and potentially linked to both mitochondrial dynamics and the immune system. Further research is needed to understand the gender differences in how neuroinflammation and mitochondrial dynamics interact during brain development following MD. Early life stress (ELS) is associated with an increased risk for neuropsychiatric disorders, and both neuroinflammation and mitochondrial dysfunction seem to be central to mental health. Herein, using an animal model of ELS, a single episode of maternal deprivation (MD, 24 h on pnd 9) extensively documented to elicit behavioural anomalies in male and female Wistar rats, we investigated its consequences in terms of neuroinflammation and mitochondrial dynamics in the prefrontal cortex (PFC) and the hippocampal formation (HCF). MD differentially affected the brain content of cytokines: MD induced a transient increase in pro-inflammatory cytokines (IL-1β and IL-6) in the PFC, as well as in the levels of the anti-inflammatory cytokine IL-10 in the HCF. MD also induced a significant decrease mitochondria citrate synthase activity, but MD did not exert significant changes in mitochondria Complex IV activity, revealing a generalized decrease in mitochondrial density without any change in mitochondrial respiration. In the present study, we demonstrate that MD induces neuroinflammatory processes in specific brain regions. Additional research is needed to better understand the temporal pattern of such changes, their impact on the developing brain, and their participation in the already well-known behavioural consequences of MD. [ABSTRACT FROM AUTHOR]

Purpose: Treatment with recombinant human growth hormone (rhGH) increases insulin growth factor-1 (IGF1) levels, therefore, monitoring both IGF1 and growth constitutes an acceptable parameter of therapeutic safety and efficacy. We aimed to investigate the relationship between IGF1 level and body composition in children and adolescents undergoing rhGH therapy for growth hormone deficiency (GHD) and idiopathic short stature (ISS). Methods: This observational retrospective study included the bioimpedance analysis (BIA) reports (n = 305) of 135 pediatric patients (age 5–18 years), 64 with GHD and 71 with ISS, conducted as part of routine clinic visits. Sociodemographic and clinical data were extracted from medical records. Generalized estimating equations linear models were used to explore the contributing factors for body composition components of fat percentage (FATP), appendicular skeletal muscle mass (ASMM) z-score, and muscle-to-fat ratio (MFR) z-score while adjusting for cumulative doses of rhGH. Results: Subjects with GHD exhibited higher body mass index z-scores (p < 0.001), higher FATP and truncal FATP scores, lower MFR z-score, and higher diastolic blood pressure percentiles than the ISS group (p = 0.010, p = 0.027, p = 0.050, and p = 0.050, respectively). Female sex (p < 0.001) and a GHD diagnosis (p < 0.001), were major contributors to higher FATP scores; female sex (p = 0.049) and ISS diagnosis (p = 0.005) were major contributors to higher MFR z-scores; and female sex (p < 0.001), older age (p < 0.001) and higher insulin-like growth factor 1 z-scores (p = 0.021) were major contributors to higher ASMM z-scores. Socioeconomic position and cumulative rhGH dose were not significant contributors to body composition parameters. Conclusion: Children with GHD, including those undergoing rhGH treatment, may be at risk for increased adiposity and associated metabolic implications. Sex- and age-adjusted IGF1 levels were related to muscle mass but not to adiposity. Hence, rhGH treatment aimed at increasing IGF1 levels may alleviate these effects by promoting muscle growth. [ABSTRACT FROM AUTHOR]

Abstract Background Aging is a complex process that involves all tissues in an organism and shows sex dimorphism. While transcriptional changes in aging have been well characterized, the majority of studies have focused on a single sex and sex differences in gene expression in aging are poorly understood. In this study, we explore sex dimorphism in gene expression in aging mice across three tissues. Methods We collected gastrocnemius muscle, liver and white adipose tissue from young (6 months, n = 14) and old (24 months, n = 14) female and male C57BL/6NIA mice and performed RNA-seq. To investigate sex dimorphism in aging, we considered two levels of comparisons: (a) differentially expressed genes between females and males in the old age group and (b) comparisons between females and males across the aging process. We utilized differential expression analysis and gene feature selection to investigate candidate genes. Gene set enrichment analysis was performed to identify candidate molecular pathways. Furthermore, we performed a co-expression network analysis and chose the gene module(s) associated with aging independent of sex or tissue-type. Results We identified both tissue-specific and tissue-independent genes associated with sex dimorphism in aged mice. Unique differentially expressed genes between old males and females across tissues were mainly enriched for pathways related to specific tissue function. We found similar results when exploring sex differences in the aging process, with the exception that in the liver genes enriched for lipid metabolism and digestive system were identified in both females and males. Combining enriched pathways across analyses, we identified amino acid metabolism, digestive system, and lipid metabolism as the core mechanisms of sex dimorphism in aging. Although the vast majority of age-related genes were sex and tissue specific, we identified 127 hub genes contributing to aging independent of sex and tissue that were enriched for the immune system and signal transduction. Conclusions There are clear sex differences in gene expression in aging across liver, muscle and white adipose. Core pathways, including amino acid metabolism, digestive system and lipid metabolism, contribute to sex differences in aging.

Background: Aging is a complex process that involves all tissues in an organism and shows sex dimorphism. While transcriptional changes in aging have been well characterized, the majority of studies have focused on a single sex and sex differences in gene expression in aging are poorly understood. In this study, we explore sex dimorphism in gene expression in aging mice across three tissues. Methods: We collected gastrocnemius muscle, liver and white adipose tissue from young (6 months, n = 14) and old (24 months, n = 14) female and male C57BL/6NIA mice and performed RNA-seq. To investigate sex dimorphism in aging, we considered two levels of comparisons: (a) differentially expressed genes between females and males in the old age group and (b) comparisons between females and males across the aging process. We utilized differential expression analysis and gene feature selection to investigate candidate genes. Gene set enrichment analysis was performed to identify candidate molecular pathways. Furthermore, we performed a co-expression network analysis and chose the gene module(s) associated with aging independent of sex or tissue-type. Results: We identified both tissue-specific and tissue-independent genes associated with sex dimorphism in aged mice. Unique differentially expressed genes between old males and females across tissues were mainly enriched for pathways related to specific tissue function. We found similar results when exploring sex differences in the aging process, with the exception that in the liver genes enriched for lipid metabolism and digestive system were identified in both females and males. Combining enriched pathways across analyses, we identified amino acid metabolism, digestive system, and lipid metabolism as the core mechanisms of sex dimorphism in aging. Although the vast majority of age-related genes were sex and tissue specific, we identified 127 hub genes contributing to aging independent of sex and tissue that were enriched for the immune system and signal transduction. Conclusions: There are clear sex differences in gene expression in aging across liver, muscle and white adipose. Core pathways, including amino acid metabolism, digestive system and lipid metabolism, contribute to sex differences in aging. Plain Language Summary: Aging is a complex process that occurs differently across tissues, and in men compared to women. However, the mechanisms that cause sex differences are not well understood. Using naturally aging mouse models we compared how specific genes were differently expressed in muscle, liver and fat of old and young female and male mice. We found that the vast majority of genes that were changed with age were only changed in one sex and specific tissues. Overall, sex differences in aging across tissues were related to genes involved in amino acid metabolism, digestive system and lipid metabolism. Notably, lipid metabolism is important in aging females across all tissues. We also identified a set of genes associated with aging independent of sex and tissue-type involved in immune pathways and signaling. These results enhance our understanding of sex differences in aging. Highlights: We performed RNA-seq in three tissues from young (6 months) and old (24 months) mice of both sexes, and applied differential expression analysis and machine learning approaches to identify candidate genes to decipher sex dimorphism in aging. We demonstrated that the vast majority of age-related genes were sex and tissue specific, with liver showing greater changes than muscle or white adipose tissue. Enriched pathways underpinning sex differences for each tissue aligned with the function of the tissues. In addition to tissue-specific findings, we also observed pathways in amino acid metabolism, digestive system and lipid metabolism contributing to tissue-wide sex dimorphism. We applied an unsupervised machine learning approach to select key genes involved in aging regardless of sex and tissue, and these genes were related to the immune system and signaling transduction. [ABSTRACT FROM AUTHOR]

There is documented sex disparity in cutaneous melanoma incidence and mortality, increasing disproportionately with age and in the male sex. However, the underlying mechanisms remain unclear. While biological sex differences and inherent immune response variability have been assessed in tumor cells, the role of the tumor-surrounding microenvironment, contextually in aging, has been overlooked. Here, we show that skin fibroblasts undergo age-mediated, sex-dependent changes in their proliferation, senescence, ROS levels, and stress response. We find that aged male fibroblasts selectively drive an invasive, therapy-resistant phenotype in melanoma cells and promote metastasis in aged male mice by increasing AXL expression. Intrinsic aging in male fibroblasts mediated by EZH2 decline increases BMP2 secretion, which in turn drives the slower-cycling, highly invasive, and therapy-resistant melanoma cell phenotype, characteristic of the aged male TME. Inhibition of BMP2 activity blocks the emergence of invasive phenotypes and sensitizes melanoma cells to BRAF/MEK inhibition. [Display omitted] • Skin fibroblasts show age- and sex-specific changes in proliferation and stress response • Male fibroblasts age faster due to elevated ROS levels • BMP2 is secreted in the aged male dermal microenvironment • BMP2 promotes slow-cycling, invasive, targeted therapy-resistant melanoma tumors Aging-driven and sex-dependent molecular changes in skin fibroblasts drive the emergence of invasive and therapy-resistant melanomas in male mice. [ABSTRACT FROM AUTHOR]

Sex differences are recognized in pulmonary hypertension. However, the progression of disease with regard to vascular lesion formation and circulating cytokines/chemokines is unknown. To determine whether vascular lesion formation, changes in hemodynamics, and alterations in circulating chemokines/cytokines differ between males and females, we used a progressive model of pulmonary arterial hypertension (PAH), Sugen/hypoxia, and analyzed cohorts of male and female rats at time points suggested to indicate worsening disease. Our analysis included echocardiography for hemodynamics, morphometry, immunofluoresecence, and chemokine/cytokine analysis of plasma at each time point in both sexes. We found that male rats had significantly increased Fulton index, compared with those for females at each time point, as well as increased medial artery thickening at 8 weeks of PAH. Furthermore, females exhibited fewer obliterative vascular lesions than males at our latest time point. Our data also show increased IL-4, granulocyte-macrophage colony-stimulating factor, IL-10, and macrophage interacting protein-1α that were not observed in females, whereas females were observed to have increased RANTES (whose name derives from Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted) and CXCL-10 that were not found in males. Males also have increased infiltrating macrophages in vascular lesions, compared with females. We found that development of progressive PAH in hemodynamics, morphology, and chemokine/cytokine circulation differs significantly between males and females. These data suggest a macrophage-driven pathology in males, whereas there may be T cell protection from vascular damage in females with PAH. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality, affecting people of all races, ages, and sexes. Substantial sex dimorphism exists in the prevalence, manifestation, and outcomes of CVDs. Understanding the role of sex hormones as well as sex-hormone-independent epigenetic mechanisms could play a crucial role in developing effective and sex-specific cardiovascular therapeutics. Existing research highlights significant disparities in sex hormones, epigenetic regulators, and gene expression related to cardiac health, emphasizing the need for a nuanced understanding of these variations between men and women. Despite these differences, current treatment approaches for CVDs often lack sex-specific considerations. A pivotal shift toward personalized medicine, informed by comprehensive insights into sex-specific DNA methylation, histone modifications, and non-coding RNA dynamics, holds the potential to revolutionize CVD management. By understanding sex-specific epigenetic complexities, independent of sex hormone influence, future cardiovascular research can be tailored to achieve effective diagnostic and therapeutic interventions for both men and women. This review summarizes the current knowledge and gaps in epigenetic mechanisms and sex dimorphism implicated in CVDs. [ABSTRACT FROM AUTHOR]

Sex differences in metabolic dysfunction-associated steatotic liver disease (MASLD) have been reported. Oxidative stress and inflammation are involved in the progression of MASLD. Thus, we aimed to evaluate liver redox homeostasis and inflammation in male and female rats fed a high-fat diet (HFD). Male and female Wistar rats were divided into the following groups: standard chow diet (SCD) or HFD during 12 weeks. HFD groups of both sexes had higher hepatocyte injury, with no differences between the sexes. Portal space liver inflammation was higher in females-HFD compared to females-SCD, whereas no differences were observed in males. Lobular inflammation and overall liver inflammation were higher in HFD groups, regardless of sex. TNF-α, IL-6, and IL-1β levels were higher in males-HFD compared to males-SCD, but no differences were observed in females. Catalase activity was higher in males compared to females, with no differences between the SCD and HFD groups of both sexes. Glutathione peroxidase activity was higher in females compared to males, with no differences between the SCD and HFD groups in both sexes. Lipid peroxidation was higher in female-SCD when compared to male-SCD, and in both male- and female-HFD compared to SCD groups. Furthermore, both cytoplasmic and nuclear NRF2 staining were lower in the HFD group compared to the SCD group in males. However, female-HFD exhibited reduced nuclear NRF2 staining compared to the female-SCD group. In conclusion, our study demonstrated that while both male and female rats developed metabolic dysfunction-associated steatohepatitis after 12 weeks of HFD, the alterations in inflammatory cytokines and redox balance were sexually dimorphic. [ABSTRACT FROM AUTHOR]

Sexually dimorphic traits such as growth and body size are often found in various crustaceans. Methyl farnesoate (MF), the main active form of sesquiterpenoid hormone in crustaceans, plays vital roles in the regulation of their molting and reproduction. However, understanding on the sex differences in their hormonal regulation is limited. Here, we carried out a comprehensive investigation on sexual dimorphic responses to MF in the hepatopancreas of the most dominant aquacultural crustacean—the white-leg shrimp (Litopenaeus vannamei). Through comparative transcriptomic analysis of the main MF target tissue (hepatopancreas) from both female and male L. vannamei, two sets of sex-specific and four sets of sex–dose-specific differentially expressed transcripts (DETs) were identified after different doses of MF injection. Functional analysis of DETs showed that the male-specific DETs were mainly related to sugar and lipid metabolism, of which multiple chitinases were significantly up-regulated. In contrast, the female-specific DETs were mainly related to miRNA processing and immune responses. Further co-expression network analysis revealed 8 sex-specific response modules and 55 key regulatory transcripts, of which several key transcripts of genes related to energy metabolism and immune responses were identified, such as arginine kinase, tropomyosin, elongation of very long chain fatty acids protein 6, thioredoxin reductase, cysteine dioxygenase, lysosomal acid lipase, estradiol 17-beta-dehydrogenase 8, and sodium/potassium-transporting ATPase subunit alpha. Altogether, our study demonstrates the sex differences in the hormonal regulatory networks of L. vannamei, providing new insights into the molecular basis of MF regulatory mechanisms and sex dimorphism in prawn aquaculture. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) epidemiology and clinical features are sexually dimorphic. However, there are no data based on EEG functional connectivity (FC). Likewise, the contribution of sex hormones on brain FC has never been evaluated. Here, we aimed to investigate the association between biological sex and sex hormones on cortical FC changes in PD using high-density EEG. This study involved 69 early-stage PD patients (F/M 27/42) and 69 age-matched healthy controls (HC) (F/M 30/39). Sex hormone levels (total-testosterone (TT), estradiol (E2), follicle-stimulating hormone (FSH), and luteinizing hormone (LH)) were assessed in PD patients. Data were recorded with a 64-channel EEG system. Source reconstruction method was used to identify brain activity. Cortico-cortical FC was analysed based on the weighted phase-lag index (wPLI) in θ-α-β-low γ bands. Network-based statistic (NBS) was used to compare FC between genders in HC and PD and to study the relationship between FC and sex hormones in PD. PD exhibited a hypoconnected network at θ and α bands and a hyperconnected network at β band compared to HC. Male HC showed a hyperconnected network at α-band compared to female HC. Conversely, males with PD showed a hypoconnected network at α-band compared to females with PD. In females and males with PD, E2 positively correlated with α-FC, while gonadotropins positively correlated with β-FC. TT positively correlated with the θ-FC only in males. Sex hormones shape EEG-FC in both males and females with PD, supporting their major influence on PD pathophysiology.

Abstract Background In gonochoristic animals, the sex determination pathway induces different morphological and behavioral features that can be observed between sexes, a condition known as sexual dimorphism. While many components of this sex differentiation cascade show high levels of diversity, factors such as the Doublesex-Mab-3-Related Transcription factor (DMRT) are widely conserved across animal taxa. Species of the phylum Tardigrada exhibit remarkable diversity in morphology and behavior between sexes, suggesting a pathway regulating this dimorphism. Despite the wealth of genomic and zoological knowledge accumulated in recent studies, the sexual differences in tardigrades genomes have not been identified. In the present study, we focused on the gonochoristic species Paramacrobiotus metropolitanus and employed omics analyses to unravel the molecular basis of sexual dimorphism. Results Transcriptome analysis between sex-identified specimens revealed numerous differentially expressed genes, of which approximately 2,000 male-biased genes were focused on 29 non-male-specific genomic loci. From these regions, we identified two Macrobiotidae family specific DMRT paralogs, which were significantly upregulated in males and lacked sex specific splicing variants. Furthermore, phylogenetic analysis indicated all tardigrade genomes lack the doublesex ortholog, suggesting doublesex emerged after the divergence of Tardigrada. In contrast to sex-specific expression, no evidence of genomic differences between the sexes was found. We also identified several anhydrobiosis genes that exhibit sex-biased expression, suggesting a possible mechanism for protection of sex-specific tissues against extreme stress. Conclusions This study provides a comprehensive analysis for analyzing the genetic differences between sexes in tardigrades. The existence of male-biased, but not male-specific, genomic loci and identification of the family specific male-biased DMRT subfamily provides the foundation for understanding the sex determination cascade. In addition, sex-biased expression of several tardigrade-specific genes which are involved their stress tolerance suggests a potential role in protecting sex-specific tissue and gametes.

Abstract Background Ankylosing spondylitis (AS) with radiographic damage is more prevalent in men than in women. IL-17, which is mainly secreted from peripheral blood mononuclear cells (PBMCs), plays an important role in the development of AS. Its expression is different between male and female. However, it is still unclear whether sex dimorphism of IL-17 contribute to sex differences in AS. Methods GSE221786, GSE73754, GSE25101, GSE181364 and GSE205812 datasets were collected from the Gene Expression Omnibus (GEO) database. Differential expressed genes (DEGs) were analyzed with the Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) methods. CIBERSORTx and EcoTyper algorithms were used for immune infiltration analyses. Machine learning based on the XGBoost algorithm model was used to identify the impact of DEGs. The Connectivity Map (CMAP) database was used as a drug discovery tool for exploring potential drugs based on the DEGs. Results According to immune infiltration analyses, T cells accounted for the largest proportion of IL-17-secreting PBMCs, and KEGG analyses suggested an enhanced activation of mast cells among male AS patients, whereas the expression of TNF was higher in female AS patients. Other signaling pathways, including those involving metastasis-associated 1 family member 3 (MAT3) or proteasome, were found to be more activated in male AS patients. Regarding metabolic patterns, oxidative phosphorylation pathways and lipid oxidation were significantly upregulated in male AS patients. In XGBoost algorithm model, DEGs including METRN and TMC4 played important roles in the disease process. we integrated the CMAP database for systematic analyses of polypharmacology and drug repurposing, which indicated that atorvastatin, famciclocir, ATN-161 and taselisib may be applicable to the treatment of AS. Conclusions We analyzed the sex dimorphism of IL-17-secreting PBMCs in AS. The results showed that mast cell activation was stronger in males, while the expression of TNF was higher in females. In addition, through machine learning and the CMAP database, we found that genes such as METRN and TMC4 may promote the development of AS, and drugs such as atorvastatin potentially could be used for AS treatment.

Morphological analysis of the frontal sinuses (FS) is one of the methods used to assess the sex of human remains. Depending on the methods, the results indicate the effectiveness of using the FS in the assessment of sex at the level of 60–85.9%. Our goal was to determine whether the morphological and morphometric methods of sex assessment based on the FS can be used for examining historical populations in anthropological studies. We assessed FS both morphologically and morphometrically on a sample of 76 dry skulls (41 females and 35 males) from 17th–18th century form Poland to evaluate the potential of applying this method for sex estimation in human remains. A total of 76 X–rays were taken in both frontal and lateral views. The morphology and morphometry of the FS were assessed with ImageJ software. There were no significant differences between the sexes in assessing the outline of the upper border of the FS, as well as the number of partial septa. There was a statistically significant difference between the sexes in the width of the right FS, the height of the right and left FS, and the right and left area of the FS. The lateral view indicated a statistically significant difference between the sexes regarding the depth and area of the FS. The accuracy rate in classifying males and females using FS morphometry ranged from 59.09% to 69.57%. The FS in the lateral view (69.57%) and the height of the left FS in the frontal view (68.18%) are the most appropriate regressors for sex determination. Statistically significant differences in some FS measurements between the sexes do not appear to be a sufficient indicator of sex. Morphological and morphometrical characteristics of the FS should not be used as a guideline for sex assessment in the historical Polish population.

Abstract Background Differences in immune responses between women and men are leading to a strong sex bias in the incidence of autoimmune diseases that predominantly affect women, such as multiple sclerosis (MS). MS manifests in more than twice as many women, making sex one of the most important risk factor. However, it is incompletely understood which genes contribute to sex differences in autoimmune incidence. To address that, we conducted a gene expression analysis in female and male human spleen and identified the transmembrane protein CD99 as one of the most significantly differentially expressed genes with marked increase in men. CD99 has been reported to participate in immune cell transmigration and T cell regulation, but sex-specific implications have not been comprehensively investigated. Methods In this study, we conducted a gene expression analysis in female and male human spleen using the Genotype-Tissue Expression (GTEx) project dataset to identify differentially expressed genes between women and men. After successful validation on protein level of human immune cell subsets, we assessed hormonal regulation of CD99 as well as its implication on T cell regulation in primary human T cells and Jurkat T cells. In addition, we performed in vivo assays in wildtype mice and in Cd99-deficient mice to further analyze functional consequences of differential CD99 expression. Results Here, we found higher CD99 gene expression in male human spleens compared to females and confirmed this expression difference on protein level on the surface of T cells and pDCs. Androgens are likely dispensable as the cause shown by in vitro assays and ex vivo analysis of trans men samples. In cerebrospinal fluid, CD99 was higher on T cells compared to blood. Of note, male MS patients had lower CD99 levels on CD4+ T cells in the CSF, unlike controls. By contrast, both sexes had similar CD99 expression in mice and Cd99-deficient mice showed equal susceptibility to experimental autoimmune encephalomyelitis compared to wildtypes. Functionally, CD99 increased upon human T cell activation and inhibited T cell proliferation after blockade. Accordingly, CD99-deficient Jurkat T cells showed decreased cell proliferation and cluster formation, rescued by CD99 reintroduction. Conclusions Our results demonstrate that CD99 is sex-specifically regulated in healthy individuals and MS patients and that it is involved in T cell costimulation in humans but not in mice. CD99 could potentially contribute to MS incidence and susceptibility in a sex-specific manner.

Background: Ankylosing spondylitis (AS) with radiographic damage is more prevalent in men than in women. IL-17, which is mainly secreted from peripheral blood mononuclear cells (PBMCs), plays an important role in the development of AS. Its expression is different between male and female. However, it is still unclear whether sex dimorphism of IL-17 contribute to sex differences in AS. Methods: GSE221786, GSE73754, GSE25101, GSE181364 and GSE205812 datasets were collected from the Gene Expression Omnibus (GEO) database. Differential expressed genes (DEGs) were analyzed with the Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) methods. CIBERSORTx and EcoTyper algorithms were used for immune infiltration analyses. Machine learning based on the XGBoost algorithm model was used to identify the impact of DEGs. The Connectivity Map (CMAP) database was used as a drug discovery tool for exploring potential drugs based on the DEGs. Results: According to immune infiltration analyses, T cells accounted for the largest proportion of IL-17-secreting PBMCs, and KEGG analyses suggested an enhanced activation of mast cells among male AS patients, whereas the expression of TNF was higher in female AS patients. Other signaling pathways, including those involving metastasis-associated 1 family member 3 (MAT3) or proteasome, were found to be more activated in male AS patients. Regarding metabolic patterns, oxidative phosphorylation pathways and lipid oxidation were significantly upregulated in male AS patients. In XGBoost algorithm model, DEGs including METRN and TMC4 played important roles in the disease process. we integrated the CMAP database for systematic analyses of polypharmacology and drug repurposing, which indicated that atorvastatin, famciclocir, ATN-161 and taselisib may be applicable to the treatment of AS. Conclusions: We analyzed the sex dimorphism of IL-17-secreting PBMCs in AS. The results showed that mast cell activation was stronger in males, while the expression of TNF was higher in females. In addition, through machine learning and the CMAP database, we found that genes such as METRN and TMC4 may promote the development of AS, and drugs such as atorvastatin potentially could be used for AS treatment. [ABSTRACT FROM AUTHOR]

Background: In gonochoristic animals, the sex determination pathway induces different morphological and behavioral features that can be observed between sexes, a condition known as sexual dimorphism. While many components of this sex differentiation cascade show high levels of diversity, factors such as the Doublesex-Mab-3-Related Transcription factor (DMRT) are widely conserved across animal taxa. Species of the phylum Tardigrada exhibit remarkable diversity in morphology and behavior between sexes, suggesting a pathway regulating this dimorphism. Despite the wealth of genomic and zoological knowledge accumulated in recent studies, the sexual differences in tardigrades genomes have not been identified. In the present study, we focused on the gonochoristic species Paramacrobiotus metropolitanus and employed omics analyses to unravel the molecular basis of sexual dimorphism. Results: Transcriptome analysis between sex-identified specimens revealed numerous differentially expressed genes, of which approximately 2,000 male-biased genes were focused on 29 non-male-specific genomic loci. From these regions, we identified two Macrobiotidae family specific DMRT paralogs, which were significantly upregulated in males and lacked sex specific splicing variants. Furthermore, phylogenetic analysis indicated all tardigrade genomes lack the doublesex ortholog, suggesting doublesex emerged after the divergence of Tardigrada. In contrast to sex-specific expression, no evidence of genomic differences between the sexes was found. We also identified several anhydrobiosis genes that exhibit sex-biased expression, suggesting a possible mechanism for protection of sex-specific tissues against extreme stress. Conclusions: This study provides a comprehensive analysis for analyzing the genetic differences between sexes in tardigrades. The existence of male-biased, but not male-specific, genomic loci and identification of the family specific male-biased DMRT subfamily provides the foundation for understanding the sex determination cascade. In addition, sex-biased expression of several tardigrade-specific genes which are involved their stress tolerance suggests a potential role in protecting sex-specific tissue and gametes. [ABSTRACT FROM AUTHOR]

Immunosenescence is the age-related changes in the immune system, namely, progressively higher levels of circulating inflammatory markers, characteristics changes of circulating immune subset cells and altered immune function. The neutrophil to lymphocyte ratio (NL ratio) has been identified as a prognostic indicator for neoplastic disease progression, in predicting chronic degenerative diseases, and as a potential indirect marker of healthy aging. This study aims to examine the longitudinal association of neutrophil, lymphocyte absolute count, and their ratio with longitudinal risk for multimorbidity and mortality. The Baltimore Longitudinal Study of Aging (BLSA) is an open observational cohort study of community-dwelling volunteers that are followed every 1–4 years depending on their age. The sample considered in the study consists of 1769 participants (5090 follow-ups) with completed data for physical examination, health history assessment, and donated a blood sample. The NL ratio increased with age and was associated with a higher risk of mortality, while a lower NL ratio was inversely correlated with multimorbidity. Neutrophils increased with aging and an increase in their absolute number predicted mortality risk. However, the absolute number of lymphocytes was associated with age only in a cross-sectional analysis. In conclusion, this study supports the importance of the NL ratio and absolute neutrophil count as markers of aging health status, and as significant predictors of all-cause mortality and multimorbidity in aging individuals. It remains to be demonstrated whether interventions contrasting these trends in circulating cells may result in improved health outcomes. [ABSTRACT FROM AUTHOR]

Arginine vasopressin (AVP) neurons of the hypothalamic paraventricular region (AVPPVN) mediate sex-biased social behaviors across most species, including mammals. In mice, neural sex differences are thought to be established during a critical window around birth (embryonic (E) day 18 to postnatal (P) day 2) whereby circulating testosterone from the fetal testis is converted to estrogen in sex-dimorphic brain regions. Here, we found that AVPPVN neurons are sexually dimorphic by E15.5, prior to this critical window, and that gestational bisphenol A (BPA) exposure permanently masculinized female AVPPVN neuronal numbers, projections, and electrophysiological properties, causing them to display male-like phenotypes into adulthood. Moreover, we showed that nearly twice as many neurons that became AVP+ by P0 were born at E11 in males and BPA-exposed females compared to control females, suggesting that AVPPVN neuronal masculinization occurs between E11 and P0. We further narrowed this sensitive period to around the timing of neurogenesis by demonstrating that exogenous estrogen exposure from E14.5 to E15.5 masculinized female AVPPVN neuronal numbers, whereas a pan-estrogen receptor antagonist exposed from E13.5 to E15.5 blocked masculinization of males. Finally, we showed that restricting BPA exposure to E7.5-E15.5 caused adult females to display increased social dominance over control females, consistent with an acquisition of male-like behaviors. Our study reveals an E11.5 to E15.5 window of estrogen sensitivity impacting AVPPVN sex differentiation, which is impacted by prenatal BPA exposure. [ABSTRACT FROM AUTHOR]

Background: Differences in immune responses between women and men are leading to a strong sex bias in the incidence of autoimmune diseases that predominantly affect women, such as multiple sclerosis (MS). MS manifests in more than twice as many women, making sex one of the most important risk factor. However, it is incompletely understood which genes contribute to sex differences in autoimmune incidence. To address that, we conducted a gene expression analysis in female and male human spleen and identified the transmembrane protein CD99 as one of the most significantly differentially expressed genes with marked increase in men. CD99 has been reported to participate in immune cell transmigration and T cell regulation, but sex-specific implications have not been comprehensively investigated. Methods: In this study, we conducted a gene expression analysis in female and male human spleen using the Genotype-Tissue Expression (GTEx) project dataset to identify differentially expressed genes between women and men. After successful validation on protein level of human immune cell subsets, we assessed hormonal regulation of CD99 as well as its implication on T cell regulation in primary human T cells and Jurkat T cells. In addition, we performed in vivo assays in wildtype mice and in Cd99-deficient mice to further analyze functional consequences of differential CD99 expression. Results: Here, we found higher CD99 gene expression in male human spleens compared to females and confirmed this expression difference on protein level on the surface of T cells and pDCs. Androgens are likely dispensable as the cause shown by in vitro assays and ex vivo analysis of trans men samples. In cerebrospinal fluid, CD99 was higher on T cells compared to blood. Of note, male MS patients had lower CD99 levels on CD4+ T cells in the CSF, unlike controls. By contrast, both sexes had similar CD99 expression in mice and Cd99-deficient mice showed equal susceptibility to experimental autoimmune encephalomyelitis compared to wildtypes. Functionally, CD99 increased upon human T cell activation and inhibited T cell proliferation after blockade. Accordingly, CD99-deficient Jurkat T cells showed decreased cell proliferation and cluster formation, rescued by CD99 reintroduction. Conclusions: Our results demonstrate that CD99 is sex-specifically regulated in healthy individuals and MS patients and that it is involved in T cell costimulation in humans but not in mice. CD99 could potentially contribute to MS incidence and susceptibility in a sex-specific manner. Plain Language Summary: The immune system protects us from bacterial and viral infections and impacts the outcome of many diseases. Thus, understanding immunological processes is crucial to unravel pathogenic mechanisms and to develop new therapeutic treatment options. Sex is a biological variable affecting immunity and it is known that females and males differ in their immunological responses. Women mount stronger immune responses leading to more rapid control of infections and greater vaccine efficacy compared to men. However, this enhanced immune responsiveness is accompanied by female preponderance and susceptibility to autoimmune diseases like systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis (MS). MS sex ratio varies around 2:1 to 3:1 with a steadily increasing incidence in female MS patients making sex one of the top risk factors for developing MS. However, the underlying biological mechanisms including sex hormones as well as genetic and epigenetic factors and their complex interplay remain largely unknown. Here, we discovered the gene and its encoded protein CD99 to be differentially expressed between women and men with men showing increased expression on many immune cell subsets including T cells. Since T cells are key contributors to MS pathogenesis, we examined the role of CD99 on T cells of healthy individuals and MS patients. We were able to identify CD99-mediated T cell regulation, which might contribute to sex differences in MS susceptibility and incidence indicating the importance to include sex as a biological variable. Of note, these differences were not reproduced in mice showing the necessity of functional research in humans. Highlights: Profiling of differential gene expression between sexes in the human immune system to delineate differential regulations that might impact immune responses. CD99 is genetically but not hormonally regulated on transcript and surface protein level with higher expression in men in healthy individuals as well as MS patients. Confirmation of CD99 as a critical co-stimulatory molecule on T cells, thus having an impact on T cell activation, proliferation and cluster formation. CD99 expression is elevated on T cells in the CSF compared to the blood. In male MS patients CD99 expression on CD4+ T cells from the CSF was lower in comparison to healthy men. Species difference in CD99 expression and its functional role with lack of differential CD99 expression in male and female mice as well as Cd99 deficiency not altering experimental autoimmune encephalomyelitis. [ABSTRACT FROM AUTHOR]

Converging evidence from clinical and experimental studies suggest the potential significance of Polo-like kinase 2 (PLK2) in regulating the phosphorylation and toxicity of the Alzheimer's disease (AD)-related protein, amyloid precursor protein (APP). These findings have prompted various experimental trials aimed at inhibiting PLK2 kinase activity in different transgenic mouse models of AD. While positive impacts on cognitive decline were reported in these studies, the cellular effects remained controversial. In the present study, we sought to assess the cognitive and cellular consequences of chronic PLK2 inhibitor treatment in the APP/PS1 transgenic mouse model of AD. First, we confirmed that inhibiting PLK2 prevented cognitive decline in a sex-dependent manner, particularly by enhancing working memory in male APP/PS1 mice. Surprisingly, cellular analysis revealed that treatment with PLK2 inhibitor increased the load of amyloid plaques and elevated levels of soluble amyloid β (Aβ) 40 and Aβ42 in the cortex, as well as insoluble Aβ42 in the hippocampus of female mice, without affecting APP pathology in males. These results underscore the potential of PLK2 inhibition to mitigate cognitive symptoms in males. However, paradoxically, it intensifies amyloid pathology in females by enhancing APP amyloidogenic processing, creating a controversial aspect to its therapeutic impact. Overall, these data highlight the sex-dependent nature of the effects of PLK2 inhibition, which may also be influenced by the genetic background of the transgenic mouse model utilized.

Abstract Introduction Esthetics plays a crucial role in orthodontics and many other dental and medical fields. To date, no study has assessed the combined effects of the 3 facial features ‘facial height, gingival display (GD), and buccal corridor size (BC)’ on facial/smile beauty. Therefore, this study was conducted for the first time. Methods In this psychometric diagnostic study, beauty of 27 randomized perceptometric images of a female model with variations in facial heights (short, normal, long), gingival displays (0, 2, 4, 6 mm), and buccal corridor sizes (2%, 10%, 15%, 20%, 25%) were evaluated by 108 judges (36 orthodontists, 36 dentists, 36 laypeople) using a 5-scale Likert scale (1 to 5). Combined effects of facial heights, GDs, BCs, judges’ sexes, ages, and jobs, and their 2-way interactions were tested using a mixed-model multiple linear regression and a Bonferroni test. Zones of ideal features were determined for all judges and also for each group using repeated-measures ANOVAs and the Bonferroni test (α=0.05). Results Judges’ sex but not their age or expertise might affect their perception of female beauty: men gave higher scores. The normal face was perceived as more beautiful than the long face (the short face being the least attractive). Zero GD was the most attractive followed by 4 mm; 6 mm was the least appealing. BCs of 15% followed by 10% were the most attractive ones, while 25% BC was the worst. The zone of ideal anatomy was: long face + 0mm GD + 15% BC; normal face + 2mm GD + 15% BC; long face + 2mm GD + 15% BC; normal face + 0mm GD + 15% BC. Conclusions Normal faces, zero GDs, and 15% BCs may be the most appealing. Facial heights affect the perception of beauty towards GDs but not BCs.

Morphological analysis of the frontal sinuses (FS) is one of the methods used to assess the sex of human remains. Depending on the methods, the results indicate the effectiveness of using the FS in the assessment of sex at the level of 60-85.9%. Our goal was to determine whether the morphological and morphometric methods of sex assessment based on the FS can be used for examining historical populations in anthropological studies. We assessed FS both morphologically and morphometrically on a sample of 76 dry skulls (41 females and 35 males) from 17th-18th century form Poland to evaluate the potential of applying this method for sex estimation in human remains. A total of 76 X-rays were taken in both frontal and lateral views. The morphology and morphometry of the FS were assessed with ImageJ software. There were no significant differences between the sexes in assessing the outline of the upper border of the FS, as well as the number of partial septa. There was a statistically significant difference between the sexes in the width of the right FS, the height of the right and left FS, and the right and left area of the FS. The lateral view indicated a statistically significant difference between the sexes regarding the depth and area of the FS. The accuracy rate in classifying males and females using FS morphometry ranged from 59.09% to 69.57%. The FS in the lateral view (69.57%) and the height of the left FS in the frontal view (68.18%) are the most appropriate regressors for sex determination. Statistically significant differences in some FS measurements between the sexes do not appear to be a sufficient indicator of sex. Morphological and morphometrical characteristics of the FS should not be used as a guideline for sex assessment in the historical Polish population. [ABSTRACT FROM AUTHOR]

Introduction: Esthetics plays a crucial role in orthodontics and many other dental and medical fields. To date, no study has assessed the combined effects of the 3 facial features 'facial height, gingival display (GD), and buccal corridor size (BC)' on facial/smile beauty. Therefore, this study was conducted for the first time. Methods: In this psychometric diagnostic study, beauty of 27 randomized perceptometric images of a female model with variations in facial heights (short, normal, long), gingival displays (0, 2, 4, 6 mm), and buccal corridor sizes (2%, 10%, 15%, 20%, 25%) were evaluated by 108 judges (36 orthodontists, 36 dentists, 36 laypeople) using a 5-scale Likert scale (1 to 5). Combined effects of facial heights, GDs, BCs, judges' sexes, ages, and jobs, and their 2-way interactions were tested using a mixed-model multiple linear regression and a Bonferroni test. Zones of ideal features were determined for all judges and also for each group using repeated-measures ANOVAs and the Bonferroni test (α=0.05). Results: Judges' sex but not their age or expertise might affect their perception of female beauty: men gave higher scores. The normal face was perceived as more beautiful than the long face (the short face being the least attractive). Zero GD was the most attractive followed by 4 mm; 6 mm was the least appealing. BCs of 15% followed by 10% were the most attractive ones, while 25% BC was the worst. The zone of ideal anatomy was: long face + 0mm GD + 15% BC; normal face + 2mm GD + 15% BC; long face + 2mm GD + 15% BC; normal face + 0mm GD + 15% BC. Conclusions: Normal faces, zero GDs, and 15% BCs may be the most appealing. Facial heights affect the perception of beauty towards GDs but not BCs. [ABSTRACT FROM AUTHOR]

Physiology underlying reduced cardiac pumping capacity in women compared with men and its interaction with aging remains unresolved. Herein, the pressure gradient (PG) driving venous return was manipulated to evidence whether cardiac structure and/or function explain sex differences in cardiac capacity. Healthy women/men matched by age and physical activity were included within young (n  = 40, age = 25 ± 4 years) and older (n  = 55, age = 60 ± 8 years) groups. Cardiac volumes/output (Q) were assessed up-to-peak exercise under 2 hemodynamic conditions ("low"/"high" PG between lower/upper body). Main outcomes included sex differences in delta ("high" − "low" PG) left ventricular (LV) end-diastolic volume (∆LVEDV), stroke volume (∆SV), and Q (∆Q). In young individuals, "high"-PG increased exercise LVEDV and SV in men (p  ≤ .002), but not in women (p  ≥ .562), relative to "low"-PG (control condition). Accordingly, peak ∆LVEDV, ∆SV, and ∆Q were enhanced in young men versus young women (p  ≤ .019). Notwithstanding, right/left atrial volumes during exercise were similarly increased by "high"-PG in both young sexes (p  ≤ .007). "High"-PG exclusively prolonged moderate exercise LV filling time in young men (p  ≤ .036). In older individuals, "high"-PG did not modify exercise cardiac volumes and reduced LV diastolic function (p  ≤ .049). In conclusion, the female young heart is unrestrained by venous return or structural factors external to the myocardium. As determined during moderate exercise, impaired LV filling time lengthening limits female-specific cardiac capacity. With older age, cardiac chambers are not distended and LV relaxation is impaired with increased PG in both sexes. During early but not late adulthood, a functional LV limitation may explain sex differences in cardiac capacity. [ABSTRACT FROM AUTHOR]

Heterotopic ossification (HO) is most dramatically manifested in the rare and severely debilitating disease, fibrodysplasia ossificans progressiva (FOP), in which heterotopic bone progressively accumulates in skeletal muscles and associated soft tissues. The great majority of FOP cases are caused by a single amino acid substitution in the type 1 bone morphogenetic protein (BMP) receptor ACVR1, a mutation that imparts responsiveness to activin A. Although it is well-established that biological sex is a critical variable in a range of physiological and disease processes, the impact of sex on HO in animal models of FOP has not been explored. We show that female FOP mice exhibit both significantly greater and more variable HO responses after muscle injury. Additionally, the incidence of spontaneous HO was significantly greater in female mice. This sex dimorphism is not dependent on gonadally derived sex hormones, and reciprocal cell transplantations indicate that apparent differences in osteogenic activity are intrinsic to the sex of the transplanted cells. By circumventing the absolute requirement for activin A using an agonist of mutant ACVR1, we show that the female-specific response to muscle injury or BMP2 implantation is dependent on activin A. These data identify sex as a critical variable in basic and pre-clinical studies of FOP. [ABSTRACT FROM AUTHOR]

Adaptive response to physiological oxygen levels (physO2; 5% O2) enables embryonic survival in a low-oxygen developmental environment. However, the mechanism underlying the role of physO2 in supporting preimplantation development, remains elusive. Here, we systematically studied oxygen responses of hallmark events in preimplantation development. Focusing on impeded transcriptional upregulation under atmospheric oxygen levels (atmosO2; 20% O2) during the 2-cell stage, we functionally identified a novel role of HIF-1α in promoting major zygotic genome activation by serving as an oxygen-sensitive transcription factor. Moreover, during blastocyst formation, atmosO2 impeded H3K4me3 and H3K27me3 deposition by deregulating histone-lysine methyltransferases, thus impairing X-chromosome inactivation in blastocysts. In addition, we found atmosO2 impedes metabolic shift to glycolysis before blastocyst formation, thus resulting a low-level histone lactylation deposition. Notably, we also reported an increased sex-dimorphic oxygen response of embryos upon preimplantation development. Together, focusing on genetic and epigenetic events that are essential for embryonic survival and development, the present study advances current knowledge of embryonic adaptive responses to physO2, and provides novel insight into mechanism underlying irreversibly impaired developmental potential due to a short-term atmosO2 exposure.

Astrocytes have been implicated in stress responses and produce ciliary neurotrophic factor (CNTF), which we have shown in the mouse medial amygdala (MeA) to promote passive stress coping response only in females. Pharmacological inhibition of focal adhesion kinase (FAK) upregulates CNTF expression. Here, we found that inducible knockout of FAK in astrocytes or systemic treatment with an FAK inhibitor increased passive coping behavior, i.e., immobility, in an acute forced swim stress test in female, but not male, mice. Strikingly, four weeks of chronic unpredictable stress (CUS) did not further increase passive coping in female astrocytic FAK knockout mice, whereas it exacerbated it in female wildtype mice and male mice of both genotypes. These data suggest that astrocyte FAK inhibition is required for chronic stress-induced passive coping in females. Indeed, CUS reduced phospho-FAK and increased CNTF in the female MeA. Progesterone treatment after ovariectomy activated amygdala FAK and alleviated ovariectomy-induced passive coping in wildtype, but not astrocytic FAK knockout females. This suggests that progesterone-mediated activation of FAK in astrocytes reduces female stress responses. Finally, astrocytic FAK knockout or FAK inhibitor treatment increased CNTF expression in the MeA of both sexes, although not in the hippocampus. As mentioned, MeA CNTF promotes stress responses only in females, which may explain the female-specific role of astrocytic FAK inhibition. Together, this study reveals a novel female-specific progesterone-astrocytic FAK pathway that counteracts CNTF-mediated stress responses and points to opportunities for developing treatments for stress-related disorders in women.

Summary: Background: The physiology of prominent prognostic factors in the cardiorespiratory system remains unchartered in the world's largest ethnic group: Hans Chinese (HC). This study assessed and contrasted the fundamental variables in HC and European-American (EA) individuals. Methods: Healthy HC and EA adults (n = 140, 43% ♀) closely matched by age, sex and physical activity were included. Body composition (DXA) and haematological variables (haemoglobin mass, blood volume (BV)) were measured at rest. Pulmonary O2 uptake (VO2) measurements along with cycle ergometry designed for accurate transthoracic echocardiography were implemented to assess cardiorespiratory structure/function up to peak effort. Findings: HC presented with higher body fat and lower lean body mass (LBM) percentage than EA irrespective of sex (P ≤ 0.014). BV did not differ whereas blood haemoglobin concentration was lower in HC compared with EA, particularly in females (P = 0.009). Myocardial diastolic and overall function at rest was enhanced in HC versus EA (P

Previous studies on the cardiac data of healthy permanent residents living in highaltitude regions such as Tibet and the Andes have yielded inconsistent findings and significant disparities. These discrepancies can be mainly attributed to the invasive methods conventionally used for parameter evaluation. However, with the introduction of cutting-edge ultrasound technology, there is now an innovative approach to addressing and reconciling these variations. In this pilot study, we employed an ultrasound-based cardiac output monitoring (USCOM) device to evaluate cardiac output and related hemodynamic variables in a group of 20 healthy high-altitude Andean residents (comprising 10 men and 10 women) aged between 26 and 35 years old. The monocentric study was carried out in La Paz, Bolivia, located between at an altitude of 3,600-4,000 m. A total of 60 hemodynamic measurements were evaluated, accounting for three technical replicates per subject. Our results showed strong intrasubject reproducibility and revealed important differences related to both sex and hemodynamic parameters in highlanders compared to individuals residing at sea level. We conclude that USCOM represents a highly reliable technology for performing hemodynamic measurements in high-altitude residents. Our preliminary findings underscore the need for larger studies, encompassing larger sample sizes, specifically tailored to gender considerations, and extendable to broader highland populations. These findings have special significant implications for the management of hemodynamics in intensive care and postoperative settings, warranting further comprehensive research efforts. [ABSTRACT FROM AUTHOR]

Background: No sex-specific guidelines for surgical anti-obesity strategies have been proposed, partially due to the controversy regarding sex-related differences in weight loss after bariatric metabolic surgery. Objectives: To explore sex dimorphism in the effect and predictors of weight loss after sleeve gastrectomy (SG), thereby providing clinical evidence for the sex-specific surgical treatment strategy. Methods: In a prospective cohort design, participants scheduled for SG at an affiliated hospital between November 2020 and January 2022 were assessed for eligibility and allocated to the Male or Female group with a 1-year follow-up after surgery. The primary outcome was the sex difference in the weight-loss effect after SG indicated by both percentage of total weight loss (TWL%) and excess weight loss (EWL%). The secondary outcome was the analysis of sex-specific preoperative predictors of weight loss after SG based on univariate and multivariate analyses. Independent predictors were obtained to construct a nomogram model. The discrimination, calibration, and clinical utility of the nomogram were based on receiver operating characteristic curve, concordance index, calibration curve, and decision curve analysis, respectively. Results: Ninety-five male and 226 female patients were initially included. After propensity score matching by baseline body mass index (BMI), 85 male and 143 female patients achieved comparable TWL% and EWL% for 1 year after SG. For male patients, baseline BMI, area under the curve for insulin during oral glucose tolerance test, and progesterone were independent predictors of weight loss after SG. Baseline BMI, age, thyroid stimulating hormone, and Self-Rating Anxiety Scale score were independent predictors for female patients. Conclusion: No obvious sex difference is detected in the weight-loss effect after SG. Sex dimorphism exists in the predictors of weight loss after SG. Further research with long-term and a multicenter design is needed to confirm the predictive model. [ABSTRACT FROM AUTHOR]

Adaptive thermogenesis is a vital physiological process for small endotherms. Female animals usually are more sensitive to cold temperature due to anatomical differences. Whether there is a sex difference at a molecular level is unclear. Stress granules (SGs) are dynamic organelles in which untranslated mRNAs reside during cellular stress. We hypothesize that the prompt response of SGs to cold stress can reveal the molecular difference between sexes. By analyzing the content in SGs of brown adipose tissue (BAT) at the early phase of cold stress for both sexes, we found more diverse mRNAs docked in the SGs in male mice and these mRNAs representing an extensive cellular reprogramming including apoptosis process and cold-induced thermogenesis. In female mice, the mRNAs in SGs dominantly were comprised of genes regulating ribonucleoprotein complex biogenesis. Conversely, the proteome in SGs was commonly characterized as structure molecules and RNA processing for both sexes. A spectrum of eukaryotic initiation factors (eIFs) was detected in the SGs of both female and male BAT, while those remained unchanged upon cold stress in male mice, various eIF3 and eIF4G isoforms were found reduced in female mice. Taken together, the unique features in SGs of male BAT reflected a prompt uncoupling protein-1 (UCP1) induction which was absent in female, and female, by contrast, were prepared for long-term transcriptional and translational adaptations. NEW & NOTEWORTHY: The proteome analysis reveals that stress granules are the predominant form of cytosolic messenger ribonucleoproteins of brown adipose tissue (BAT) at the early phase of cold exposure in mice for both sexes. The transcriptome of stress granules of BAT unveils a sex difference of molecular response in early phase of cold exposure in mice, and such difference prepares for a prompt response to cold stress in male mice while for long-term adaptation in female mice. [ABSTRACT FROM AUTHOR]

Gender-related methodology in biomedical sciences receives considerable attention, with numerous studies highlighting biological differences between cisgender males and females. These differences influence the clinical symptoms of various diseases and impact therapeutic approaches. In this in vitro study, we investigate the potential role of sex-chromosome-related dimorphism on steroidogenic enzymes, androgen receptor (AR) expression, and cellular translocation in primary human skeletal muscle cells before and after exposure to testosterone. We analyzed 46XY and 46XX cells for 17β-hydroxysteroid dehydrogenase (17β-HSD), 5α-reductase (5α-R2), aromatase (Cyp-19), and AR gene expression. We also compared AR expression and intracellular translocation after increasing exposure to testosterone. At baseline, we observed higher mRNA expression for 5α-R2 and AR in 46XY cells and higher Cyp-19 mRNA expression in 46XX cells. Following testosterone exposure, we observed an increase in AR expression and translocation in 46XX cells, even at the lowest dose of 0.5 nM, while significant changes in 46XY cells were observed only from 10 nM. Our in vitro results demonstrate that the diverse sex chromosome assets reflect important differences in muscle steroidogenesis. They support the concept that chromosomal disparities between males and females, even in vitro, lead to pivotal variations in cellular physiology and response. This understanding represents a crucial starting point in gender medicine, ensuring a precise approach in clinical practice, sports, and exercise settings and facilitating the translation of in vitro data to in vivo applicability. [ABSTRACT FROM AUTHOR]

Background: The 3D position of the mental foramen (MF) is of significant clinical value in dental implantology and mandibular surgeries or in local anesthesia. Despite its importance, it is not clearly known how the position of MF can alter in different individuals, since the literature on the associations between the MF position with vertical growth patterns is non-existent and those on links between the MF position and skeletal malocclusions are scarce. Therefore, we aimed to investigate these, for the first time, on cone-beam computed tomographies (CBCTs). Methods: Archival CBCTs of 9 sub-groups (i.e., 3 skeletal Classes I, II, and III × 3 vertical growth patterns 'long face, short face, normal face') were collected by evaluating patients' SNA, SNB, ANB, facial angle, lower facial height, and FMA (n = 9 × 40 = 360). Included cases were older than 17 years and without any history of orthodontic/orthognathic treatments (243 women, 117 men, mean age: 22.28 ± 2.80 years). Perpendicular distances between the MF and 3 fixed bony structures (the mandibular symphysis [S/width], the mandibular ramus [R/length], and the mandibular lower cortex [C/height]) were measured on different sectional planes on both hemimandibles. Left- and right-side measurements were combined. Data were analyzed using the 3-way ANCOVA, Bonferroni, one-way ANOVA, Tamhane, Pearson, and t-test (α = 0.05). Results: Width was the smallest in Class II and greatest in Class III cases (all P values < 0.000001, Bonferroni). It was the shortest in long faces and longest in short faces (all P values ≤ 0.00008). The inferior-superior height was larger in Class III than both Classes I and II (both P values ≤ 0.003); there was no significant difference between Classes I and II in terms of height (P = 0.684). Height was the largest in long faces and smallest in short faces (all P values < 0.000001). The anterior-posterior length was the largest in Class III and smallest in Class II (all P values < 0.000001). Length was larger in short-face people versus normal- or long-face individuals (P ≤ 0.00003); nevertheless, long and normal faces did not differ in terms of length (P = 0.448). Subjects' age was not correlated with their MF positions (P ≥ 0.579, Pearson coefficient). Sex dimorphism existed only for height (P = 0.009, t-test) but not for length or width. Conclusions: The MF position may considerably differ in various horizontal or vertical growth patterns and sexes. This should be noted in mandible surgeries. [ABSTRACT FROM AUTHOR]

Sex-related differences are a current topic in contemporary science. In addition to hormonal regulation, cell-autonomous mechanisms are important in bone homeostasis and regeneration. In this study, human skeletal stem cells (SSCs) from female and male adults were cultured and analyzed with immunological assays and osteogenic differentiation assessments. Female SSCs exhibited a mean doubling time of 100.6 h, whereas male SSCs displayed a mean doubling time of 168.0 h. Immunophenotyping revealed the expression of the stem cell markers Nestin, CD133, and CD164, accompanied by the neural-crest marker SOX9. Furthermore, multiparameter flow cytometric analyses revealed a substantial population of multipotent SSCs, comprising up to 80% in both sexes. An analysis of the osteogenic differentiation potential demonstrated a strong mineralization in both male and female SSCs under physiological conditions. Recognizing the prevailing association of bone diseases with inflammatory processes, we also analyzed the osteogenic potential of SSCs from both sexes under pro-inflammatory conditions. Upon TNF-α and IL-1β treatment, we observed no sexual dimorphism on osteogenesis. In summary, we demonstrated the successful isolation and characterization of SSCs capable of rapid osteogenic differentiation. Taken together, in vitro cultured SSCs might be a suitable model to study sexual dimorphisms and develop drugs for degenerative bone diseases. [ABSTRACT FROM AUTHOR]

Children with attention-deficit/hyperactivity disorder (ADHD) demonstrate reduced response inhibition, increased response time variability, and atypical frontal lobe white matter microstructure with emerging evidence of sex differences. This study aims to examine whether frontal lobe white matter microstructure is differentially impacted in ADHD by sex and whether this relates to Go/No-Go (GNG) task performance. Diffusion tensor imaging (DTI) from 187 children (8–12 years), including ADHD (n = 94) and typically developing controls (TD; n = 93). Participants completed three GNG tasks with varying cognitive demands and incentives (standard, cognitive, and motivational). Fractional anisotropy (FA) was examined as an index of white matter microstructure within bilateral frontal lobe regions of interest. Children with ADHD showed reduced FA in primary motor (M1) and supplementary motor area (SMA) regardless of sex. Sex-based dissociation for the effect of diagnosis was observed in medial orbitofrontal cortex (mOFC), with higher FA in girls with ADHD and lower FA in boys with ADHD. Both diagnosis and sex contributed to performance on measures of response inhibition and reaction time (RT) variability, with all children with ADHD demonstrating poorer performance on all GNG tasks, but boys with ADHD demonstrating more impulsivity on standard and motivational behavioral paradigms compared to girls with ADHD. Analyses revealed associations between reduced FA in M1, SMA, and mOFC and increased response inhibition and RT variability with some sex-based differences. These findings provide novel insights regarding the brain basis of ADHD and associated impairments in response inhibition and RT variability, and contribute to our understanding of sexual dimorphic behavioral outcomes. [ABSTRACT FROM AUTHOR]

The interest of the scientific community on sex and gender differences in health and disease has increased substantially over the past 25 to 30 y as a result of a long process of events and policies in the biomedical field. This is crucial as compelling evidence from human and animal model studies has demonstrated that sex and gender influence health, molecular and cellular processes, and response and predisposition to disease. The present scoping review aims to provide a synthesis of sex differences in oral diseases, ranging from periodontal disease to orofacial pain conditions, from risk of caries development to apical periodontitis. Overall, findings from this review further support a role for sexual dimorphism influencing disease predisposition and/or progression in oral diseases. Of note, this review also highlights the lack of consideration of additional factors such as gender and other psychosocial and external factors potentially influencing oral health and disease. New conceptual frameworks capable of capturing multiple fundamental domains and measurements should be developed in clinical and preclinical studies to inform sex-based individualized preventive and treatment strategies. [ABSTRACT FROM AUTHOR]

Liver fibrosis is a common and reversible feature of liver damage associated with many chronic liver diseases, and its onset is influenced by sex. In this study, we investigated the mechanisms of liver fibrosis and regeneration, focusing on understanding the mechanistic gaps between females and males. We injected increasing doses of carbon tetrachloride into female and male mice and maintained them for a washout period of eight weeks to allow for liver regeneration. We found that male mice were more prone to developing severe liver fibrosis as a consequence of early chronic liver damage, supported by the recruitment of a large number of Ly6Chigh MoMφs and neutrophils. Although prolonged liver damage exacerbated the fibrosis in mice of both sexes, activated HSCs and Ly6Chigh MoMφs were more numerous and active in the livers of female mice than those of male mice. After eight weeks of washout, only fibrotic females reported no activated HSCs, and a phenotype switching of Ly6Chigh MoMφs to anti-fibrogenic Ly6Clow MoMφs. The early stages of liver fibrosis mostly affected males rather than females, while long-term chronic liver damage was not influenced by sex, at least for liver fibrosis. Liver repair and regeneration were more efficient in females than in males. [ABSTRACT FROM AUTHOR]

Objective: This study was conducted to investigate the performance difference for current World (Junior and Senior) and Paralympic (Senior) record holders according to origin of impairment (acquired or congenital), level of competition, and sex and to describe the performance progression of Paralympic Powerlifting records holders. Design: This retrospective cohort study involving 60 current world (20 Junior and 20 Senior) and Paralympic (20 Senior) Para powerlifting record holders with 15 males congenital impairment and 14 acquired impairment, while 18 females were acquired impairment and 9 congenital impairments. Results: The origin of impairment did not influence the absolute and relative load of male and female recordists. However, for males, acquired athletes were older and heavier when compared with congenital athletes, but without differences for females. The absolute load of Junior World recordists was lower in relation to Senior World and Paralympic recordists independently of the sex. Congenital athletes more often reached the world record in the Junior category, while the acquired athletes were the ones who obtained most of the records in senior categories. Conclusions: Our results show that origin of impairment did not influence the absolute and relative load of current World (Junior and Senior) and Paralympic (Senior) recordists. [ABSTRACT FROM AUTHOR]

The objective of this study was to determine whether there is an association between sex and outcome in trauma patients presented with severe traumatic brain injury (TBI). A retrospective multicenter study was performed in trauma patients aged ≥ 16 years who presented with severe TBI (Head Abbreviated Injury Scale (AIS) ≥ 4) over a 4-year-period. Subgroup analyses were performed for ages 16–44 and ≥45 years. Also, patients with isolated severe TBI (other AIS ≤ 2) were assessed, likewise, with subgroup analysis for age. Sex differences in mortality, Glasgow Outcome Score (GOS), ICU admission/length of stay (LOS), hospital LOS, and mechanical ventilation (MV) were examined. A total of 1566 severe TBI patients were included (831 patients with isolated TBI). Crude analysis shows an association between female sex and lower ICU admission rates, shorter ICU/hospital LOS, and less frequent and shorter MV in severe TBI patients ≥ 45 years. After adjusting, female sex appears to be associated with shorter ICU/hospital LOS. Sex differences in mortality and GOS were not found. In conclusion, this study found sex differences in patient outcomes following severe TBI, potentially favoring (older) females, which appear to indicate shorter ICU/hospital LOS (adjusted analysis). Large prospective studies are warranted to help unravel sex differences in outcomes after severe TBI. [ABSTRACT FROM AUTHOR]

This study determined changes in lower limb joint stiffness when running with body-borne load, and whether they differ with stride or sex. Twenty males and 16 females had joint stiffness quantified when running (4.0 m/s) with body-borne load (20, 25, 30, and 35 kg) and 3 stride lengths (preferred or 15% longer and shorter). Lower limb joint stiffness, flexion range of motion (RoM), and peak flexion moment were submitted to a mixed-model analysis of variance. Knee and ankle stiffness increased 19% and 6% with load (P <.001, P =.049), but decreased 8% and 6% as stride lengthened (P =.004, P <.001). Decreased knee RoM (P <.001, 0.9°–2.7°) and increased knee (P =.007, up to 0.12 N.m/kg.m) and ankle (P =.013, up to 0.03 N.m/kg.m) flexion moment may stiffen joints with load. Greater knee (P <.001, 4.7°–5.4°) and ankle (P <.001, 2.6°–7.2°) flexion RoM may increase joint compliance with longer strides. Females exhibited 15% stiffer knee (P =.025) from larger reductions in knee RoM (4.3°–5.4°) with load than males (P <.004). Stiffer lower limb joints may elevate injury risk while running with load, especially for females. [ABSTRACT FROM AUTHOR]

AbstractIntradermal administration of low-molecular-weight hyaluronan (LMWH) in the hind paw induced dose-dependent (0.1, 1, or 10 µg) mechanical hyperalgesia of similar magnitude in male and female rats. However, the duration of LMWH hyperalgesia was greater in females. This sexual dimorphism was eliminated by bilateral ovariectomy and by intrathecal administration of an oligodeoxynucleotide (ODN) antisense to the G-protein-coupled estrogen receptor (GPR30) mRNA in females, indicating estrogen dependence. To assess the receptors at which LMWH acts to induce hyperalgesia, LMWH was administered to groups of male and female rats that had been pretreated with ODN antisense (or mismatch) to the mRNA for 1 of 3 hyaluronan receptors, cluster of differentiation 44 (CD44), toll-like receptor 4, or receptor for hyaluronan-mediated motility (RHAMM). Although LMWH-induced hyperalgesia was attenuated in both male and female rats pretreated with ODN antisense for CD44 and toll-like receptor 4 mRNA, RHAMM antisense pretreatment only attenuated LMWH-induced hyperalgesia in males. Oligodeoxynucleotide antisense for RHAMM, however, attenuated LMWH-induced hyperalgesia in female rats treated with ODN antisense to GPR30, as well as in ovariectomized females. Low-molecular-weight hyaluronan-induced hyperalgesia was significantly attenuated by pretreatment with high-molecular-weight hyaluronan (HMWH) in male, but not in female rats. After gonadectomy or treatment with ODN antisense to GPR30 expression in females, HMWH produced similar attenuation of LMWH-induced hyperalgesia to that seen in males. These experiments identify nociceptors at which LMWH acts to produce mechanical hyperalgesia, establishes estrogen dependence in the role of RHAMM in female rats, and establishes estrogen dependence in the inhibition of LMWH-induced hyperalgesia by HMWH.

AbstractAlthough clinical studies support the suggestion that stress is a risk factor for painful chemotherapy-induced peripheral neuropathy (CIPN), there is little scientific validation to support this link. Here, we evaluated the impact of stress on CIPN induced by oxaliplatin, and its underlying mechanisms, in male and female rats. A single dose of oxaliplatin produced mechanical hyperalgesia of similar magnitude in both sexes, still present at similar magnitude in both sexes, on day 28. Adrenalectomy mitigated oxaliplatin-induced hyperalgesia, in both sexes. To confirm the role of neuroendocrine stress axes in CIPN, intrathecal administration of antisense oligodeoxynucleotide targeting β₂-adrenergic receptor mRNA both prevented and reversed oxaliplatin-induced hyperalgesia, only in males. By contrast, glucocorticoid receptor antisense oligodeoxynucleotide prevented and reversed oxaliplatin-induced hyperalgesia in both sexes. Unpredictable sound stress enhanced CIPN, in both sexes. The administration of stress hormones, epinephrine, corticosterone, and their combination, at stress levels, mimicked the effects of sound stress on CIPN, in males. In females, only corticosterone mimicked the effect of sound stress. Also, a risk factor for CIPN, early-life stress, was evaluated by producing both stress-sensitive (produced by neonatal limited bedding) and stress-resilient (produced by neonatal handling) phenotypes in adults. Although neonatal limited bedding significantly enhanced CIPN only in female adults, neonatal handling significantly attenuated CIPN, in both sexes. Our study demonstrates a sexually dimorphic role of the 2 major neuroendocrine stress axes in oxaliplatin-induced neuropathic pain.

Previous studies on the cardiac data of healthy permanent residents living in high-altitude regions such as Tibet and the Andes have yielded inconsistent findings and significant disparities. These discrepancies can be mainly attributed to the invasive methods conventionally used for parameter evaluation. However, with the introduction of cutting-edge ultrasound technology, there is now an innovative approach to addressing and reconciling these variations. In this pilot study, we employed an ultrasound-based cardiac output monitoring (USCOM) device to evaluate cardiac output and related hemodynamic variables in a group of 20 healthy high-altitude Andean residents (comprising 10 men and 10 women) aged between 26 and 35 years old. The monocentric study was carried out in La Paz, Bolivia, located between at an altitude of 3,600–4,000 m. A total of 60 hemodynamic measurements were evaluated, accounting for three technical replicates per subject. Our results showed strong intrasubject reproducibility and revealed important differences related to both sex and hemodynamic parameters in highlanders compared to individuals residing at sea level. We conclude that USCOM represents a highly reliable technology for performing hemodynamic measurements in high-altitude residents. Our preliminary findings underscore the need for larger studies, encompassing larger sample sizes, specifically tailored to gender considerations, and extendable to broader highland populations. These findings have special significant implications for the management of hemodynamics in intensive care and postoperative settings, warranting further comprehensive research efforts.

The Brown-backed Parrotlet, Touit melanonotus, is a rare endemic bird to the Brazilian Atlantic Forest, currently considered as "Vulnerable" in the Brazilian Red List of Threatened Species. We estimated the sex ratio of a wild flock of T. melanonotus using molecular markers, examined morphological variation in 34 museum specimens to test for sexual dimorphism, and conducted a literature review about sex ratio in Psittacidae for comparative purposes. We found a sex ratio of 0.8:1 (male/female; n = 29) in T. melanonotus, and a χ2 Goodness-of-fit test showed no significant difference from equality (p > 0.05). We describe three main categories in plumage: the first (and most common) comprises uniformly lime green birds, slightly darker on the head. The second is composed of individuals who are overall lighter, with the breast feathers washed with light greenish gray, and feathers of the head being dark lime green, presenting a sharp contrast with the breast feathers. The third and the rarest one is composed of birds with light greenish gray underparts with emerald green and darker upper parts. T. melanonotus has no apparent sexual dimorphism. We found no evidence of geographic variation. Sex ratio deviation may not be a parameter increasing the vulnerability of the species. Data like these represent a big leap in the knowledge of the species and has the potential to help and inform conservation efforts. [ABSTRACT FROM AUTHOR]