Background: Sex differences exist in the prevalence and clinical manifestation of several mental disorders, suggesting that sex-specific brain phenotypes may play key roles. Previous research used machine learning models to classify sex from imaging data of the whole brain and studied the association of class probabilities with mental health, potentially overlooking regional specific characteristics.
Methods: We here investigated if a regionally constrained model of brain volumetric imaging data may provide estimates that are more sensitive to mental health than whole brain-based estimates. Given its known role in emotional processing and mood disorders, we focused on the limbic system. Using two different cohorts of healthy subjects, the Human Connectome Project and the Queensland Twin IMaging, we investigated sex differences and heritability of brain volumes of limbic structures compared to non-limbic structures, and subsequently applied regionally constrained machine learning models trained solely on limbic or non-limbic features. To investigate the biological underpinnings of such models, we assessed the heritability of the obtained sex class probability estimates, and we investigated the association with major depression diagnosis in an independent clinical sample. All analyses were performed both with and without controlling for estimated total intracranial volume (eTIV).
Results: Limbic structures show greater sex differences and are more heritable compared to non-limbic structures in both analyses, with and without eTIV control. Consequently, machine learning models performed well at classifying sex based solely on limbic structures and achieved performance as high as those on non-limbic or whole brain data, despite the much smaller number of features in the limbic system. The resulting class probabilities were heritable, suggesting potentially meaningful underlying biological information. Applied to an independent population with major depressive disorder, we found that depression is associated with male-female class probabilities, with largest effects obtained using the limbic model. This association was significant for models not controlling for eTIV whereas in those controlling for eTIV the associations did not pass significance correction.
Conclusions: Overall, our results highlight the potential utility of regionally constrained models of brain sex to better understand the link between sex differences in the brain and mental disorders.
{"title":"Modeling brain sex in the limbic system as phenotype for female-prevalent mental disorders.","authors":"Gloria Matte Bon, Dominik Kraft, Erika Comasco, Birgit Derntl, Tobias Kaufmann","doi":"10.1186/s13293-024-00615-1","DOIUrl":"10.1186/s13293-024-00615-1","url":null,"abstract":"<p><strong>Background: </strong>Sex differences exist in the prevalence and clinical manifestation of several mental disorders, suggesting that sex-specific brain phenotypes may play key roles. Previous research used machine learning models to classify sex from imaging data of the whole brain and studied the association of class probabilities with mental health, potentially overlooking regional specific characteristics.</p><p><strong>Methods: </strong>We here investigated if a regionally constrained model of brain volumetric imaging data may provide estimates that are more sensitive to mental health than whole brain-based estimates. Given its known role in emotional processing and mood disorders, we focused on the limbic system. Using two different cohorts of healthy subjects, the Human Connectome Project and the Queensland Twin IMaging, we investigated sex differences and heritability of brain volumes of limbic structures compared to non-limbic structures, and subsequently applied regionally constrained machine learning models trained solely on limbic or non-limbic features. To investigate the biological underpinnings of such models, we assessed the heritability of the obtained sex class probability estimates, and we investigated the association with major depression diagnosis in an independent clinical sample. All analyses were performed both with and without controlling for estimated total intracranial volume (eTIV).</p><p><strong>Results: </strong>Limbic structures show greater sex differences and are more heritable compared to non-limbic structures in both analyses, with and without eTIV control. Consequently, machine learning models performed well at classifying sex based solely on limbic structures and achieved performance as high as those on non-limbic or whole brain data, despite the much smaller number of features in the limbic system. The resulting class probabilities were heritable, suggesting potentially meaningful underlying biological information. Applied to an independent population with major depressive disorder, we found that depression is associated with male-female class probabilities, with largest effects obtained using the limbic model. This association was significant for models not controlling for eTIV whereas in those controlling for eTIV the associations did not pass significance correction.</p><p><strong>Conclusions: </strong>Overall, our results highlight the potential utility of regionally constrained models of brain sex to better understand the link between sex differences in the brain and mental disorders.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11097569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140943902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-15DOI: 10.1186/s13293-024-00618-y
Ingo Winschel, Anne Willing, Jan Broder Engler, Mark Walkenhorst, Nina Meurs, Lars Binkle-Ladisch, Marcel S Woo, Lena Kristina Pfeffer, Jana K Sonner, Uwe Borgmeyer, Sven Hendrik Hagen, Benjamin Grünhagel, Janna M Claussen, Marcus Altfeld, Manuel A Friese
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.
背景:女性和男性在免疫反应方面的差异导致了主要影响女性的自身免疫性疾病(如多发性硬化症)发病率的强烈性别偏见。多发性硬化症的女性发病率是男性的两倍多,因此性别是最重要的风险因素之一。然而,目前还不完全清楚哪些基因导致了自身免疫性疾病发病率的性别差异。为了解决这个问题,我们对女性和男性人体脾脏进行了基因表达分析,发现跨膜蛋白 CD99 是表达差异最大的基因之一,男性表达明显增加。据报道,CD99参与了免疫细胞的转运和T细胞的调控,但其性别特异性影响尚未得到全面研究:在这项研究中,我们利用基因型-组织表达(GTEx)项目数据集对女性和男性人类脾脏进行了基因表达分析,以确定男女之间的差异表达基因。在成功验证了人类免疫细胞亚群的蛋白质水平后,我们评估了激素对 CD99 的调控,以及它对原代人类 T 细胞和 Jurkat T 细胞中 T 细胞调控的影响。此外,我们还在野生型小鼠和 Cd99 缺失型小鼠体内进行了试验,以进一步分析 CD99 表达差异的功能性后果:结果:我们发现男性脾脏中 CD99 基因的表达高于女性,并在 T 细胞和 pDCs 表面的蛋白水平上证实了这种表达差异。体外检测和对跨性别男性样本的体内外分析表明,雄激素可能是造成这种现象的主要原因。与血液相比,脑脊液中 T 细胞的 CD99 含量更高。值得注意的是,与对照组不同,男性多发性硬化症患者脑脊液中 CD4+ T 细胞的 CD99 水平较低。相比之下,在小鼠体内,雌雄小鼠的 CD99 表达相似,Cd99 缺失的小鼠与野生型小鼠相比,对实验性自身免疫性脑脊髓炎的易感性相同。从功能上讲,CD99 在人类 T 细胞活化后会增加,并在阻断后抑制 T 细胞增殖。相应地,CD99缺失的Jurkat T细胞显示出细胞增殖和集群形成的减少,而CD99的重新引入可挽救这种情况:我们的研究结果表明,CD99 在健康人和多发性硬化症患者中具有性别特异性调控,它参与了人类 T 细胞的成本刺激,但在小鼠中却没有参与。CD99 有可能以性别特异性的方式导致多发性硬化症的发病率和易感性。
{"title":"Sex- and species-specific contribution of CD99 to T cell costimulation during multiple sclerosis.","authors":"Ingo Winschel, Anne Willing, Jan Broder Engler, Mark Walkenhorst, Nina Meurs, Lars Binkle-Ladisch, Marcel S Woo, Lena Kristina Pfeffer, Jana K Sonner, Uwe Borgmeyer, Sven Hendrik Hagen, Benjamin Grünhagel, Janna M Claussen, Marcus Altfeld, Manuel A Friese","doi":"10.1186/s13293-024-00618-y","DOIUrl":"10.1186/s13293-024-00618-y","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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<sup>+</sup> 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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11097467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140943903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-07DOI: 10.1186/s13293-024-00616-0
Rafiad Islam, Jordon D White, Tanzil M Arefin, Sameet Mehta, Xinran Liu, Baruh Polis, Lauryn Giuliano, Sahabuddin Ahmed, Christian Bowers, Jiangyang Zhang, Arie Kaffman
Background: Early life adversity impairs hippocampal development and function across diverse species. While initial evidence indicated potential variations between males and females, further research is required to validate these observations and better understand the underlying mechanisms contributing to these sex differences. Furthermore, most of the preclinical work in rodents was performed in adult males, with only few studies examining sex differences during adolescence when such differences appear more pronounced. To address these concerns, we investigated the impact of limited bedding (LB), a mouse model of early adversity, on hippocampal development in prepubescent and adolescent male and female mice.
Methods: RNA sequencing, confocal microscopy, and electron microscopy were used to evaluate the impact of LB and sex on hippocampal development in prepubescent postnatal day 17 (P17) mice. Additional studies were conducted on adolescent mice aged P29-36, which included contextual fear conditioning, retrograde tracing, and ex vivo diffusion magnetic resonance imaging (dMRI).
Results: More severe deficits in axonal innervation and myelination were found in the perforant pathway of prepubescent and adolescent LB males compared to LB female littermates. These sex differences were due to a failure of reelin-positive neurons located in the lateral entorhinal cortex (LEC) to innervate the dorsal hippocampus via the perforant pathway in males, but not LB females, and were strongly correlated with deficits in contextual fear conditioning.
Conclusions: LB impairs the capacity of reelin-positive cells located in the LEC to project and innervate the dorsal hippocampus in LB males but not female LB littermates. Given the critical role that these projections play in supporting normal hippocampal function, a failure to establish proper connectivity between the LEC and the dorsal hippocampus provides a compelling and novel mechanism to explain the more severe deficits in myelination and contextual freezing found in adolescent LB males.
{"title":"Early adversity causes sex-specific deficits in perforant pathway connectivity and contextual memory in adolescent mice.","authors":"Rafiad Islam, Jordon D White, Tanzil M Arefin, Sameet Mehta, Xinran Liu, Baruh Polis, Lauryn Giuliano, Sahabuddin Ahmed, Christian Bowers, Jiangyang Zhang, Arie Kaffman","doi":"10.1186/s13293-024-00616-0","DOIUrl":"10.1186/s13293-024-00616-0","url":null,"abstract":"<p><strong>Background: </strong>Early life adversity impairs hippocampal development and function across diverse species. While initial evidence indicated potential variations between males and females, further research is required to validate these observations and better understand the underlying mechanisms contributing to these sex differences. Furthermore, most of the preclinical work in rodents was performed in adult males, with only few studies examining sex differences during adolescence when such differences appear more pronounced. To address these concerns, we investigated the impact of limited bedding (LB), a mouse model of early adversity, on hippocampal development in prepubescent and adolescent male and female mice.</p><p><strong>Methods: </strong>RNA sequencing, confocal microscopy, and electron microscopy were used to evaluate the impact of LB and sex on hippocampal development in prepubescent postnatal day 17 (P17) mice. Additional studies were conducted on adolescent mice aged P29-36, which included contextual fear conditioning, retrograde tracing, and ex vivo diffusion magnetic resonance imaging (dMRI).</p><p><strong>Results: </strong>More severe deficits in axonal innervation and myelination were found in the perforant pathway of prepubescent and adolescent LB males compared to LB female littermates. These sex differences were due to a failure of reelin-positive neurons located in the lateral entorhinal cortex (LEC) to innervate the dorsal hippocampus via the perforant pathway in males, but not LB females, and were strongly correlated with deficits in contextual fear conditioning.</p><p><strong>Conclusions: </strong>LB impairs the capacity of reelin-positive cells located in the LEC to project and innervate the dorsal hippocampus in LB males but not female LB littermates. Given the critical role that these projections play in supporting normal hippocampal function, a failure to establish proper connectivity between the LEC and the dorsal hippocampus provides a compelling and novel mechanism to explain the more severe deficits in myelination and contextual freezing found in adolescent LB males.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11075329/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140875740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-25DOI: 10.1186/s13293-024-00613-3
Steve Mabry, Jessica L. Bradshaw, Jennifer J. Gardner, E. Wilson, Rebecca L. Cunningham
{"title":"Sex-dependent effects of chronic intermittent hypoxia: implication for obstructive sleep apnea","authors":"Steve Mabry, Jessica L. Bradshaw, Jennifer J. Gardner, E. Wilson, Rebecca L. Cunningham","doi":"10.1186/s13293-024-00613-3","DOIUrl":"https://doi.org/10.1186/s13293-024-00613-3","url":null,"abstract":"","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140656554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-23DOI: 10.1186/s13293-024-00611-5
Hongren Huang, Xue Liu, Liping Wang, Feng Wang
{"title":"Whole-brain connections of glutamatergic neurons in the mouse lateral habenula in both sexes","authors":"Hongren Huang, Xue Liu, Liping Wang, Feng Wang","doi":"10.1186/s13293-024-00611-5","DOIUrl":"https://doi.org/10.1186/s13293-024-00611-5","url":null,"abstract":"","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140670964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-21DOI: 10.1186/s13293-024-00609-z
Alexander Kautzky, Stephan Nopp, Dietlinde Gattinger, Milos Petrovic, Martin Antlinger, Dustin Schomacker, Alexandra Kautzky-Willer, Ralf Harun Zwick
Following years of pandemic severe acute respiratory syndrome coronavirus 2 infections labelled Covid-19, long lasting impairment summarized as post-Covid syndrome (PCS) challenges worldwide healthcare. Patients benefit from rehabilitation programs, but sex specific aspects of improvement remain little understood. The aim of the study was to assess whether women and men differ in response to outpatient pulmonary rehabilitation for PCS. 263 (54.4% female) patients partaking in outpatient pulmonary rehabilitation (OPR) due to PCS between March 2020 and July 2022 were included in a prospective observational cohort study. Outcomes were assessed at baseline and before discharge from OPR and included six-minute walking distance (6MWD), 1-second forced expiratory volume (FEV1), diffusion capacity for carbon monoxide, maximal inspiratory pressure (MIP), dyspnea (medical research council scale), and post-Covid functional status scale (PCFS). Sexspecific changes in outcomes following OPR were assessed by linear mixed model and presented as mean differences (MD) with 95% confidence intervals. Linear regression was applied to test whether 6MWD correlates with PCFS and the minimal clinically important difference (MCID) in 6MWD regarding an improvement of at least one point in PCFS was computed with logistic regression. Significant improvement throughout OPR was observed for all outcomes (all p < 0.0001). Despite less severe Covid-19 infections, PCFS scores remained higher in females after OPR (p = 0.004) and only 19.4% of women compared to 38.5% of men achieved remission of functional impairment. At baseline as well as after OPR, females showed higher symptom load compared to men in dyspnea (p = 0.0027) and scored lower in FEV1 (p = 0.009) and MIP (p = 0.0006) assessment. Performance in 6MWD was comparable between men and women. An increase of 35 m in 6MWD was computed as minimal clinically important difference to improve functional impairment. Both subjective symptoms such as fatigue and dyspnea and objective impairment in performance in pulmonary function were more frequently observed among women. Despite improvement throughout OPR in both women and men, the sex-gap in symptom load could not be closed as women less often achieved remission from functional impairment due to PCS. Intensified treatment of these symptoms should be considered in women undergoing rehabilitation for PCS. While female sex is protective during the acute infection of Covid-19, women are at increased risk of developing post-Covid syndrome (PCS) even after only mild Covid-19 infections. Severity and frequency of symptoms such as fatigue and shortness of breath are known to be higher in women compared to men. Many different rehabilitation protocols are used for PCS, but a knowledge gap regarding sex related differences in rehabilitation success remains. Both female and male patients with PCS undergoing outpatient pulmonary rehabilitation improved in the maximum walking distance achieved
{"title":"Sex differences of post-Covid patients undergoing outpatient pulmonary rehabilitation","authors":"Alexander Kautzky, Stephan Nopp, Dietlinde Gattinger, Milos Petrovic, Martin Antlinger, Dustin Schomacker, Alexandra Kautzky-Willer, Ralf Harun Zwick","doi":"10.1186/s13293-024-00609-z","DOIUrl":"https://doi.org/10.1186/s13293-024-00609-z","url":null,"abstract":"Following years of pandemic severe acute respiratory syndrome coronavirus 2 infections labelled Covid-19, long lasting impairment summarized as post-Covid syndrome (PCS) challenges worldwide healthcare. Patients benefit from rehabilitation programs, but sex specific aspects of improvement remain little understood. The aim of the study was to assess whether women and men differ in response to outpatient pulmonary rehabilitation for PCS. 263 (54.4% female) patients partaking in outpatient pulmonary rehabilitation (OPR) due to PCS between March 2020 and July 2022 were included in a prospective observational cohort study. Outcomes were assessed at baseline and before discharge from OPR and included six-minute walking distance (6MWD), 1-second forced expiratory volume (FEV1), diffusion capacity for carbon monoxide, maximal inspiratory pressure (MIP), dyspnea (medical research council scale), and post-Covid functional status scale (PCFS). Sexspecific changes in outcomes following OPR were assessed by linear mixed model and presented as mean differences (MD) with 95% confidence intervals. Linear regression was applied to test whether 6MWD correlates with PCFS and the minimal clinically important difference (MCID) in 6MWD regarding an improvement of at least one point in PCFS was computed with logistic regression. Significant improvement throughout OPR was observed for all outcomes (all p < 0.0001). Despite less severe Covid-19 infections, PCFS scores remained higher in females after OPR (p = 0.004) and only 19.4% of women compared to 38.5% of men achieved remission of functional impairment. At baseline as well as after OPR, females showed higher symptom load compared to men in dyspnea (p = 0.0027) and scored lower in FEV1 (p = 0.009) and MIP (p = 0.0006) assessment. Performance in 6MWD was comparable between men and women. An increase of 35 m in 6MWD was computed as minimal clinically important difference to improve functional impairment. Both subjective symptoms such as fatigue and dyspnea and objective impairment in performance in pulmonary function were more frequently observed among women. Despite improvement throughout OPR in both women and men, the sex-gap in symptom load could not be closed as women less often achieved remission from functional impairment due to PCS. Intensified treatment of these symptoms should be considered in women undergoing rehabilitation for PCS. While female sex is protective during the acute infection of Covid-19, women are at increased risk of developing post-Covid syndrome (PCS) even after only mild Covid-19 infections. Severity and frequency of symptoms such as fatigue and shortness of breath are known to be higher in women compared to men. Many different rehabilitation protocols are used for PCS, but a knowledge gap regarding sex related differences in rehabilitation success remains. Both female and male patients with PCS undergoing outpatient pulmonary rehabilitation improved in the maximum walking distance achieved","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140635138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-15DOI: 10.1186/s13293-024-00607-1
Wei Yang, Joshua B. Rubin
The significant sex and gender differences that exist in cancer mechanisms, incidence, and survival, have yet to impact clinical practice. One barrier to translation is that cancer phenotypes cannot be segregated into distinct male versus female categories. Instead, within this convenient but contrived dichotomy, male and female cancer phenotypes are highly overlapping and vary between female- and male- skewed extremes. Thus, sex and gender-specific treatments are unrealistic, and our translational goal should be adaptation of treatment to the variable effects of sex and gender on targetable pathways. To overcome this obstacle, we profiled the similarities in 8370 transcriptomes of 26 different adult and 4 different pediatric cancer types. We calculated the posterior probabilities of predicting patient sex and gender based on the observed sexes of similar samples in this map of transcriptome similarity. Transcriptomic index (TI) values were derived from posterior probabilities and allowed us to identify poles with local enrichments for male or female transcriptomes. TI supported deconvolution of transcriptomes into measures of patient-specific activity in sex and gender-biased, targetable pathways. It identified sex and gender-skewed extremes in mechanistic phenotypes like cell cycle signaling and immunity, and precisely positioned each patient’s whole transcriptome on an axis of continuously varying sex and gender phenotypes. Cancer type, patient sex and gender, and TI value provides a novel and patient- specific mechanistic identifier that can be used for realistic sex and gender-adaptations of precision cancer treatment planning. Some efforts to improve cancer therapy involve the idea of personalizing treatments to who a patient is and how their cancer operates. Personalizing treatment can involve straighforward features like a patient’s age, family cancer history, personal disease and surgical histories, as well as more complex features like analysis of their specific cancer’s mechanisms of growth and spread throughout the body. One glaring omission in common personalization schemes is the sex and gender of the patient. While patient sex and gender is known to substantially affect cancer rates and response to treatment, we do not yet use this information in treatment planning. There are multiple reasons for this but among them is that we tend to think about sex and gender as an either/or categorization. You are either a male/man or a female/woman. This is not accurate as there are many variables that contribute to who an individual is as a male/man or female/woman. This variability is a challenge to incorporating these features into personalized treatment planning. Here, we have developed a method to address this challenge. It is our great hope that this will enable the use of this critically important element of personalization in cancer treatment planning and improve survival rates for all patients.
癌症发病机制、发病率和存活率方面存在的重大性别差异尚未对临床实践产生影响。转化的一个障碍是,癌症表型无法划分为明显的男性和女性类别。相反,在这种方便但臆造的二分法中,男性和女性癌症表型高度重叠,并在女性和男性两个极端之间变化。因此,针对不同性别的治疗方法是不现实的,我们的转化目标应该是根据性别对可靶向途径的不同影响调整治疗方法。为了克服这一障碍,我们分析了 26 种不同成人癌症和 4 种不同儿童癌症的 8370 个转录组的相似性。我们根据转录组相似性图谱中观察到的相似样本的性别,计算了预测患者性别的后验概率。转录组指数(TI)值来自后验概率,使我们能够识别出男性或女性转录组局部富集的极点。转录组指数支持将转录组解构为衡量患者在性别和性别偏倚的目标通路中的特异性活动。它确定了细胞周期信号转导和免疫等机理表型的性别倾斜极端,并将每位患者的整个转录组精确定位在持续变化的性别表型轴上。癌症类型、患者性别和 TI 值提供了一种新颖的患者特异性机理标识符,可用于对癌症精准治疗计划进行现实的性别适应。改善癌症治疗的一些努力包括根据患者的身份及其癌症的运作方式进行个性化治疗。个性化治疗可能涉及患者的年龄、家族癌症史、个人疾病史和手术史等直接特征,以及分析特定癌症的生长和全身扩散机制等更复杂的特征。在常见的个性化方案中,一个明显的疏漏就是病人的性别。众所周知,患者的性别会对癌症发病率和治疗反应产生重大影响,但我们还没有在治疗计划中使用这些信息。造成这种情况的原因有很多,但其中之一是我们倾向于将性和性别视为非此即彼的分类。你要么是男性/男人,要么是女性/女人。这是不准确的,因为一个人是男是女有很多变数。这种可变性是将这些特征纳入个性化治疗计划的一个挑战。在此,我们开发了一种方法来应对这一挑战。我们殷切希望,这将有助于在癌症治疗规划中使用这一至关重要的个性化元素,并提高所有患者的生存率。
{"title":"Treating sex and gender differences as a continuous variable can improve precision cancer treatments","authors":"Wei Yang, Joshua B. Rubin","doi":"10.1186/s13293-024-00607-1","DOIUrl":"https://doi.org/10.1186/s13293-024-00607-1","url":null,"abstract":"The significant sex and gender differences that exist in cancer mechanisms, incidence, and survival, have yet to impact clinical practice. One barrier to translation is that cancer phenotypes cannot be segregated into distinct male versus female categories. Instead, within this convenient but contrived dichotomy, male and female cancer phenotypes are highly overlapping and vary between female- and male- skewed extremes. Thus, sex and gender-specific treatments are unrealistic, and our translational goal should be adaptation of treatment to the variable effects of sex and gender on targetable pathways. To overcome this obstacle, we profiled the similarities in 8370 transcriptomes of 26 different adult and 4 different pediatric cancer types. We calculated the posterior probabilities of predicting patient sex and gender based on the observed sexes of similar samples in this map of transcriptome similarity. Transcriptomic index (TI) values were derived from posterior probabilities and allowed us to identify poles with local enrichments for male or female transcriptomes. TI supported deconvolution of transcriptomes into measures of patient-specific activity in sex and gender-biased, targetable pathways. It identified sex and gender-skewed extremes in mechanistic phenotypes like cell cycle signaling and immunity, and precisely positioned each patient’s whole transcriptome on an axis of continuously varying sex and gender phenotypes. Cancer type, patient sex and gender, and TI value provides a novel and patient- specific mechanistic identifier that can be used for realistic sex and gender-adaptations of precision cancer treatment planning. Some efforts to improve cancer therapy involve the idea of personalizing treatments to who a patient is and how their cancer operates. Personalizing treatment can involve straighforward features like a patient’s age, family cancer history, personal disease and surgical histories, as well as more complex features like analysis of their specific cancer’s mechanisms of growth and spread throughout the body. One glaring omission in common personalization schemes is the sex and gender of the patient. While patient sex and gender is known to substantially affect cancer rates and response to treatment, we do not yet use this information in treatment planning. There are multiple reasons for this but among them is that we tend to think about sex and gender as an either/or categorization. You are either a male/man or a female/woman. This is not accurate as there are many variables that contribute to who an individual is as a male/man or female/woman. This variability is a challenge to incorporating these features into personalized treatment planning. Here, we have developed a method to address this challenge. It is our great hope that this will enable the use of this critically important element of personalization in cancer treatment planning and improve survival rates for all patients. ","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-08DOI: 10.1186/s13293-024-00603-5
María del Mar Fernández-Arjona, Juan Antonio Navarro, Antonio Jesús López-Gambero, Marialuisa de Ceglia, Miguel Rodríguez, Leticia Rubio, Fernando Rodríguez de Fonseca, Vicente Barrios, Julie A. Chowen, Jesús Argente, Patricia Rivera, Juan Suárez
Children with pregnancy-associated plasma protein-A2 (PAPP-A2) mutations resulting in low levels of bioactive insulin-like growth factor-1 (IGF1) and progressive postnatal growth retardation have improved growth velocity and height following recombinant human (rh)IGF1 treatment. The present study aimed to evaluate whether Pappa2 deficiency and pharmacological manipulation of GH/IGF1 system are associated with sex-specific differences in growth-related signaling pathways. Plasma, hypothalamus, pituitary gland and liver of Pappa2ko/ko mice of both sexes, showing reduced skeletal growth, and liver of these mice treated with rhGH, rhIGF1 and rhPAPP-A2 from postnatal day (PND) 5 to PND35 were analyzed. Reduced body and femur length of Pappa2ko/ko mice was associated with increases in: (1) components of IGF1 ternary complexes (IGF1, IGFBP5/Igfbp5, Igfbp3, Igfals) in plasma, hypothalamus and/or liver; and (2) key signaling regulators (phosphorylated PI3K, AKT, mTOR, GSK3β, ERK1/2 and AMPKα) in hypothalamus, pituitary gland and/or liver, with Pappa2ko/ko females having a more prominent effect. Compared to rhGH and rhIGF1, rhPAPP-A2 specifically induced: (1) increased body and femur length, and reduced plasma total IGF1 and IGFBP5 concentrations in Pappa2ko/ko females; and (2) increased Igf1 and Igf1r levels and decreased Ghr, Igfbp3 and Igfals levels in the liver of Pappa2ko/ko females. These changes were accompanied by lower phospho-STAT5, phospho-AKT and phospho-ERK2 levels and higher phospho-AMPK levels in the liver of Pappa2ko/ko females. Sex-specific differences in IGF1 system and signaling pathways are associated with Pappa2 deficiency, pointing to rhPAPP-A2 as a promising drug to alleviate postnatal growth retardation underlying low IGF1 bioavailability in a female-specific manner. Understanding the physiological role of pregnancy-associated plasma protein-A2 (PAPP-A2), a proteinase involved in the insulin-like growth factor-1 (IGF1) availability to regulate growth, could provide insight into new treatments for patients with short stature and skeletal abnormalities. Although progressive postnatal growth retardation in patients with PAPP-A2 mutations can differ between males and females, we do not know the underlying differences in IGF1 system and signaling, and their response to treatment that contribute to growth improvement. The present study examines whether Pappa2 deficiency and pharmacological administration of rhGH, rhIGF1 and rhPAPP-A2 are associated with sex-specific differences in IGF1 ternary complexes and IGF1 signaling pathways. Reduced body and femur length of Pappa2-deficient mice was associated with sex- and tissue-specific alteration of IGF ternary/binary complexes and IGF1 signaling pathways. rhPAPP-A2 treatment induced female-specific increase in body and femur length and reduction in IGF ternary/binary complexes through STAT5-AKT-ERK2-AMPK signaling pathways in liver. The involvement of PAPP-A2 in sex-based growth physiology sup
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Pub Date : 2024-04-03DOI: 10.1186/s13293-024-00608-0
Isabel R. K. Kuebler, Mauricio Suárez, Ken T. Wakabayashi
Recent preclinical research exploring how neuropeptide transmitter systems regulate motivated behavior reveal the increasing importance of sex as a critical biological variable. Neuropeptide systems and their central circuits both contribute to sex differences in a range of motivated behaviors and regulate sex-specific behaviors. In this short review, we explore the current research of how sex as a biological variable influences several distinct motivated behaviors that are modulated by the melanin-concentrating hormone (MCH) neuropeptide system. First, we review how MCH regulates feeding behavior within the context of energy homeostasis differently between male and female rodents. Then, we focus on MCH’s role in lactation as a sex-specific process within the context of energy homeostasis. Next, we discuss the sex-specific effects of MCH on maternal behavior. Finally, we summarize the role of MCH in drug-motivated behaviors. While these topics are traditionally investigated from different scientific perspectives, in this short review we discuss how these behaviors share commonalities within the larger context of motivated behaviors, and that sex differences discovered in one area of research may impact our understanding in another. Overall, our review highlights the need for further research into how sex differences in energy regulation associated with reproduction and parental care contribute to regulating motivated behaviors.
{"title":"Sex differences and sex-specific regulation of motivated behavior by Melanin-concentrating hormone: a short review","authors":"Isabel R. K. Kuebler, Mauricio Suárez, Ken T. Wakabayashi","doi":"10.1186/s13293-024-00608-0","DOIUrl":"https://doi.org/10.1186/s13293-024-00608-0","url":null,"abstract":"Recent preclinical research exploring how neuropeptide transmitter systems regulate motivated behavior reveal the increasing importance of sex as a critical biological variable. Neuropeptide systems and their central circuits both contribute to sex differences in a range of motivated behaviors and regulate sex-specific behaviors. In this short review, we explore the current research of how sex as a biological variable influences several distinct motivated behaviors that are modulated by the melanin-concentrating hormone (MCH) neuropeptide system. First, we review how MCH regulates feeding behavior within the context of energy homeostasis differently between male and female rodents. Then, we focus on MCH’s role in lactation as a sex-specific process within the context of energy homeostasis. Next, we discuss the sex-specific effects of MCH on maternal behavior. Finally, we summarize the role of MCH in drug-motivated behaviors. While these topics are traditionally investigated from different scientific perspectives, in this short review we discuss how these behaviors share commonalities within the larger context of motivated behaviors, and that sex differences discovered in one area of research may impact our understanding in another. Overall, our review highlights the need for further research into how sex differences in energy regulation associated with reproduction and parental care contribute to regulating motivated behaviors.","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-03DOI: 10.1186/s13293-024-00605-3
Ryan T. McCallum, Rachel-Karson Thériault, Joshua D. Manduca, Isaac S. B. Russell, Angel M. Culmer, Janan Shoja Doost, Tami A. Martino, Melissa L. Perreault
Correction: Biol Sex Differ 15, 16 (2024)
https://doi.org/10.1186/s13293-024-00589-0
Following publication of the original article [1], the authors reported an error in the methodology for calculating the discrimination ratio in the novel object recognition and object location tests.
Incorrect: The discrimination ratio was calculated as the time of exploration of relocated object/total object exploration time*100.
Correct: For the novel object recognition test the discrimination ratio was calculated as the time exploring the novel object – the time exploring the familiar object/total exploration time.
For the object location test the discrimination ratio was calculated as the time exploring the novel location – the time exploring the familiar location/total exploration time.
The authors also report an error in sampling for original Figs. 4 and 5. Therefore, all of the original microglia data in the results and figures have been removed and Fig. 6 renumbered as Fig. 4. The associated immunohistochemistry methodologies were removed, and any associated discussion of the microglia findings deleted. References were renumbered and the Abstract and Highlights also revised to remove the microglia findings.
McCallum RT, Thériault RK, Manduca JD, et al. Nrf2 activation rescues stress-induced depression-like behaviour and inflammatory responses in male but not female rats. Biol Sex Differ. 2024;15:16. https://doi.org/10.1186/s13293-024-00589-0.
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Department of Biomedical Sciences, University of Guelph, 50 Stone Rd. E, Guelph, ON, N1G 2W1, Canada
Ryan T. McCallum, Rachel-Karson Thériault, Joshua D. Manduca, Isaac S. B. Russell, Angel M. Culmer, Janan Shoja Doost, Tami A. Martino & Melissa L. Perreault
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更正:Biol Sex Differ 15, 16 (2024)https://doi.org/10.1186/s13293-024-00589-0 原文[1]发表后,作者报告了在新物体识别和物体定位测试中计算辨别率的方法中的一个错误。错误:辨别率的计算方法是探索重新定位的物体的时间/探索物体的总时间*100.正确:在新物体识别测试中,区分度比率的计算方法是:探索新物体的时间-探索熟悉物体的时间/总探索时间。作者还报告了原始图 4 和图 5 的取样误差。因此,结果和图表中的所有原始小胶质细胞数据均已删除,图 6 重新编号为图 4。删除了相关的免疫组化方法,并删除了对小胶质细胞研究结果的相关讨论。McCallum RT, Thériault RK, Manduca JD, et al. Nrf2 activation rescues stress-induced depression-like behaviour and inflammatory responses in male but not female rats.Biol Sex Differ.2024;15:16. https://doi.org/10.1186/s13293-024-00589-0.Article CAS PubMed PubMed Central Google Scholar 下载参考文献作者及单位Department of Biomedical Sciences, University of Guelph, 50 Stone Rd.E, Guelph, ON, N1G 2W1, CanadaRyan T. McCallum, Rachel-Karson Thériault, Joshua D. Manduca, Isaac S. B. Russell, Angel M. Culmer, Janan Shoja Doost, Tami A. Martino & Melissa L. Perreault作者Ryan T.McCallum查看作者发表的作品您也可以在PubMed谷歌学术中搜索该作者Rachel-Karson Thériault查看作者发表的作品您也可以在PubMed谷歌学术中搜索该作者Joshua D.ManducaView 作者发表论文您也可以在 PubMed Google ScholarIsaac S. B. RussellView 作者发表论文您也可以在 PubMed Google ScholarAngel M. CulmerView 作者发表论文您也可以在 PubMed Google ScholarJanan Shoja DoostView 作者发表论文您也可以在 PubMed Google ScholarTami A. MartinoView 作者发表论文您也可以在 PubMed Google ScholarTami A. MartinoView 作者发表论文MartinoView author publications您也可以在PubMed Google Scholar中搜索该作者Melissa L. PerreaultView author publications您也可以在PubMed Google Scholar中搜索该作者Corresponding authorCorrespondence to Melissa L. Perreault.Publisher's NoteSpringer Nature对出版地图和机构隶属关系中的管辖权主张保持中立。本文采用知识共享署名 4.0 国际许可协议(Creative Commons Attribution 4.0 International License)进行许可,允许以任何媒介或形式使用、共享、改编、分发和复制,只要您适当注明原作者和来源,提供知识共享许可协议的链接,并说明是否进行了修改。本文中的图片或其他第三方材料均包含在文章的知识共享许可协议中,除非在材料的署名栏中另有说明。如果材料未包含在文章的知识共享许可协议中,且您打算使用的材料不符合法律规定或超出许可使用范围,您需要直接从版权所有者处获得许可。要查看该许可的副本,请访问 http://creativecommons.org/licenses/by/4.0/。除非在数据的信用行中另有说明,否则知识共享公共领域专用豁免 (http://creativecommons.org/publicdomain/zero/1.0/) 适用于本文提供的数据。转载与许可引用本文McCallum, R.T., Thériault, RK., Manduca, J.D. et al. Correction:Nrf2激活可挽救雄性大鼠而非雌性大鼠的应激诱导抑郁样行为和炎症反应。Biol Sex Differ 15, 31 (2024). https://doi.org/10.1186/s13293-024-00605-3Download citationPublished: 03 April 2024DOI: https://doi.org/10.1186/s13293-024-00605-3Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative
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