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Aromatase, testosterone, TMPRSS2: determinants of COVID-19 severity. 芳香化酶、睾酮、TMPRSS2:COVID-19 严重程度的决定因素。
IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-24 DOI: 10.1186/s13293-024-00658-4
Eric C Mohan, Jude P J Savarraj, Gabriela D Colpo, Diego Morales, Carson E Finger, Alexis McAlister, Hilda Ahnstedt, HuiMahn Choi, Louise D McCullough, Bharti Manwani
<p><strong>Background: </strong>Male sex has been identified as a risk factor for worse COVID-19 outcomes. This sex difference has been mostly attributed to the complex role of sex hormones. Cell surface entry of SARS-CoV-2 is mediated by the transmembrane protease serine 2 (TMPRSS2) which is under transcriptional regulation by androgens. P450 aromatase enzyme converts androgens to estrogens. This study measured concentrations of aromatase enzyme, testosterone, estradiol, and TMPRSS-2 in plasma of hospitalized COVID-19 patients to elucidate the dynamics of sex-linked disparity in COVID-19 and correlate them with disease severity and mortality.</p><p><strong>Methods: </strong>In this prospective cohort study, a total of 265 patients (41% women), age 18 years and older, who had a positive COVID-19 PCR test and were hospitalized for COVID-19 at Memorial Hermann Hospital in Houston, (between May 2020 and May 2021) were enrolled in the study if met inclusion criteria. Plasma concentrations of Testosterone, aromatase, TMPRSS-2, and estradiol were measured by ELISA. COVID-19 patients were dichotomized based on disease severity into moderate-severe (n = 146) or critical (n = 119). Mann Whitney U and logistic regression were used to correlate the analytes with disease severity and mortality.</p><p><strong>Results: </strong>TMPRSS2 (2.5 ± 0.31 vs. 1.73 ± 0.21 ng/mL, p < 0.01) and testosterone (1.2 ± 0.1 vs. 0.44 ± 0.12 ng/mL, p < 0.01) were significantly higher in men as compared to women with COVID-19 after adjusting for age in a multivariate model. There was no sex difference seen in the level of estradiol and aromatase in COVID-19 patients. TMPRSS2 and aromatase were higher, while testosterone was lower in patients with increased COVID-19 severity. They were independently associated with COVID-19 severity, after adjusting for several baseline risk factors in a multivariate logistic regression model. In terms of mortality, TMPRRS2 and aromatase levels were significantly higher in non-survivors.</p><p><strong>Conclusions: </strong>Our study demonstrates that testosterone, aromatase, and TMPRSS2 are markers of COVID-19 severity. Estradiol levels do not change with disease severity in COVID-19. In terms of mortality prediction, higher aromatase and TMPRSS-2 levels can be used to predict mortality from COVID-19 in hospitalized patients. COVID-19 has caused over a million deaths in the U.S., with men often getting sicker than women. Testosterone, a male hormone, helps control a protein called TMPRSS-2, which allows the COVID-19 virus to spread more easily in the body. A protein called aromatase converts the male hormone testosterone into the female hormone estrogen. It is thought that female hormone estrogen helps protect women from getting seriously ill from COVID-19. To understand the role of these hormones in COVID-19 and sex differences, we measured levels of testosterone, estrogen, aromatase (which turns testosterone into estrogen), and TMPRSS-2 in hospi
背景:男性已被确定为 COVID-19 结果较差的风险因素。这种性别差异主要归因于性激素的复杂作用。SARS-CoV-2 进入细胞表面是由跨膜丝氨酸蛋白酶 2(TMPRSS2)介导的,该蛋白酶受雄激素的转录调节。P450 芳香化酶可将雄激素转化为雌激素。本研究测量了住院COVID-19患者血浆中芳香化酶、睾酮、雌二醇和TMPRSS-2的浓度,以阐明COVID-19中性别相关性差异的动态变化,并将其与疾病严重程度和死亡率联系起来:在这项前瞻性队列研究中,休斯顿赫尔曼纪念医院(2020年5月至2021年5月期间)共招募了265名COVID-19 PCR检测呈阳性并因COVID-19住院的18岁及以上患者(41%为女性),只要符合纳入标准即可参与研究。通过酶联免疫吸附法测定血浆中睾酮、芳香化酶、TMPRSS-2和雌二醇的浓度。COVID-19 患者根据疾病严重程度分为中度-重度(146 人)和危重(119 人)。曼-惠特尼U和逻辑回归用于将分析物与疾病严重程度和死亡率相关联:结果:TMPRSS2(2.5 ± 0.31 vs. 1.73 ± 0.21 ng/mL,p 结论:我们的研究表明,睾酮、芳香化酶和 TMPRSS2 是 COVID-19 严重程度的标志物。雌二醇水平并不随 COVID-19 疾病严重程度而变化。在预测死亡率方面,较高的芳香化酶和 TMPRSS-2 水平可用于预测住院患者的 COVID-19 死亡率。在美国,COVID-19 已造成一百多万人死亡,其中男性的发病率往往高于女性。睾酮是一种雄性激素,它有助于控制一种名为TMPRSS-2的蛋白质,使COVID-19病毒更容易在体内传播。一种名为芳香化酶的蛋白质会将雄性激素睾酮转化为雌性激素。人们认为,女性荷尔蒙雌激素有助于保护女性免受 COVID-19 病毒的严重侵袭。为了了解这些激素在 COVID-19 中的作用和性别差异,我们测量了 COVID-19 住院患者体内睾酮、雌激素、芳香化酶(将睾酮转化为雌激素)和 TMPRSS-2 的水平。我们还检查了这一水平如何反映疾病的严重程度。我们发现,COVID-19 重症患者(重症监护室患者)的 TMPRSS-2 和芳香化酶水平较高,而睾酮水平较低。当我们用这些激素水平来预测住院的COVID-19患者的死亡时,TMPRSS-2和芳香化酶水平较高的患者存活几率较低。
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引用次数: 0
The influence of sex on neuroimmune communication, pain, and physiology. 性别对神经免疫交流、疼痛和生理学的影响。
IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-22 DOI: 10.1186/s13293-024-00660-w
Shevon N Alexander, Audrey R Green, Emily K Debner, Lindsey E Ramos Freitas, Hanna M K Abdelhadi, Thomas A Szabo-Pardi, Michael D Burton

With the National Institutes of Health's mandate to consider sex as a biological variable (SABV), there has been a significant increase of studies utilizing both sexes. Historically, we have known that biological sex and hormones influence immunological processes and now studies focusing on interactions between the immune, endocrine, and nervous systems are revealing sex differences that influence pain behavior and various molecular and biochemical processes. Neuroendocrine-immune interactions represent a key integrative discipline that will reveal critical processes in each field as it pertains to novel mechanisms in sex differences and necessary therapeutics. Here we appraise preclinical and clinical literature to discuss these interactions and key pathways that drive cell- and sex-specific differences in immunity, pain, and physiology.

随着美国国立卫生研究院(National Institutes of Health)授权将性别视为一种生物变量(SABV),利用两性进行的研究大幅增加。从历史上看,我们已经知道生物性别和激素会影响免疫过程,而现在侧重于免疫、内分泌和神经系统之间相互作用的研究则揭示了影响疼痛行为及各种分子和生化过程的性别差异。神经内分泌-免疫相互作用是一门关键的综合性学科,它将揭示每个领域的关键过程,因为它涉及到性别差异的新机制和必要的治疗方法。在此,我们对临床前和临床文献进行评估,讨论这些相互作用以及驱动免疫、疼痛和生理学中细胞和性别特异性差异的关键途径。
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引用次数: 0
Sex-specific phenotypical, functional and metabolic profiles of human term placenta macrophages. 人类足月胎盘巨噬细胞的性别表型、功能和代谢特征。
IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-17 DOI: 10.1186/s13293-024-00652-w
Daniel E Paparini, Esteban Grasso, Franco Aguilera, M Agustina Arslanian, Victoria Lella, Brenda Lara, Ana Schafir, Soledad Gori, Fátima Merech, Vanesa Hauk, Claudio Schuster, Marcelo Martí, Cesar Meller, Rosanna Ramhorst, Daiana Vota, Claudia Pérez Leirós

Background: Placental macrophages, Hofbauer cells (HBC) are the only fetal immune cell population within the stroma of healthy placenta along pregnancy. They are central players in maintaining immune tolerance during pregnancy. Immunometabolism emerged a few years ago as a new field that integrates cellular metabolism with immune responses, however, the immunometabolism of HBC has not been explored yet. Here we studied the sex-specific differences in the phenotypic, functional and immunometabolic profile of HBC.

Methods: HBC were isolated from human term placentas (N = 31, 16 from male and 15 female neonates). Ex vivo assays were carried out to assess active metabolic and endoplasmic reticulum stress pathways by flow cytometry, confocal microscopy, gene expression and in silico approaches.

Results: HBC from female placentas displayed a stronger M2 phenotype accompanied by high rates of efferocytosis majorly sustained on lipid metabolism. On the other hand, male HBC expressed a weaker M2 phenotype with higher glycolytic metabolism. LPS stimulation reinforced the glycolytic metabolism in male but not in female HBC. Physiological endoplasmic reticulum stress activates IRE-1 differently, since its pharmacological inhibition increased lipid mobilization, accumulation and efferocytosis only in female HBC. Moreover, differential sex-associated pathways accompanying the phenotypic and functional profiles of HBC appeared related to the placental villi environment.

Conclusions: These results support sex-associated effects on the immunometabolism of the HBC and adds another layer of complexity to the intricate maternal-fetal immune interaction.

背景:胎盘巨噬细胞和霍夫鲍尔细胞(HBC)是孕期健康胎盘基质中唯一的胎儿免疫细胞群。它们是维持孕期免疫耐受的核心角色。免疫代谢学是几年前兴起的一个新领域,它将细胞代谢与免疫反应结合在一起,然而,HBC的免疫代谢尚未被研究。方法:从人类足月胎盘中分离出 HBC(31 个,其中 16 个来自男性新生儿,15 个来自女性新生儿)。通过流式细胞术、共聚焦显微镜、基因表达和硅学方法进行体内外检测,以评估活跃的代谢和内质网应激途径:结果:雌性胎盘中的HBC显示出更强的M2表型,并伴随着主要依靠脂质代谢维持的高流出率。另一方面,雄性 HBC 的 M2 表型较弱,糖代谢较高。LPS 刺激加强了雄性 HBC 的糖代谢,而雌性 HBC 则没有。生理内质网应激对 IRE-1 的激活作用不同,因为只有在雌性 HBC 中药物抑制 IRE-1 才会增加脂质动员、积累和排泄。此外,伴随 HBC 表型和功能特征的不同性别相关途径似乎与胎盘绒毛环境有关:这些结果支持了性别对 HBC 免疫代谢的影响,并为错综复杂的母胎免疫相互作用增添了另一层复杂性。
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引用次数: 0
Sex Differences in Human Brain Structure at Birth. 人类出生时大脑结构的性别差异。
IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-17 DOI: 10.1186/s13293-024-00657-5
Yumnah T Khan, Alex Tsompanidis, Marcin A Radecki, Lena Dorfschmidt, Topun Austin, John Suckling, Carrie Allison, Meng-Chuan Lai, Richard A I Bethlehem, Simon Baron-Cohen

Background: Sex differences in human brain anatomy have been well-documented, though remain significantly underexplored during early development. The neonatal period is a critical stage for brain development and can provide key insights into the role that prenatal and early postnatal factors play in shaping sex differences in the brain.

Methods: Here, we assessed on-average sex differences in global and regional brain volumes in 514 newborns aged 0-28 days (236 birth-assigned females and 278 birth-assigned males) using data from the developing Human Connectome Project. We also assessed sex-by-age interactions to investigate sex differences in early postnatal brain development.

Results: On average, males had significantly larger intracranial and total brain volumes, even after controlling for birth weight. After controlling for total brain volume, females showed significantly greater total cortical gray matter volumes, whilst males showed greater total white matter volumes. After controlling for total brain volume in regional comparisons, females had significantly increased white matter volumes in the corpus callosum and increased gray matter volumes in the bilateral parahippocampal gyri (posterior parts), left anterior cingulate gyrus, bilateral parietal lobes, and left caudate nucleus. Males had significantly increased gray matter volumes in the right medial and inferior temporal gyrus (posterior part) and right subthalamic nucleus. Effect sizes ranged from small for regional comparisons to large for global comparisons. Significant sex-by-age interactions were noted in the left anterior cingulate gyrus and left superior temporal gyrus (posterior parts).

Conclusions: Our findings demonstrate that sex differences in brain structure are already present at birth and remain comparatively stable during early postnatal development, highlighting an important role of prenatal factors in shaping sex differences in the brain.

背景:人类大脑解剖学中的性别差异已被充分证明,但对早期发育过程的研究仍显不足。新生儿期是大脑发育的关键阶段,可为了解产前和产后早期因素在形成大脑性别差异方面所起的作用提供重要信息。方法:在此,我们利用正在开展的人类连接组项目的数据,评估了 514 名 0-28 天大的新生儿(236 名出生时指定的女性和 278 名出生时指定的男性)在整体和区域脑容量方面的平均性别差异。我们还评估了性别与年龄的相互作用,以研究出生后早期大脑发育的性别差异:结果:平均而言,即使控制了出生体重,男性的颅内体积和大脑总体积也明显更大。在控制了大脑总体积后,女性的皮层灰质总体积明显更大,而男性的白质总体积更大。在控制了区域比较中的脑总量后,女性胼胝体的白质体积明显增加,双侧海马旁回(后部)、左扣带回前部、双侧顶叶和左尾状核的灰质体积增加。男性右侧颞内侧和颞下回(后部)以及右侧丘脑下核的灰质体积明显增加。效应大小从区域比较的小到整体比较的大不等。左侧扣带回前部和左侧颞上回(后部)存在显著的性别-年龄交互作用:我们的研究结果表明,大脑结构的性别差异在出生时就已经存在,并在出生后早期发育过程中保持相对稳定,这凸显了产前因素在大脑性别差异形成过程中的重要作用。
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引用次数: 0
Sex differences in prelimbic cortex calcium dynamics during stress and fear learning. 压力和恐惧学习过程中前缘皮层钙动态的性别差异
IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-16 DOI: 10.1186/s13293-024-00653-9
Ignacio Marin-Blasco, Giorgia Vanzo, Joaquin Rusco-Portabella, Lucas Perez-Molina, Leire Romero, Antonio Florido, Raul Andero

In recent years, research has progressively increased the importance of considering sex differences in stress and fear memory studies. Many studies have traditionally focused on male subjects, potentially overlooking critical differences with females. Emerging evidence suggests that males and females can exhibit distinct behavioral and neurophysiological responses to stress and fear conditioning. These differences may be attributable to variations in hormone levels, brain structure, and neural circuitry, particularly in regions such as the prefrontal cortex (PFC). In the present study, we explored sex differences in prelimbic cortex (PL) calcium activity in animals submitted to immobilization stress (IMO), fear conditioning (FC), and fear extinction (FE). While no significant sex differences were found in behavioral responses, we did observe differences in several PL calcium activity parameters. To determine whether these results were related to behaviors beyond stress and fear memory, we conducted correlation studies between the movement of the animals and PL activity during IMO and freezing behavior during FC and FE. Our findings revealed a clear correlation between PL calcium activity with movement during stress exposure and freezing behavior, with no sex differences observed in these correlations. These results suggest a significant role for the PL in movement and locomotion, in addition to its involvement in fear-related processes. The inclusion of both female and male subjects is crucial for studies like this to fully understand the role of the PFC and other brain areas in stress and fear responses. Recognizing sex differences enhances our comprehension of brain function and can lead to more personalized and effective approaches in the study and treatment of stress and fear-related conditions.

近年来,研究逐渐增加了在压力和恐惧记忆研究中考虑性别差异的重要性。传统上,许多研究都以男性受试者为研究对象,可能忽略了与女性的关键差异。新的证据表明,男性和女性对压力和恐惧条件反射会表现出不同的行为和神经生理反应。这些差异可能归因于激素水平、大脑结构和神经回路的变化,尤其是前额叶皮层(PFC)等区域的变化。在本研究中,我们探讨了动物在接受固定应激(IMO)、恐惧条件反射(FC)和恐惧消退(FE)后边缘前皮层(PL)钙活动的性别差异。虽然在行为反应方面没有发现明显的性别差异,但我们确实观察到了几种前边缘皮层钙活动参数的差异。为了确定这些结果是否与应激和恐惧记忆以外的行为有关,我们对 IMO 期间动物的运动和 PL 活性以及 FC 和 FE 期间的冻结行为进行了相关性研究。我们的研究结果表明,PL钙活性与应激暴露时的运动和冻结行为之间存在明显的相关性,而且在这些相关性中没有观察到性别差异。这些结果表明,除了参与恐惧相关过程外,钙离子在运动和运动中也扮演着重要角色。要想充分了解前脑功能区和其他脑区在压力和恐惧反应中的作用,同时纳入女性和男性受试者对于此类研究至关重要。认识到性别差异会增强我们对大脑功能的理解,并能在研究和治疗压力和恐惧相关疾病时采用更加个性化和有效的方法。
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引用次数: 0
Isolated during adolescence: long-term impact on social behavior, pain sensitivity, and the oxytocin system in male and female rats. 青春期隔离:对雌雄大鼠社交行为、疼痛敏感性和催产素系统的长期影响。
IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-15 DOI: 10.1186/s13293-024-00655-7
Akseli P Graf, Anita C Hansson, Rainer Spanagel

Background: Adolescent social isolation (ASI) has profound long-term effects on behavioral and neural development. Despite this, the specific long-term impact of ASI during different adolescent stages and across sexes remain underexplored.

Methods: Our study addresses this gap by examining the effects of early- and late- adolescent social isolation on both male and female rats. Rats were either isolated (or group-housed) starting from PD 21 (early) or PD 42 (late) for three weeks and then rehoused into groups. In adulthood (PD 90), rats underwent a battery of tests: elevated plus-maze, open field, novel object recognition, social interaction and social recognition memory and hotplate tests. Finally, we analyzed oxytocin receptor binding in several regions in the brains of a second cohort of rats.

Results: Both, male and female rats from the late adolescent social isolation (LASI) groups spent significantly less time interacting in the social interaction test. Additionally, we observed a general decrease in social recognition memory regardless of sex. Both male ASI groups demonstrated heightened thermal pain sensitivity, while the opposite was observed in early adolescent social isolation (EASI) female rats. In the brain, we observed changes in oxytocin receptor (OTR) binding in the paraventricular nucleus of the hypothalamus (PVN) and paraventricular nucleus of the thalamus (PVT) and central amygdala (CeA) with the largest changes in EASI and LASI female rats.

Conclusion: Our model demonstrates long-lasting alterations on behavior and oxytocin receptor binding levels following ASI providing insights into the long-term effects of ASI in a time- and sex-specific manner.

背景:青少年社会隔离(ASI)会对行为和神经发育产生深远的长期影响。尽管如此,不同青春期阶段和不同性别的青少年社会隔离的具体长期影响仍未得到充分探索:我们的研究通过考察青春期早期和晚期社会隔离对雄性和雌性大鼠的影响来填补这一空白。大鼠从青春期21(早期)或42(晚期)开始被隔离(或群居)三周,然后重新群居。在成年期(PD 90),大鼠接受了一系列测试:高架迷宫、开阔地、新物体识别、社会互动和社会识别记忆以及热板测试。最后,我们分析了第二批大鼠大脑中多个区域的催产素受体结合情况:结果:青春期晚期社会隔离(LASI)组的雄性和雌性大鼠在社会互动测试中的互动时间都明显减少。此外,我们还观察到,无论性别如何,大鼠的社会识别记忆力普遍下降。两组雄性 ASI 大鼠的热痛敏感性都有所提高,而青春期早期社会隔离(EASI)雌性大鼠的情况则恰恰相反。在大脑中,我们观察到下丘脑室旁核(PVN)、丘脑室旁核(PVT)和杏仁核中央(CeA)的催产素受体(OTR)结合发生了变化,其中EASI和LASI雌性大鼠的变化最大:我们的模型显示了 ASI 对大鼠行为和催产素受体结合水平的持久改变,这有助于深入了解 ASI 在时间和性别上的特异性长期影响。
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引用次数: 0
Integration of long-read sequencing, DNA methylation and gene expression reveals heterogeneity in Y chromosome segment lengths in phenotypic males with 46,XX testicular disorder/difference of sex development. 长线程测序、DNA甲基化和基因表达的整合揭示了46,XX睾丸疾病/性别发育差异表型男性Y染色体片段长度的异质性。
IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-08 DOI: 10.1186/s13293-024-00654-8
Agnethe Berglund, Emma B Johannsen, Anne Skakkebæk, Simon Chang, Julia Rohayem, Sandra Laurentino, Arne Hørlyck, Simon O Drue, Ebbe Norskov Bak, Jens Fedder, Frank Tüttelmann, Jörg Gromoll, Jesper Just, Claus H Gravholt

Background: 46,XX testicular disorder/difference of sex development (46,XX DSD) is a rare congenital condition, characterized by a combination of the typical female sex chromosome constitution, 46,XX, and a variable male phenotype. In the majority of individuals with 46,XX DSD, a Y chromosome segment containing the sex-determining region gene (SRY) has been translocated to the paternal X chromosome. However, the precise genomic content of the translocated segment and the genome-wide effects remain elusive.

Methods: We performed long-read DNA sequencing, RNA sequencing and DNA methylation analyses on blood samples from 46,XX DSD (n = 11), male controls (46,XY; variable cohort sizes) and female controls (46,XX; variable cohort sizes), in addition to RNA sequencing and DNA methylation analysis on blood samples from males with Klinefelter syndrome (47,XXY, n = 22). We also performed clinical measurements on all 46,XX DSD and a subset of 46,XY (n = 10).

Results: We identified variation in the translocated Y chromosome segments, enabling subcategorization into 46,XX DSD (1) lacking Y chromosome material (n = 1), (2) with short Yp arms (breakpoint at 2.7-2.8 Mb, n = 2), (3) with medium Yp arms (breakpoint at 7.3 Mb, n = 1), and (4) with long Yp arms (n = 7), including deletions of AMELY, TBLY1 and in some cases PRKY. We also identified variable expression of the X-Y homologues PRKY and PRKX. The Y-chromosomal transcriptome and methylome reflected the Y chromosome segment lengths, while changes to autosomal and X-chromosomal regions indicated global effects. Furthermore, transcriptional changes tentatively correlated with phenotypic traits of 46,XX DSD, including reduced height, lean mass and testicular size.

Conclusion: This study refines our understanding of the genetic composition in 46,XX DSD, describing the translocated Y chromosome segment in more detail than previously and linking variability herein to genome-wide changes in the transcriptome and methylome.

背景:46,XX睾丸发育障碍/性别发育差异(46,XX DSD)是一种罕见的先天性疾病,其特征是典型的女性性染色体结构(46,XX)和可变的男性表型的结合。在大多数 46,XX DSD 患者中,含有性别决定区基因(SRY)的 Y 染色体片段被易位到父方的 X 染色体上。然而,该易位片段的精确基因组内容及其对全基因组的影响仍然难以捉摸:我们对 46,XX DSD(n = 11)、男性对照组(46,XY;队列大小不一)和女性对照组(46,XX;队列大小不一)的血液样本进行了长线程 DNA 测序、RNA 测序和 DNA 甲基化分析,此外还对 Klinefelter 综合征(47,XXY,n = 22)男性患者的血液样本进行了 RNA 测序和 DNA 甲基化分析。我们还对所有 46,XX DSD 和 46,XY 子集(n = 10)进行了临床测量:结果:我们确定了易位 Y 染色体片段的变异,从而将 46,XX DSD 分成以下几类:(1)缺乏 Y 染色体材料(n = 1);(2)短 Yp 臂(断点在 2.7-2.8 Mb,n = 2);(3)中等 Yp 臂(断点在 7.3 Mb,n = 1);(4)长 Yp 臂(n = 7),包括 AMELY、TBLY1 和某些 PRKY 的缺失。我们还发现了 X-Y 同源物 PRKY 和 PRKX 的可变表达。Y 染色体转录组和甲基组反映了 Y 染色体片段的长度,而常染色体和 X 染色体区域的变化则显示了整体效应。此外,转录变化还与 46,XX DSD 的表型特征(包括身高、瘦体重和睾丸大小的减少)初步相关:这项研究完善了我们对 46,XX DSD 遗传组成的认识,比以前更详细地描述了易位的 Y 染色体片段,并将其中的变异与转录组和甲基组的全基因组变化联系起来。
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引用次数: 0
Female-bias in systemic lupus erythematosus: How much is the X chromosome to blame? 系统性红斑狼疮的女性偏爱:X染色体的责任有多大?
IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-10-07 DOI: 10.1186/s13293-024-00650-y
Adriana A Vieira, Inês Almada-Correia, Joana Inácio, Patrícia Costa-Reis, S T da Rocha

Systemic lupus erythematosus (SLE or lupus) is an immune-mediated disease associated with substantial medical burden. Notably, lupus exhibits a striking female bias, with women having significantly higher susceptibility compared to men, up to 14-fold higher in some ethnicities. Supernumerary X chromosome syndromes, like Klinefelter (XXY) and Triple X syndrome (XXX), also present higher SLE prevalence, whereas Turner syndrome (XO) displays lower prevalence. Taken together, SLE prevalence in different X chromosome dosage sceneries denotes a relationship between the number of X chromosomes and the risk of developing lupus. The dosage of X-linked genes, many of which play roles in the immune system, is compensated between males and females through the inactivation of one of the two X chromosomes in female cells. X-chromosome inactivation (XCI) initiates early in development with a random selection of which X chromosome to inactivate, a choice that is then epigenetically maintained in the daughter cells. This process is regulated by the X-Inactive-Specific Transcript (XIST), encoding for a long non-coding RNA, exclusively expressed from the inactive X chromosome (Xi). XIST interacts with various RNA binding proteins and chromatin modifiers to form a ribonucleoprotein (RNP) complex responsible for the transcriptional silencing and heterochromatinization of the Xi. This ensures stable silencing of most genes on the X chromosome, with only a few genes able to escape this process. Recent findings suggest that the molecular components involved in XCI, or their dysregulation, contribute to the pathogenesis of lupus. Indeed, nonrandom XCI, elevated gene escape from XCI, and the autoimmune potential of the XIST RNP complex have been suggested to contribute to auto-immune diseases, such as lupus. This review examines these current hypotheses concerning how this dosage compensation mechanism might impact the development of lupus, shedding light on potential mechanisms underlying the pathogenesis of the disease.

系统性红斑狼疮(SLE 或狼疮)是一种由免疫介导的疾病,给患者带来沉重的医疗负担。值得注意的是,狼疮有明显的女性偏向,女性的易感性明显高于男性,在某些种族中,女性的易感性可高达男性的14倍。X 染色体超常综合征,如 Klinefelter(XXY)和三X 综合征(XXX),其系统性红斑狼疮发病率也较高,而特纳综合征(XO)的发病率则较低。总之,不同 X 染色体剂量情况下系统性红斑狼疮的发病率表明,X 染色体的数量与患狼疮的风险之间存在一定的关系。许多在免疫系统中发挥作用的 X 连锁基因的剂量是通过女性细胞中两条 X 染色体中的一条失活来在男性和女性之间进行补偿的。X 染色体失活(XCI)始于发育早期,随机选择要失活的 X 染色体,然后在子细胞中通过表观遗传学保持这一选择。这一过程受 X 非活性特异性转录本(XIST)的调控,该转录本编码一种非编码长 RNA,仅由非活性 X 染色体(Xi)表达。XIST 与各种 RNA 结合蛋白和染色质修饰因子相互作用,形成一个核糖核蛋白(RNP)复合物,负责 Xi 的转录沉默和异染色质化。这确保了 X 染色体上大多数基因的稳定沉默,只有少数基因能够逃脱这一过程。最近的研究结果表明,参与 XCI 的分子成分或它们的失调有助于红斑狼疮的发病机制。事实上,非随机 XCI、基因从 XCI 中逃逸的程度升高以及 XIST RNP 复合物的自身免疫潜能都被认为是红斑狼疮等自身免疫性疾病的诱因。这篇综述探讨了目前关于剂量补偿机制如何影响红斑狼疮发病的假设,揭示了该病发病机制的潜在机制。
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引用次数: 0
Sex differences in symptoms following the administration of BNT162b2 mRNA COVID-19 vaccine in children below 5 years of age in Germany (CoVacU5): a retrospective cohort study. 德国 5 岁以下儿童接种 BNT162b2 mRNA COVID-19 疫苗(CoVacU5)后症状的性别差异:一项回顾性队列研究。
IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-26 DOI: 10.1186/s13293-024-00651-x
Jeanne Moor, Nicole Toepfner, Wolfgang C G von Meißner, Reinhard Berner, Matthias B Moor, Karolina Kublickiene, Christoph Strumann, Cho-Ming Chao

Background: Sex differences exist not only in the efficacy but also in adverse event rates of many vaccines. Here we compared the safety of BNT162b2 vaccine administered off-label in female and male children younger than 5 years in Germany.

Methods: This is a retrospective cohort study, in which we performed a post-hoc analysis of a dataset collected through an authentication-based survey of individuals having registered children aged 0-<5 years for vaccination against SARS-CoV-2 in six private practices and/or two lay person-initiated vaccination campaigns. We analyzed the safety profiles of the first 3 doses of 3-10 µg BNT162b2. Primary outcome was comparison in frequencies of 4 common post-vaccination symptom categories such as local, general, musculoskeletal symptoms and fever. Data were analyzed according to sex in bivariate analyses and regression models adjusting for age, weight, and dosage. Interaction between sex and BNT162b2 dosage was assessed. An active-comparator analysis was applied to compare post-vaccination symptoms after BNT162b2 versus non-SARS-CoV-2 vaccines.

Results: The dataset for the present analysis consisted of 7801 participants including 3842 females (49%) and 3977 males (51%) with an age of 3 years (median, interquartile: 2 years). Among individuals receiving 3 µg BNT162b2, no sex differences were noted, but after a first dose of 5-10 µg BNT162b2, local injection-site symptoms were more prevalent in girls compared to boys. In logistic regression, female sex was associated with higher odds of local symptoms, odds ratio (OR) of 1.33 (95% confidence interval [CI]: 1.15-1.55, p < 0.05) and general symptoms with OR 1.21 (95% CI: 1.01-1.44, p < 0.05). Following non-BNT162b2 childhood vaccinations, female sex was associated with a lower odds of post-vaccination musculoskeletal symptoms (OR: 0.29, 95% CI: 0.11-0.82, p < 0.05). An active comparator analysis between BNT162b2 and non-SARS-CoV-2 vaccinations revealed that female sex positively influenced the association between BNT162b2 vaccine type and musculoskeletal symptoms.

Conclusions: Sex differences exist in post-vaccination symptoms after BNT162b2 administration even in young children. These are of importance for the conception of approval studies, for post-vaccination monitoring and for future vaccination strategies (German Clinical Trials Register ID: DRKS00028759).

背景:许多疫苗不仅在效力上存在性别差异,在不良反应率上也是如此。在此,我们比较了德国 5 岁以下男女儿童在标签外接种 BNT162b2 疫苗的安全性:这是一项回顾性队列研究,我们对通过认证调查收集的数据集进行了事后分析,调查对象是登记有 0 岁儿童的个人:本次分析的数据集包括 7801 名参与者,其中女性 3842 名(占 49%),男性 3977 名(占 51%),年龄为 3 岁(中位数,四分位数之间为 2 岁)。在接受 3 µg BNT162b2 治疗的患者中,没有发现性别差异,但在首次接受 5-10 µg BNT162b2 治疗后,女孩出现注射部位局部症状的比例高于男孩。在逻辑回归中,女性出现局部症状的几率更高,几率比(OR)为 1.33(95% 置信区间 [CI]:1.15-1.55,P<0.05):1.33(95% 置信区间 [CI]:1.15-1.55,P 结论:接种疫苗后存在性别差异:即使是幼儿,接种 BNT162b2 后的症状也存在性别差异。这对审批研究的构思、疫苗接种后的监测以及未来的疫苗接种策略都具有重要意义(德国临床试验注册编号:DRKS00028759)。
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引用次数: 0
Sex-dependent effects of acute stress and alcohol exposure during adolescence on mRNA expression of brain signaling systems involved in reward and stress responses in young adult rats. 青春期急性应激和酒精暴露对年轻成年大鼠大脑奖赏和应激反应信号系统 mRNA 表达的性别依赖性影响
IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-26 DOI: 10.1186/s13293-024-00649-5
Carlotta Gobbi, Laura Sánchez-Marín, María Flores-López, Dina Medina-Vera, Francisco Javier Pavón-Morón, Fernando Rodríguez de Fonseca, Antonia Serrano

Background: Adolescent stress and alcohol exposure increase the risk of maladaptive behaviors and mental disorders in adulthood, with distinct sex-specific differences. Understanding the mechanisms underlying these early events is crucial for developing targeted prevention and treatment strategies.

Methods: Male and female Wistar rats were exposed to acute restraint stress and intermittent alcohol during adolescence. We assessed lasting effects on plasma corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels, and mRNA expression of genes related to corticotropin releasing hormone (CRH), neuropeptide Y (NPY), corticoid, opioid, and arginine vasopressin systems in the amygdala and hypothalamus.

Results: The main findings are as follows: (1) blood alcohol concentrations (BAC) increased after the final alcohol administration, but stressed males had lower BAC than non-stressed males; (2) Males gained significantly more weight than females; (3) Stressed females showed higher ACTH levels than non-stressed females, with no changes in males; (4) Stress increased CORT levels in males, while stressed, alcohol-treated females had lower CORT levels than non-stressed females; (5) CRH: Females had lower Crhr1 levels in the amygdala, while alcohol reduced Crhr2 levels in males but not females. Significant interactions among sex, stress, and alcohol were found in the hypothalamus, with distinct patterns between sexes; (6) NPY: In the amygdala, stress reduced Npy and Npy1r levels in males but increased them in females. Alcohol decreased Npy2r levels in males, with varied effects in females. Similar sex-specific patterns were observed in the hypothalamus; (7) Corticoid system: Stress and alcohol had complex, sex-dependent effects on Pomc, Nr3c1, and Nr3c2 in both brain regions; (8) Opioid receptors: Stress and alcohol blunted the elevated expression of Oprm1, Oprd1, and Oprk1 in the amygdala of males and the hypothalamus of females; (8) Vasopressin: Stress and alcohol interacted significantly to affect Avp and Avpr1a expression in the amygdala, with stronger effects in females. In the hypothalamus, alcohol increased Avp levels in females.

Conclusions: This study demonstrates that adolescent acute stress and alcohol exposure induce lasting, sex-specific alterations in systems involved in reward and stress responses. These findings emphasize the importance of considering sex differences in the prevention and management of HPA dysfunction and psychiatric disorders.

背景:青少年时期的压力和酗酒会增加成年后出现适应不良行为和精神障碍的风险,并具有明显的性别差异。了解这些早期事件的内在机制对于制定有针对性的预防和治疗策略至关重要:方法:雄性和雌性 Wistar 大鼠在青春期受到急性束缚应激和间歇性酒精的影响。我们评估了对血浆皮质酮(CORT)和促肾上腺皮质激素(ACTH)水平以及杏仁核和下丘脑中促肾上腺皮质激素释放激素(CRH)、神经肽 Y(NPY)、类皮质激素、阿片类和精氨酸加压素系统相关基因 mRNA 表达的持久影响:主要研究结果如下(结果:主要发现如下:(1) 血液中酒精浓度(BAC)在最后一次给药后升高,但应激男性的 BAC 水平低于非应激男性;(2) 男性体重增加明显多于女性;(3) 应激女性的促肾上腺皮质激素(ACTH)水平高于非应激女性,男性无变化;(4) 应激增加了男性的促肾上腺皮质激素(CORT)水平,而应激、酒精处理的女性的促肾上腺皮质激素(CORT)水平低于非应激女性;(5) CRH:杏仁核中女性的 Crhr1 水平较低,而酒精会降低男性的 Crhr2 水平,但不会降低女性的 Crhr2 水平。在下丘脑中发现了性别、压力和酒精之间的显著交互作用,不同性别之间有不同的模式;(6)NPY:在杏仁核中,压力降低了男性的 Npy 和 Npy1r 水平,但增加了女性的 Npy 和 Npy1r 水平。酒精会降低男性的 Npy2r 水平,但对女性的影响各不相同。在下丘脑中也观察到类似的性别特异性模式;(7)皮质类固醇系统:压力和酒精对两个脑区的 Pomc、Nr3c1 和 Nr3c2 都有复杂的性别依赖性影响;(8)阿片受体:压力和酒精削弱了男性杏仁核和女性下丘脑中 Oprm1、Oprd1 和 Oprk1 的表达;(8)血管加压素:压力和酒精对杏仁核中 Avp 和 Avpr1a 的表达有明显的交互作用,对女性的影响更大。在下丘脑中,酒精会增加女性的 Avp 水平:本研究表明,青少年急性应激反应和酒精暴露会诱导奖赏和应激反应系统发生持久的、有性别特异性的改变。这些发现强调了在预防和处理 HPA 功能障碍和精神疾病时考虑性别差异的重要性。
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引用次数: 0
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