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Browsing by Subject "Sexual dimorphism"
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Item Fluctuating Asymmetry and Sexual Dimorphism in Human Facial Morphology: A Multi-Variate Study(MDPI, 2021-02) Ekrami, Omid; Claes, Peter; Van Assche, Ellen; Shriver, Mark D.; Weinberg, Seth M.; Marazita, Mary L.; Walsh, Susan; Van Dongen, Stefan; Biology, School of ScienceBackground: Fluctuating asymmetry is often used as an indicator of developmental instability, and is proposed as a signal of genetic quality. The display of prominent masculine phenotypic features, which are a direct result of high androgen levels, is also believed to be a sign of genetic quality, as these hormones may act as immunosuppressants. Fluctuating asymmetry and masculinity are therefore expected to covary. However, there is lack of strong evidence in the literature regarding this hypothesis. Materials and methods: In this study, we examined a large dataset of high-density 3D facial scans of 1260 adults (630 males and 630 females). We mapped a high-density 3D facial mask onto the facial scans in order to obtain a high number of quasi-landmarks on the faces. Multi-dimensional measures of fluctuating asymmetry were extracted from the landmarks using Principal Component Analysis, and masculinity/femininity scores were obtained for each face using Partial Least Squares. The possible correlation between these two qualities was then examined using Pearson's coefficient and Canonical Correlation Analysis. Results: We found no correlation between fluctuating asymmetry and masculinity in men. However, a weak but significant correlation was found between average fluctuating asymmetry and masculinity in women, in which feminine faces had higher levels of fluctuating asymmetry on average. This correlation could possibly point to genetic quality as an underlying mechanism for both asymmetry and masculinity; however, it might also be driven by other fitness or life history traits, such as fertility. Conclusions: Our results question the idea that fluctuating asymmetry and masculinity should be (more strongly) correlated in men, which is in line with the recent literature. Future studies should possibly focus more on the evolutionary relevance of the observed correlation in women.Item Interaction of sexual dimorphism and gene dosage imbalance in skeletal deficits associated with Down syndrome(Elsevier, 2020-04-17) Thomas, Jared R.; LaCombe, Jonathan; Long, Rachel; Lana-Elola, Eva; Watson-Scales, Sheona; Wallace, Joseph M.; Fisher, Elizabeth M. C.; Tybulewicz, Victor L. J.; Roper, Randall J.; Biology, School of Sciencepresent with skeletal abnormalities typified by craniofacial features, short stature and low bone mineral density (BMD). Differences in skeletal deficits between males and females with DS suggest a sexual dimorphism in how trisomy affects bone. Dp1Tyb mice contain three copies of all of the genes on mouse chromosome 16 that are homologous to human chromosome 21, males and females are fertile, and therefore are an excellent model to test the hypothesis that gene dosage influences the sexual dimorphism of bone abnormalities in DS. Dp1Tyb as compared to control littermate mice at time points associated with bone accrual (6 weeks) and skeletal maturity (16 weeks) showed deficits in BMD and trabecular architecture that occur largely through interactions between sex and genotype and resulted in lower percent bone volume in all female and Dp1Tyb male mice. Cortical bone in Dp1Tyb as compared to control mice exhibited different changes over time influenced by sex × genotype interactions including reduced cortical area in both male and female Dp1Tyb mice. Mechanical testing analyses suggested deficits in whole bone properties such as bone mass and geometry, but improved material properties in female and Dp1Tyb mice. Sexual dimorphisms and the influence of trisomic gene dosage differentially altered cellular properties of male and female Dp1Tyb bone. These data establish sex, gene dosage, skeletal site and age as important factors in skeletal development of DS model mice, paving the way for identification of the causal dosage-sensitive genes. Skeletal differences in developing male and female Dp1Tyb DS model mice replicated differences in less-studied adolescents with DS and established a foundation to understand the etiology of trisomic bone deficits.Item A Multivariate Approach to Determine the Dimensionality of Human Facial Asymmetry(MDPI, 2020-03) Ekrami, Omid; Claes, Peter; White, Julie D.; Weinberg, Seth M.; Marazita, Mary L.; Walsh, Susan; Shriver, Mark D.; Van Dongen, Stefan; Biology, School of ScienceMany studies have suggested that developmental instability (DI) could lead to asymmetric development, otherwise known as fluctuating asymmetry (FA). Several attempts to unravel the biological meaning of FA have been made, yet the main step in estimating FA is to remove the effects of directional asymmetry (DA), which is defined as the average bilateral asymmetry at the population level. Here, we demonstrate in a multivariate context that the conventional method of DA correction does not adequately compensate for the effects of DA in other dimensions of asymmetry. This appears to be due to the presence of between-individual variation along the DA dimension. Consequently, we propose to decompose asymmetry into its different orthogonal dimensions, where we introduce a new measure of asymmetry, namely fluctuating directional asymmetry (F-DA). This measure describes individual variation in the dimension of DA, and can be used to adequately correct the asymmetry measurements for the presence of DA. We provide evidence that this measure can be useful in disentangling the different dimensions of asymmetry, and further studies on this measure can provide valuable insight into the underlying biological processes leading to these different asymmetry dimensions.Item Sex specificity of pancreatic cancer cachexia phenotypes, mechanisms, and treatment in mice and humans: role of Activin(Wiley, 2022) Zhong, Xiaoling; Narasimhan, Ashok; Silverman, Libbie M.; Young, Andrew R.; Shahda, Safi; Liu, Sheng; Wan, Jun; Liu, Yunlong; Koniaris, Leonidas G.; Zimmers, Teresa A.; Surgery, School of MedicineBackground: Cachexia is frequent, deadly, and untreatable for patients with pancreatic ductal adenocarcinoma (PDAC). The reproductive hormone and cytokine Activin is a mediator of PDAC cachexia, and Activin receptor targeting was clinically tested for cancer cachexia therapy. However, sex-specific manifestations and mechanisms are poorly understood, constraining development of effective treatments. Methods: Cachexia phenotypes, muscle gene/protein expression, and effects of the Activin blocker ACVR2B/Fc were assessed in LSL-KrasG12D/+ , LSL-Trp53R172H/+ , and Pdx-1-Cre (KPC) mice with autochthonic PDAC. Effects of PDAC and sex hormones were modelled by treating C2C12 myotubes with KPC-cell conditioned medium (CM) and estradiol. Muscle gene expression by RNAseq and change in muscle from serial CT scans were measured in patients with PDAC. Results: Despite equivalent tumour latency (median 17 weeks) and mortality (24.5 weeks), male KPC mice showed earlier and more severe cachexia than females. In early PDAC, male gastrocnemius, quadriceps, and tibialis anterior muscles were reduced (-21.7%, -18.9%, and -20.8%, respectively, all P < 0.001), with only gastrocnemius reduced in females (-16%, P < 0.01). Sex differences disappeared in late PDAC. Plasma Activin A was similarly elevated between sexes throughout, while oestrogen and testosterone levels suggested a virilizing effect of PDAC in females. Estradiol partially protected myotubes from KPC-CM induced atrophy and promoted expression of the potential Activin inhibitor Fstl1. Early-stage female mice showed greater muscle expression of Activin inhibitors Fst, Fstl1, and Fstl3; this sex difference disappeared by late-stage PDAC. ACVR2B/Fc initiated in early PDAC preserved muscle and fat only in male KPC mice, with increases of 41.2%, 52.6%, 39.3%, and 348.8%, respectively, in gastrocnemius, quadriceps, tibialis, and fat pad weights vs. vehicle controls, without effect on tumour. No protection was observed in females. At protein and RNA levels, pro-atrophy pathways were induced more strongly in early-stage males, with sex differences less evident in late-stage disease. As with mass, ACVR2B/Fc blunted atrophy-associated pathways only in males. In patients with resectable PDAC, muscle expression of Activin inhibitors FSTL1, FSLT3, and WFIKKN2/GASP2 were higher in women than men. Overall, among 124 patients on first-line gemcitabine/nab-paclitaxel for PDAC, only men displayed muscle loss (P < 0.001); average muscle wasting in men was greater (-6.63 ± 10.70% vs. -1.62 ± 12.00% mean ± SD, P = 0.038) and more rapid (-0.0098 ± 0.0742%/day vs. -0.0466 ± 0.1066%/day, P = 0.017) than in women. Conclusions: Pancreatic ductal adenocarcinoma cachexia displays sex-specific phenotypes in mice and humans, with Activin a preferential driver of muscle wasting in males. Sex is a major modulator of cachexia mechanisms. Consideration of sexual dimorphism is essential for discovery and development of effective treatments.Item Skeletal Deficits in Male and Female down Syndrome Model Mice Arise Independent of Normalized Dyrk1a Expression in Osteoblasts(MDPI, 2021-10-28) Thomas, Jared R.; Sloan, Kourtney; Cave, Kelsey; Wallace, Joseph M.; Roper, Randall J.; Biology, School of ScienceTrisomy 21 (Ts21) causes alterations in skeletal development resulting in decreased bone mass, shortened stature and weaker bones in individuals with Down syndrome (DS). There is a sexual dimorphism in bone mineral density (BMD) deficits associated with DS with males displaying earlier deficits than females. The relationships between causative trisomic genes, cellular mechanisms, and influence of sex in DS skeletal abnormalities remain unknown. One hypothesis is that the low bone turnover phenotype observed in DS results from attenuated osteoblast function, contributing to impaired trabecular architecture, altered cortical geometry, and decreased mineralization. DYRK1A, found in three copies in humans with DS, Ts65Dn, and Dp1Tyb DS model mice, has been implicated in the development of postnatal skeletal phenotypes associated with DS. Reduced copy number of Dyrk1a to euploid levels from conception in an otherwise trisomic Ts65Dn mice resulted in a rescue of appendicular bone deficits, suggesting DYRK1A contributes to skeletal development and homeostasis. We hypothesized that reduction of Dyrk1a copy number in trisomic osteoblasts would improve cellular function and resultant skeletal structural anomalies in trisomic mice. Female mice with a floxed Dyrk1a gene (Ts65Dn,Dyrk1afl/wt) were mated with male Osx-Cre+ (expressed in osteoblasts beginning around E13.5) mice, resulting in reduced Dyrk1a copy number in mature osteoblasts in Ts65Dn,Dyrk1a+/+/Osx-Cre P42 male and female trisomic and euploid mice, compared with littermate controls. Male and female Ts65Dn,Dyrk1a+/+/+ (3 copies of DYRK1A in osteoblasts) and Ts65Dn,Dyrk1a+/+/Osx-Cre (2 copies of Dyrk1a in osteoblasts) displayed similar defects in both trabecular architecture and cortical geometry, with no improvements with reduced Dyrk1a in osteoblasts. This suggests that trisomic DYRK1A does not affect osteoblast function in a cell-autonomous manner at or before P42. Although male Dp1Tyb and Ts65Dn mice exhibit similar skeletal deficits at P42 in both trabecular and cortical bone compartments between euploid and trisomic mice, female Ts65Dn mice exhibit significant cortical and trabecular deficits at P42, in contrast to an absence of genotype effect in female Dp1Tyb mice in trabecular bone. Taken together, these data suggest skeletal deficits in DS mouse models and are sex and age dependent, and influenced by strain effects, but are not solely caused by the overexpression of Dyrk1a in osteoblasts. Identifying molecular and cellular mechanisms, disrupted by gene dosage imbalance, that are involved in the development of skeletal phenotypes associated with DS could help to design therapies to rescue skeletal deficiencies seen in DS.Item Sustained Stimulus Paradigms and Sexual Dimorphism of the Aortic Baroreflex in Rat(2019-05) Mintch, Landan M.; Schild, John; Yoshida, Ken; Mirro, MichaelThe neurophysiological pathways associated with beat-to-beat regulation of mean arterial pressure are well known. Less known are the control dynamics associated with short term maintained of arterial blood pressure about a homeostatic set point. The barorefex (BRx), the most rapid and robust of neural refexes within the autonomic nervous system, is a negative feedback controller that monitors and regulates heart rate and blood pressure. By leveraging the parasympathetic and sympathetic divisions of the autonomic nervous system, the BRx can change blood pressure within a single heart beat. To better understand these controller dynamics, a classic BRx refexogenic experimental preparation was carried out. This thesis recon rmed previous observations of an electrically-evoked sexually-dimorphic peak depressor response in the BRx of Sprague-Dawley rats and veri ed that these functional refexogenic differences carry over to sustained electrical paradigms. Further, it uncovered interesting recovery dynamics in both blood pressure and heart rate. The rat aortic depressor nerve was used as an experimental target for electrical activation of the parasympathetic-mediated reduction in mean arterial pressure. The duration, frequency, and patterning of stimulation were explored, with emphasis on differences between sexes. By measuring the normalized percent decrease in mean arterial pressure as well as the differences in beats per minute during rest and during stimulation, the null hypothesis was rejected.Item Using data‐driven phenotyping to investigate the impact of sex on 3D human facial surface morphology(Wiley, 2023) Matthews, Harold S.; Mahdi, Soha; Penington, Anthony J.; Marazita, Mary L.; Shaffer, John R.; Walsh, Susan; Shriver, Mark D.; Claes, Peter; Weinberg, Seth M.; Biology, School of ScienceThe effects of sex on human facial morphology have been widely documented. Because sexual dimorphism is relevant to a variety of scientific and applied disciplines, it is imperative to have a complete and accurate account of how and where male and female faces differ. We apply a comprehensive facial phenotyping strategy to a large set of existing 3D facial surface images. We investigate facial sexual dimorphism in terms of size, shape, and shape variance. We also assess the ability to correctly assign sex based on shape, both for the whole face and for subregions. We applied a predefined data-driven segmentation to partition the 3D facial surfaces of 2446 adults into 63 hierarchically linked regions, ranging from global (whole face) to highly localized subparts. Each facial region was then analyzed with spatially dense geometric morphometrics. To describe the major modes of shape variation, principal components analysis was applied to the Procrustes aligned 3D points comprising each of the 63 facial regions. Both nonparametric and permutation-based statistics were then used to quantify the facial size and shape differences and visualizations were generated. Males were significantly larger than females for all 63 facial regions. Statistically significant sex differences in shape were also seen in all regions and the effects tended to be more pronounced for the upper lip and forehead, with more subtle changes emerging as the facial regions became more granular. Males also showed greater levels of shape variance, with the largest effect observed for the central forehead. Classification accuracy was highest for the full face (97%), while most facial regions showed an accuracy of 75% or greater. In summary, sex differences in both size and shape were present across every part of the face. By breaking the face into subparts, some shape differences emerged that were not apparent when analyzing the face as a whole. The increase in facial shape variance suggests possible evolutionary origins and may offer insights for understanding congenital facial malformations. Our classification results indicate that a high degree of accuracy is possible with only parts of the face, which may have implications for biometrics applications.