Introduction This study aimed to assess whether sagittal maxillary-mandibular skeletal relationships influence perceived facial esthetics in patients with varying sagittal skeletal discrepancies. Methods We analyzed 3-dimensional facial models from cone-beam computed tomography scans of 40 patients (17 males and 23 females aged 14-48 years; ANB = 0°-10°), lacking skin color or hair, to isolate shape. A total of 100 laypeople rated these for esthetics and sexual dimorphism using visual analogue scales. Procrustes-based 3-dimensional geometric morphometrics quantified shape, and multivariate linear regression estimated vectors for visual analogue scales ratings. Linear regression tested correlations between shapes linked to the ANB angle and esthetics. Results Perceived attractiveness was unrelated to age, asymmetry, or deviation from the population average shape. Esthetics correlated with lower facial third shape (r2 = 0.473, P = 0.058, 4.5% variation), particularly with anterior or inferior gnathion and pogonion displacement, with consistent patterns across sexes (rv = 69.2°, P <0.0001). Shapes associated with higher ANB angles (indicating convexity) showed a negative association with attractiveness (r2 = 0.494, P <0.001). Sexual dimorphism was linked to cheek placement, facial roundness, and nasal tip position (r2 = 0.558, P = 0.001, 9.0% variation). Conclusions Sagittal maxillary-mandibular relationships, as measured by the ANB angle and sagittal skeletal discrepancy, modestly influence facial esthetics, with straighter profiles and prominent chins rated more attractive. These findings suggest a partial biological basis for esthetic preferences, though individual and cultural factors, including smile esthetics and dental symmetry, also play a role. The study informs orthodontic treatment planning by highlighting the esthetic impact of jaw alignment.

The analysis of patterns of trait covariance is of tremendous importance in the study of evolution and development as well as in quantitative genetics. Multivariate quantitative genetics and morphological integration were combined in the 1980s under the latent variable model for integration developed by Wagner and Cheverud. The palimpsest framework builds on this model. Based on a definition of integration as disposition, it distinguishes between the developmental determinants of covariation (integration) and observed phenotypic covariance patterns. Further, the palimpsest distinguishes between the role of the distribution of variance across latent processes that generate covariance versus the developmental architectural features that connect those processes to phenotypic traits. In this paper, we construct a simple simulation to illustrate how these two different aspects of integration relate to observed phenotypic covariance patterns. We show that: (1) changes in the distribution of variance across latent processes can significantly alter both integratedness and covariance structure, (2) increases in the variance of leading processes tend to increase integratedness and the circumstances under which integratedness decreases are more restricted, (3) changes in the relative variances of latent processes can result in discontinuous change covariance structure, (4) changes in which developmental processes are linked to which traits (the process-trait map) can also alter covariance structure and interact with how variance is allocated among processes in complex ways. These findings can serve to inform and ground hypotheses about covariance structures and their interpretation in real biological settings.

Craniofacial abnormalities are among the most prevalent congenital defects, significantly affecting appearance, function, and quality of life. While the role of genetic mutations in craniofacial malformations is recognized, the underlying molecular mechanisms remain poorly understood. In this study, we investigate the role of p75 neurotrophin receptor (p75NTR) in craniofacial development by comparing wild-type (p75NTR+/+) mice against p75NTR-deficient (p75NTR-/-) knockout mice. We employed histology, micro-CT surface distance, volumetric analysis, and geometric morphometric analysis to assess craniofacial development and growth. On postnatal day 7 (P7), p75NTR-/- mice exhibited reduced skull length compared to wild-type controls. By P28, micro-CT analysis revealed significant reductions in calvarial bone volume and trabecular bone thickness in p75NTR-/- mice. Geometric morphometric analysis identified significant shape alterations in the nasal, parietal, and occipital regions, with p75NTR-/- mice showing a shortened cranium and tapered nasal bone morphology. These findings highlight the critical role of p75NTR in regulating postnatal craniofacial development. Disruption of p75NTR signaling impairs both the growth and morphological integrity of craniofacial structures, which may contribute to the pathogenesis of congenital craniofacial abnormalities. In the future, a better understanding of the molecular mechanisms through which p75NTR mediates craniofacial development may offer valuable insights for future targeted therapeutic strategies for craniofacial defects.

IntroductionSpecific scapula shapes are associated with full-thickness tears of the supraspinatus tendon. A primary role of the supraspinatus is to actively stabilize the glenohumeral joint against muscles that generate destabilizing shear forces. Mechanisms that increase the supraspinatus load required to perform this stabilizing function may increase an individual's susceptibility to tears. Previous work has shown that tear-associated scapula shapes increase the destabilizing action of the deltoid during arm-raising, but no work has investigated whether tear-associated shapes inhibit the stabilizing potential of the supraspinatus itself.MethodsWe combined statistical shape modeling, kinematics-driven simulations of the glenohumeral joint, and a finite element model of the supraspinatus to investigate the interactions among shape, kinematics, and the stabilizing potential of the supraspinatus. First, we identified tear-associated 3D scapula shapes using partial least squares discriminant analysis. Second, we examined how tear-associated shapes alter the stabilizing potential of the supraspinatus given the same kinematic path. Finally, we examined the extent to which kinematic perturbations could modulate differences in stabilizing potential.ResultsRelative to asymptomatic controls, individuals with full-thickness tears possessed a suite of 3D shape differences including narrower supraspinous fossae and anteverted glenoids. For the same abduction path, tear-associated scapula shapes caused supraspinatus fibres to act more anteriorly and less compressively compared to the control shapes, potentially inhibiting the supraspinatus' ability to stabilize the humeral head. When the abduction path of the tear-associated scapula was internally rotated and shifted anteriorly, the supraspinatus line-of-action closely resembled that of the control-associated scapula; however, the tear-associated shape still possessed a narrower breadth in its supraspinatus line-of-action.DiscussionOur findings indicate that tear-associated scapula geometry may inhibit the stabilizing potential of the supraspinatus, but this shape-driven change could be partially modulated when the abduction path of the tear-associated shape was perturbed. The magnitude of kinematic perturbations required to modulate function exceeded the magnitude of shape differences, indicating that the perturbations are not correcting for a simple offset, but rather complex changes in muscle geometry that occur due to 3D shape differences.

Our current understanding of healthy scapula motion is mainly based on studying the shoulder when it is generating an abduction torque against gravity. However, the shoulder can perform diverse tasks beyond abduction. In particular, little attention has been given to how scapula motion contributes to concentric adduction despite its involvement in high-demand tasks such as rock climbing and wheelchair transfers. Investigating scapular kinematics during concentrically loaded arm-lowering can provide insight into the mechanical demands underlying healthy scapula motion. In this study, we combined biplanar videoradiography and optical motion capture with a controllable cable machine to compare the three-dimensional humerothoracic, glenohumeral, and scapulothoracic kinematics between a weighted pull-down task (involving concentric shoulder adduction) and a weighted press-up task (involving concentric shoulder abduction) in ten healthy adults. We observed significantly more scapulothoracic upward rotation and less glenohumeral abduction during concentric adduction than concentric abduction. Our findings indicate that scapula upward rotation is not simply a function of overall humerothoracic elevation, but instead varies in a load-specific manner-potentially to orient the glenoid in a way that facilitates glenohumeral joint stability. We also observed substantial inter-individual variability in scapular kinematics within a task, and in how individuals responded to the different tasks. Our findings help provide a more well-rounded understanding of healthy scapular kinematics such that we can better identify and treat unhealthy motion (i.e., dyskinesis). Our findings can also inform musculoskeletal models that simulate scapulothoracic kinematics.

Craniosynostosis is a common yet complex birth defect, characterized by premature fusion of the cranial sutures that can be syndromic or nonsyndromic. With over 180 syndromic associations, reaching genetic diagnoses and understanding variations in underlying cellular mechanisms remains a challenge. Variants of FGFR2 are highly associated with craniosynostosis and warrant further investigation. Using the missense mutation FGFR2 W290R , an effective mouse model of Crouzon syndrome, craniofacial features were analyzed using geometric morphometrics across developmental time (E10.5—adulthood, n  = 665 total). Given the interrelationship between the cranial vault and basicranium in craniosynostosis patients, the basicranium and synchondroses were analyzed in perinates. Embryonic time points showed minimal significant shape differences. However, hetero- and homozygous mutant perinates and adults showed significant differences in shape and size of the cranial vault, face, and basicranium, which were associated with cranial doming and shortening of the basicranium and skull. Although there were also significant shape and size differences associated with the basicranial bones and clear reductions in basicranial ossification in cleared whole-mount samples, there were no significant alterations in chondrocyte cell shape, size, or orientation along the spheno-occipital synchondrosis. Finally, shape differences in the cranial vault and basicranium were interrelated at perinatal stages. These results point toward the possibility that facial shape phenotypes in craniosynostosis may result in part from pleiotropic effects of the causative mutations rather than only from the secondary consequences of the sutural defects, indicating a novel direction of research that may shed light on the etiology of the broad changes in craniofacial morphology observed in craniosynostosis syndromes.

Since the first discovery of human fossils in the mid-19th century, two subjects-our phylogenetic relationship to living and fossil apes and the ancestral locomotor behaviors preceding bipedalism-have driven the majority of discourse in the study of human origins. With few fossils and thus limited comparative evidence available to inform or constrain them, morphologists of the 19th and early mid-20th centuries posited a range of scenarios for the evolution of bipedalism. In contrast, there exists a rich hominin fossil record and the acceptance of Pan (chimpanzees and bonobos) as our closest living relatives is nearly universal, yet consensus about the ancestral condition from which hominins evolved remains elusive. Notably, while the earliest known hominins are generally congruent with parsimonious inferences of an African ape-like last common ancestor, our more distantly related Miocene ape cousins are frequently invoked as evidence in favor of more complex scenarios that require substantial homoplasy. Debate over these alternatives suggests that how we infer ancestral nodes and weigh evidence to test their relative likelihoods remains a stumbling block. Here we argue that a key contributor to this impasse includes the history of terminology associated with positional behavior, which has become confused over the last century. We aim to clarify positional behavior concepts and contextualize knuckle-walking and other forms of posture and locomotion chimpanzees and gorillas engage in, while arguing that the presence of homoplasy in ape evolution does not alter the weight of evidence in favor of an African ape-like evolutionary history of hominins.

Shoulder shape directly impacts forelimb function by contributing to glenohumeral (GH) range-of-motion (ROM). However, identifying traits that contribute most to ROM and visualizing how they do so remains challenging, ultimately limiting our ability to reconstruct function and behaviour in fossil species. To address these limitations, we developed an in silico proximity-driven model to simulate and visualize three-dimensional (3D) GH rotations in living primate species with diverse locomotor profiles, identify those shapes that are most predictive of ROM using geometric morphometrics, and apply subsequent insights to interpret function and behaviour in the fossil hominin Australopithecus sediba. We found that ROM metrics that incorporated 3D rotations best discriminated locomotor groups, and the magnitude of ROM (mobility) was decoupled from the anatomical location of ROM (e.g. high abduction versus low abduction). Morphological traits that enhanced mobility were decoupled from those that enabled overhead positions, and all non-human apes possessed the latter but not necessarily the former. Model simulation in A. sediba predicted high mobility and a ROM centred at lower abduction levels than in living apes but higher than in modern humans. Together these results identify novel form-to-function relationships in the shoulder and enhance visualization tools to reconstruct past function and behaviour.

Normal facial morphogenesis involves the precise spatiotemporal choreography of independent facial prominences that must grow, contact each other, and fuse to form a functional upper jaw. We previously identified in reptiles, birds, and mammals (amniotes) a significant shift in the trajectory of facial growth at the time of primary palatal prominence fusion that is associated with reduced variance in shape across species. We speculated that this period is associated with developmental constraints derived from a shared embryonic bauplan, while reduced variance represents selection to minimize the likelihood of palatal clefts. We further hypothesized that these constraints operate within species and so should observe a similar pattern not only across but within species. In addition, because facial growth occurs in the context of underlying brain growth, we hypothesized that it is a significant co‐factor in establishing this pattern. To begin to test these ideas we collected a sample of iodine‐contrast chicken (Gallus gallus) embryos (N=200) spanning the period of facial prominence formation, fusion, and outgrowth (HH16‐30), imaged them using micro‐computed tomography, and used three‐dimensional geometric morphometrics and principal components analysis (PCA) constructed a “developmental morphospace”. Our results confirm that chickens undergo a U‐shaped shift in developmental trajectory and reduced shape variance at the time of primary palatal fusion, that this occurs in both the face and brain, and it is highly coordinated (partial least squares (PLS) analysis: RV=0.995, P<0.0001). Specifically, after contact and fusion the relative the frontonasal and maxillary growth rates (i.e., allometry) switch, as does the relative growth of the forebrain and eyes. Future analyses will focus on identifying key regulators of this switch in growth profile and whether a similar pattern occur in other species (mouse, human). Ultimately, this developmental morphospace approach may provide a generalized model for predicting how perturbations to facial prominence shape variability, growth trajectory, and brain size can combine to impact a range of contact and fusion events, both normal and abnormal.

Complex morphological traits are the product of many genes with transient or lasting developmental effects that interact in anatomical context. Mouse models are a key resource for disentangling such effects, because they offer myriad tools for manipulating the genome in a controlled environment. Unfortunately, phenotypic data are often obtained using laboratory-specific protocols, resulting in self-contained datasets that are difficult to relate to one another for larger scale analyses. To enable meta-analyses of morphological variation, particularly in the craniofacial complex and brain, we created MusMorph, a database of standardized mouse morphology data spanning numerous genotypes and developmental stages, including E10.5, E11.5, E14.5, E15.5, E18.5, and adulthood. To standardize data collection, we implemented an atlas-based phenotyping pipeline that combines techniques from image registration, deep learning, and morphometrics. Alongside stage-specific atlases, we provide aligned micro-computed tomography images, dense anatomical landmarks, and segmentations (if available) for each specimen (N = 10,056). Our workflow is open-source to encourage transparency and reproducible data collection. The MusMorph data and scripts are available on FaceBase (www.facebase.org, https://doi.org/10.25550/3-HXMC) and GitHub (https://github.com/jaydevine/MusMorph).

Canonical Wnt signaling plays multiple roles critical to normal craniofacial development while its dysregulation is known to be involved in structural birth defects of the face. However, when and how Wnt signaling influences phenotypic variation, including those associated with disease, remains unclear. One potential mechanism is via Wnt signaling's role in the patterning of an early facial signaling center, the frontonasal ectodermal zone (FEZ), and its subsequent regulation of early facial morphogenesis. For example, Wnt signaling may directly alter the shape and/or magnitude of expression of the sonic hedgehog (SHH) domain in the FEZ. To test this idea, we used a replication-competent avian sarcoma retrovirus (RCAS) encoding Wnt3a to modulate its expression in the facial mesenchyme. We then quantified and compared ontogenetic changes in treated to untreated embryos in the three-dimensional (3D) shape of both the SHH expression domain of the FEZ, and the morphology of the facial primordia and brain using iodine-contrast microcomputed tomography imaging and 3D geometric morphometrics (3DGM). We found that increased Wnt3a expression in early stages of head development produces correlated variation in shape between both structural and signaling levels of analysis. In addition, altered Wnt3a activation disrupted the integration between the forebrain and other neural tube derivatives. These results show that activation of Wnt signaling influences facial shape through its impact on the forebrain and SHH expression in the FEZ, and highlights the close relationship between morphogenesis of the forebrain and midface.

BACKGROUND:Anatomic parameters, such as the critical shoulder angle and acromion index, have emerged as methods to quantify scapular anatomy and may contribute to rotator cuff pathology. The purpose of this paper is to investigate the published literature on influences of scapular morphology on the development of re-tears and patient-reported outcomes following rotator cuff repair.METHODS:A systematic review of the Embase and PubMed databases was performed to identify published studies on the potential influence of scapular bony morphology and re-tear rates and patient-reported outcomes after rotator cuff repair. Studies were reviewed by two authors.RESULTS:A total of 615 unique titles and 49 potentially relevant abstracts were reviewed, with eight published manuscripts identified for inclusion. Two of three papers reported no relationship between these acromion index and rotator cuff re-tear rate, while one paper found an increased re-tear rate. All three studies on critical shoulder angle found a significant association between critical shoulder angle and cuff re-tear rate. There was no clear relationship between any bony morphologic measurement and patient-reported outcomes after rotator cuff repair.CONCLUSIONS:Rotator cuff re-tear rate appears to be significantly associated with the critical shoulder angle and glenoid inclination, while not clearly associated with acromial morphologic measurements.

Background: Numerous studies have reported an association between rotator cuff injury and two-dimensional measures of scapular morphology. However, the mechanical underpinnings explaining how these shape features affect glenohumeral joint function and lead to injury are poorly understood. We hypothesized that three-dimensional features of scapular morphology differentiate asymptomatic shoulders from those with rotator cuff tears, and that these features would alter the mechanical advantage of the supraspinatus. Methods: Twenty-four individuals with supraspinatus tears and twenty-seven age-matched controls were recruited. A statistical shape analysis identified scapular features distinguishing symptomatic patients from asymptomatic controls. We examined the effect of injury-associated morphology on mechanics by developing a morphable model driven by six degree-of-freedom biplanar videoradiography data. We used the model to simulate abduction for a range of shapes and computed the supraspinatus moment arm. Findings: Rotator cuff injury was associated with a cranial orientation of the glenoid and scapular spine (P = .011, d = 0.75) and/or decreased subacromial space (P = .001, d = 0.94). The shape analysis also identified previously undocumented features associated with superior inclination and subacromial narrowing. In our computational model, warping the scapula from a cranial to a lateral orientation increased the supraspinatus moment arm at 20 degrees of abduction and decreased the moment arm at 160 degrees of abduction. Interpretations: Three-dimensional analysis of scapular morphology indicates a stronger relationship between morphology and cuff tears than two-dimensional measures. Insight into how morphological features affect rotator cuff mechanics may improve patient-specific strategies for prevention and treatment of cuff tears.

Variations in craniofacial morphology may arise as a result of adaptation to different environmental factors such as soft diet (SD), which lessens functional masticatory load. Prior studies have shown that changes in the masticatory muscle function associated with a switch to short-term SD led to changes in craniofacial morphology and alveolar bone architecture. However, the long-term effects of SD and the associated adaptive changes in craniofacial shape are unclear. Our novel study set out to profile prospective skull changes in mice fed with SDs over multiple generations using three-dimensional (3D) geometric morphometric analysis (GMA). Our results revealed that short-term SD consumption led to a significant decrease in craniofacial size, along with numerous shape changes. Long-term SD consumption over 15 continuous generations was not associated with changes in craniofacial size; however, shape analysis revealed mice with shortened crania and mandibles in the anteroposterior dimension, as well as relative widening in the transverse dimension compared to the average shape of all mice analyzed in our study. Moreover, changes in shape and size associated with different functional loads appeared to be independent - shape changes persisted after diets were switched for one generation, whereas size decreased after one generation and then returned to baseline size. Our study is the first to study the role of prolonged, multi-generational SD consumption in the determination of craniofacial size and shape.

BACKGROUND:Cleft lip and palate is one of the most common human birth defects, but the underlying etiology is poorly understood. The A/WySn mouse is a spontaneously occurring model of multigenic clefting in which 20% to 30% of individuals develop an orofacial cleft. Recent work has shown altered methylation at a specific retrotransposon insertion downstream of the Wnt9b locus in clefting animals, which results in decreased Wnt9b expression.RESULTS:Using a newly developed protocol that allows us to measure morphology, gene expression, and DNA methylation in the same embryo, we relate gene expression in an individual embryo directly to its three-dimensional morphology for the first time. We find that methylation at the retrotransposon relates to Wnt9b expression and morphology. IAP methylation relates to shape of the nasal process in a manner consistent with clefting. Embryos with low IAP methylation exhibit increased among-individual variance in facial shape.CONCLUSIONS:Methylation and gene expression relate nonlinearly to nasal process morphology. Individuals at one end of a continuum of phenotypic states display a clinical phenotype and increased phenotypic variation. Variable penetrance and expressivity in this model is likely determined both by among-individual variation in methylation and changes in phenotypic robustness along the underlying liability distribution for orofacial clefting.

Craniosynostosis is a severe disorder that may be caused by activating mutations in Fibroblast growth factor receptors (FgfRs) that affects development of the skull and is characterized by premature fusion of the cranial sutures. In addition to dysmorphology of the skull, affected individuals also have facial dysmorphology. We have previously used an avian model to explore the role that a disease‐causing allele of FgfR2 (FgfR2C278F) plays in producing malformations of the middle and upper face at early stages of development. In that work we observed a wider midface, which resembles what is observed in human patients, and this was directly related to decreased cell proliferation and a disrupted net polarization of the mesenchymal cells in the growing facial primordia. We have extended this work by examining the role of the Map kinase, PLC‐gamma, and PI3K pathways downstream of Fgf signaling in producing facial dysmorphology, as well as directly blocking FgfR activation. We implanted beads soaked in small molecular inhibitors (MEK1/2: U0126, PLC‐gamma: U‐73122, PI3K: LY 294002, FgfR activation: SU5402) into the right side of the developing avian face at HH22 and examined morphological and cellular outcomes at various times of development. First, we determined that each inhibitor substantially and specifically down‐regulated its respective pathway using immunohistochemistry to assess expression of down‐stream targets of activation of each pathway. We then determined that each pathway significantly reduced cell proliferation and altered cell polarization in the mesenchyme. Blocking each pathway also created severe craniofacial malformations that were observed at early and late time points. There are many inputs to each of these pathways, and our data suggest that each participate in regulation of a similar set of cellular processes that contribute to the emergence of morphogenetic processes in facial development.Support or Funding InformationNIH: R01DE019638, R01DE018234, R21DE028198This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.