Volumetric Analyses of Dysmorphic Maxillofacial Structures Using 3D Surface-Based Approaches: A Scoping Review.

Background/Objectives: Three-dimensional (3D) analysis of maxillofacial structures in dysmorphic patients offers clinical advantages over 2D analysis due to its high accuracy and precision in measuring many morphological parameters. Currently, no reliable gold standard exists for calculating 3D volumetric measurements of maxillofacial structures when captured by 3D surface imaging techniques. The aim of this scoping review is to provide an overview of the scientific literature related to 3D surface imaging methods used for volumetric analysis of the dysmorphic maxillofacial structures of patients affected by CL/P or other syndromes and to provide an update on the existing protocols, methods, and, when available, reference data. Methods: A total of 17 papers selected according to strict inclusion and exclusion criteria were reviewed for the qualitative analysis out of more than 4500 articles published between 2002 and 2024 that were retrieved from the main electronic scientific databases according to the PRISMA-ScR guidelines. A qualitative synthesis of the protocols used for the selection of the anatomical areas of interest and details on the methods used for the calculation of their volume was completed. Results: The results suggest a great degree of heterogeneity between the reviewed studies in all the aspects analysed (patient population, anatomical structure, area selection, and volume calculation), which prevents any chance of direct comparison between the reported volumetric data. Conclusions: Our qualitative analysis revealed dissimilarities in the procedures specified in the studies, highlighting the need to develop uniform methods and protocols and the need for comparative studies to verify the validity of methods in order to achieve high levels of scientific evidence, homogeneity of volumetric data, and clinical consensus on the methods to use for 3D volumetric surface-based analysis.

Identification of small-molecule ligand-binding sites on and in the ARNT PAS-B domain.

Transcription factors are challenging to target with small-molecule inhibitors due to their structural plasticity and lack of catalytic sites. Notable exceptions include naturally ligand-regulated transcription factors, including our prior work with the hypoxia-inducible factor (HIF)-2 transcription factor, showing that small-molecule binding within an internal pocket of the HIF-2α Per-Aryl hydrocarbon Receptor Nuclear Translocator (ARNT)-Sim (PAS)-B domain can disrupt its interactions with its dimerization partner, ARNT. Here, we explore the feasibility of targeting small molecules to the analogous ARNT PAS-B domain itself, potentially opening a promising route to modulate several ARNT-mediated signaling pathways. Using solution NMR fragment screening, we previously identified several compounds that bind ARNT PAS-B and, in certain cases, antagonize ARNT association with the transforming acidic coiled-coil containing protein 3 transcriptional coactivator. However, these ligands have only modest binding affinities, complicating characterization of their binding sites. We address this challenge by combining NMR, molecular dynamics simulations, and ensemble docking to identify ligand-binding "hotspots" on and within the ARNT PAS-B domain. Our data indicate that the two ARNT/transforming acidic coiled-coil containing protein 3 inhibitors, KG-548 and KG-655, bind to a ß-sheet surface implicated in both HIF-2 dimerization and coactivator recruitment. Furthermore, while KG-548 binds exclusively to the ß-sheet surface, KG-655 can additionally bind within a water-accessible internal cavity in ARNT PAS-B. Finally, KG-279, while not a coactivator inhibitor, exemplifies ligands that preferentially bind only to the internal cavity. All three ligands promoted ARNT PAS-B homodimerization, albeit to varying degrees. Taken together, our findings provide a comprehensive overview of ARNT PAS-B ligand-binding sites and may guide the development of more potent coactivator inhibitors for cellular and functional studies.

An exclusionary screening method based on 3D morphometric features to sort commingled atlases and axes.

In forensic commingled contexts, when the disarticulation occurs uniquely at the atlantoaxial joint, the correct match of atlas and axis may lead to the desirable assembly of the entire body. Notwithstanding the importance of this joint in such scenarios, no study has so far explored three-dimensional (3D) methodologies to match these two adjoining bones. In the present study, we investigated the potential of re-associating atlas and axis through 3D-3D superimposition by testing their articular surfaces congruency in terms of point-to-point distance (Root Mean Square, RMS). We analysed vertebrae either from the same individual (match) and from different individuals (mismatch). The RMS distance values were assessed for both groups (matches and mismatches) and a threshold value was determined to discriminate matches with a sensitivity of 100%. The atlas and the corresponding axis from 41 documented skeletons (18 males and 23 females), in addition to unpaired elements (the atlas or the axis) from 5 individuals, were superimposed, resulting in 41 matches and 1851 mismatches (joining and non-joining elements). No sex-related significant differences were found in matches and mismatches (p = 0.270 and p = 0.210, respectively), allowing to pool together the two sexes in each group. RMS values ranged between 0.41 to 0.77 mm for matches and between 0.37 and 2.18 mm for mismatches. Significant differences were found comparing the two groups (p < 0.001) and the highest RMS of matches (0.77 mm) was used as the discriminative value that provided a sensitivity of 100% and a specificity of 41%. In conclusion, the 3D-3D superimposition of the atlanto-axial articular facets cannot be considered as a re-association method per se, but rather as a screening one. However, further research on the validation of the 3D approach and on its application to other joints might provide clues to the complex topic of the reassociation of crucial adjoining bones.

The potential of facial nevi in personal identification.

Forensic anthropologists dealing with personal identification (PI) of human remains have recently stressed the need to explore the potential of "secondary identifiers" for identifying victims who died in particular events for whom images often represent the main antemortem data available. Being the face the part most exposed in images, characteristics as pigmented skin lesions (PSLs), can be crucial if combined with other input. Since no data is available on frequencies and distribution of facial PSLs in the general population, this study aims at systematically collecting such data to verify their potential in PI and to open a debate on the aid that "secondary identifiers", regardless of their specific nature, can give to the identification of the deceased in specific forensic contexts. A retrospective analysis on three-dimensional facial models of 1039 Italian subjects (from 4 to 84 years old) was conducted to examine the incidence of PSLs discriminated according to size and position in well-defined facial areas. From the collected data we developed a probabilistic approach providing the likelihood ratio (LR) for two settings: (1) the relative frequencies of nevi in the various facial areas, providing the deriving compound probability of owning a certain facial PSLs pattern; and (2) codes describing the facial nevi pattern of each individual of our population, thus testing their uniqueness and so their potential in PI. The calculated LRs mostly proved high identifying strength, particularly when provided by the compound probability-based approach. Data on incidence and position of facial nevi, their generated codes, and the probabilistic approach here presented, all constitute a starting point for advancing secondary identifiers. Nonetheless, although this preliminary study proved facial PSLs as valuable and potentially useful for identification, their significance and validity should be interpreted with caution as we are still at the first theoretical step clearly based on ideal conditions, and thus further investigations are due on the limitations of their use in practical identifying settings. Therefore, being this systematic study only a preliminary one in its nature, it is recommended not to use this kind of approach until further studies will test its validity in several practical conditions.

Impact of obesity on the structures and functions of the stomatognathic system: A morphofunctional approach.

OBJECTIVE: The prevalence of obesity is increasing significantly worldwide, raising great concern among health professionals. This observational study evaluated the electromyographic activity and thickness of the masseter and temporalis muscles, in addition to the maximum molar bite force, in obese and eutrophic subjects. METHODS: Sixty subjects were divided into three groups: I (7-12 years), II (13-20 years), III (21-40 years) and sex: with 10 men and 10 women for each group. Electromyographic recordings of the masticatory muscles were obtained during mandibular tasks. The masticatory muscles thicknesses were obtained at rest and during dental clenching. The maximum molar bite forces were measured on the right and left sides. The difference in outcome measures between the groups and sex was analyzed using Mann-Whitney U test (p < 0.05) and analysis of covariance (ANCOVA). RESULTS: Electromyographic activity in the masseter and temporal muscles consistently displayed lower levels in obese subjects of both sexes across all three age groups during mandibular tasks. Additionally, greater thickness of the masticatory muscles was observed in obese subjects of both sexes across all three age groups. Obese women in Group II displayed higher values of molar bite force, both on the right and left sides, compared to eutrophic women. On the other hand, women in Group III exhibited higher values of molar bite force on the right side in comparison to eutrophic women. CONCLUSIONS: This study underscores the potential impact of obesity on the morphofunctional aspects of the stomatognathic system in subjects aged 7 to 40 years.

Identification of Small Molecule Ligand Binding Sites On and In the ARNT PAS-B Domain.

Transcription factors are generally challenging to target with small molecule inhibitors due to their structural plasticity and lack of catalytic sites. Notable exceptions to this include a number of transcription factors which are naturally ligand-regulated, a strategy we have successfully exploited with the heterodimeric HIF-2 transcription factor, showing that a ligand-binding internal pocket in the HIF-2α PAS-B domain could be utilized to disrupt its dimerization with its partner, ARNT. Here, we explore the feasibility of directly targeting small molecules to the structurally similar ARNT PAS-B domain, potentially opening a promising route to simultaneously modulate several ARNT-mediated signaling pathways. Using solution NMR screening of an in-house fragment library, we previously identified several compounds that bind ARNT PAS-B and, in certain cases, antagonize ARNT association with the TACC3 transcriptional coactivator. However, these ligands only have mid-micromolar binding affinities, complicating characterization of their binding sites. Here we combine NMR, MD simulations, and ensemble docking to identify ligand-binding 'hotspots' on and within the ARNT PAS-B domain. Our data indicate that the two ARNT/TACC3 inhibitors, KG-548 and KG-655, bind to a ß-sheet surface implicated in both HIF-2 dimerization and coactivator recruitment. Furthermore, KG-548 binds exclusively to the ß-sheet surface, while KG-655 binds to the same site but can also enter a water-accessible internal cavity in ARNT PAS-B. Finally, KG-279, while not a coactivator inhibitor, exemplifies ligands that preferentially bind only to the internal cavity. Taken together, our findings provide a comprehensive overview of ARNT PAS-B ligand-binding sites and may guide the development of more potent coactivator inhibitors for cellular and functional studies.