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The purpose of this in vitro investigation was to compare in primary molars, the validity of DIAGNOdent™ 2095 on occlusal caries diagnosis used either separately or in combination with direct and/or indirect visual examinations, based on histological examination as the reference method. In 24 extracted primary molars, 111 occlusal pits were examined for caries by one trained operator (intra-examiner reliability k > 0.80), using the following examination methods: direct visual (DV), indirect visual (IDV), radiographic (XR), and fluorescence (DD) with the DIAGNOdent™. The extent of caries was then determined histologically. Sensitivity, specificity, accuracy, and the area under the ROC curve (AUC) were calculated for each method separately as well as for the combination of DD with DV and/or IDV. The DD accuracy was found both for lesions into enamel and into dentin to be 0.70 while the accuracy of the DD combination with DV and IDV was found to be 0.89. The DD AUC for lesions into enamel and into dentin, 0.68, were not statistically significant different from the other methods (p > 0.5), however the AUC of the combination of DD with DV and IDV, found to be 0.82, was higher than all the other methods, and this was statistically significant for enamel lesions. The validity of DIAGNOdent™ for occlusal caries diagnosis in primary molars was much higher when the DD was used in combination with direct and indirect visual examination, than when used by itself. [ABSTRACT FROM AUTHOR]

The prevalence of multivariate time series data across several disciplines fosters a demand and, subsequently, significant growth in the research and advancement of multivariate time series analysis. Drawing inspiration from a popular natural language processing model, the Transformer, we propose the Spatio-Temporal Transformer with Relative Embeddings (STTRE) to address multivariate time series forecasting. This work primarily focuses on developing a Transformer-based framework that can fully exploit the spatio-temporal nature of a multivariate time series by incorporating several of the Transformer's key components, but with augmentations that allow them to excel in multivariate time series forecasting. Current Transformer-based models for multivariate time series often neglect the data's spatial component(s) and utilize absolute position embeddings as their only means to detect the data's temporal component(s), which we show is flawed for time series applications. The lack of emphasis on fully exploiting the spatio-temporality of the data can incur subpar results in terms of accuracy. We redesign relative position representations, which we rename to relative embeddings, to unveil a new method for detecting latent spatial, temporal, and spatio-temporal dependencies more effectively than previous Transformer-based models. We couple these relative embeddings with a restructuring of the Transformer's primary sequence learning mechanism, multi-head attention, in a way that allows for full utilization of relative embeddings, thus achieving up to a 24% improvement in accuracy over other state-of-the-art multivariate time series models on a comprehensive selection of publicly available multivariate time series forecasting datasets., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

FRA10AC1 , the causative gene for the manifestation of the FRA10A fragile site, encodes a well-conserved nuclear protein characterized as a non-core spliceosomal component. Pre-mRNA splicing perturbations have been linked with neurodevelopmental diseases. FRA10AC1 variants have been, recently, causally linked with severe neuropathological and growth retardation phenotypes. To further elucidate the participation of FRA10AC1 in spliceosomal multiprotein complexes and its involvement in neurological phenotypes related to splicing, we exploited protein-protein interaction experimental data and explored network information and information deduced from transcriptomics. We confirmed the direct interaction of FRA10AC1with ESS2, a non-core spliceosomal protein, mapped their interacting domains, and documented their tissue co-localization and physical interaction at the level of intracellular protein stoichiometries. Although FRA10AC1 and SF3B2, a major core spliceosomal protein, were shown to interact under in vitro conditions, the endogenous proteins failed to co-immunoprecipitate. A reconstruction of a comprehensive, strictly binary, protein-protein interaction network of FRA10AC1 revealed dense interconnectivity with many disease-associated spliceosomal components and several non-spliceosomal regulatory proteins. The topological neighborhood of FRA10AC1 depicts an interactome associated with multiple severe monogenic and multifactorial neurodevelopmental diseases mainly referring to spliceosomopathies. Our results suggest that FRA10AC1 involvement in pre-mRNA processing might be strengthened by interconnecting splicing with transcription and mRNA export, and they propose the broader role(s) of FRA10AC1 in cell pathophysiology.

Introduction: Craniosynostosis, the premature fusion of cranial sutures, is usually divided into 2 major categories: syndromic and nonsyndromic. Mutations in the FGFR1 , FGFR2 , FGFR3 , TWIST1 , and EFNB1 genes cause the common craniosynostosis syndromes Muenke, Crouzon and Crouzon with acanthosis nigricans, Apert, Pfeiffer, Saethre-Chotzen, and Craniofrontonasal. Overlapping features among craniosynostosis syndromes, phenotypic heterogeneity even within the same syndrome, especially in the case of Muenke syndrome, and inadequate clinical evaluation can lead to misdiagnosis, which molecular testing can help clarify., Objective: The aim of this study is to investigate the underlying genetic cause in 46 patients with syndromic or nonsyndromic craniosynostosis by direct sequencing and/or microdeletion/microduplication analysis of the FGFR1-3 , TWIST1 , and EFNB1 genes., Results: Genetic analysis identified 3 novel mutations, c.413T>C - p.(Leu138Pro) [p.(L138P)] in TWIST1 , the previously reported c.373G>A - p.(Glu125Lys) [p.(E125K)], and c.717dupA - p.(Leu240IlefsTer79) [p.(L240fs)] mutation in EFNB1 gene as well as 6 previously known mutations and a heterozygous TWIST1 gene deletion. The 2 novel mutations within EFNB1 gene arose de novo, but the novel mutation p.(L138P) within TWIST1 gene was inherited from the patient's father, who was found to be mosaic for the mutation. To our knowledge, this is the first case of mosaicism described for TWIST1 gene., Conclusions: The contribution of molecular genetic analysis to the diagnosis of patients with syndromic craniosynostosis was useful because some were originally misdiagnosed. Conversely, thorough clinical evaluation can guide molecular testing and result in a correct diagnosis.

Background/aim: Uveal melanoma is the most common primary adult intraocular malignancy. It is known to have a strong metastatic potential, fatal for the vast majority of patients. In recent years, meticulous cytogenetic and molecular profiling has led to precise prognostication, that unfortunately is not matched by advancements in adjuvant therapies. G Protein subunits alpha Q (GNAQ) and alpha 11 (GNA11) are two of the major driver genes that contribute to the development of uveal melanoma. Understanding their prognostic significance can allow tailored management and facilitate their use in the on-going quest of targeted uveal melanoma therapies., Materials and Methods: Formalin-fixed, paraffin-embedded specimens were obtained from 47 patients of Greek origin, with uveal melanoma. GNAQ and GNA11 genes were screened for mutations in exons 4 and 5, by polymerase chain reaction and Sanger sequencing., Results: The overall mutation frequency of GNAQ/GNA11 genes was 42.4%. A novel mutation c.625_626delinsGC was identified in GNA11. No correlation was observed between the mutation status and metastasis occurrence or overall survival time of patients., Conclusion: Mutations in GNAQ and GNA11 genes in this Greek population present frequencies that qualify them as potential targets for customized therapy., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Craniofrontonasal syndrome is mainly characterized by frontonasal dysplasia, telorbitism, a broad nasal root, and frequently a bifid nose and coronal craniosynostosis. Craniofrontonasal syndrome is an X-linked disorder with an unusual pattern of inheritance because heterozygous females are more severely affected than hemizygous males. The craniofrontonasal syndrome-causing gene is EFNB1, localized in the border region of chromosome Xq12 and Xq13.1, encoding for protein ephrin-B1. Here we aim to investigate the underlying genetic defect of a young girl with craniofrontonasal syndrome. The patient underwent surgical correction of her craniofacial deformities. Genetic analysis was carried out by polymerase chain reaction. Products of exon 2 of the EFNB1 gene were sequenced as well as digested with BpmI enzyme. A novel de novo missense mutation 373G>A was identified within the EFNB1 gene, leading to the replacement of glutamic acid at amino acid position 125 with lysine. The replacement of Glu125 with Lys, which lies within the G-H loop, part of the dimerization ligand-receptor interface, is expected to disrupt the interaction between the Eph receptor and ephrin B1 ligand, thus leading to craniofrontonasal syndrome.

Fibroblast Growth Factor Receptor 3 (FGFR3) related skeletal dysplasias are caused by mutations in the FGFR3 gene that result in increased activation of the receptors causing alterations in the process of endochondral ossification in all long bones, and include achondroplasia, hypochondroplasia, thanatophoric dysplasia, and SADDAN. Reports of prenatal diagnosis of FGFR3 related skeletal dysplasias are not rare; however, the correlation between 2nd trimester ultrasonographic findings and underlying molecular defect in these cases is relatively poor. There is a need for specific ultrasound (U/S) predictors than can distinguish lethal from non-lethal cases and aid an earlier prenatal diagnosis. Here we present one familial and 16 sporadic cases with FGFR3 related skeletal dysplasia, and we evaluate biometric parameters and U/S findings consistent with the diagnosis of skeletal dysplasia. U/S scan performed even at the 18th week of gestation can indicate a decreased rate of development of the femora (femur length (FL) <5th centile), while the mean gestational age at diagnosis is still around the 26th week. The utility of other biometric parameters and ratios is discussed (foot length, BPD, HC, FL/foot, and FL/AC). Prenatal cytogenetic and molecular genetic analyses were performed. A final diagnosis was reached by molecular analysis. In two cases of discontinued pregnancy, fetal autopsy led to a phenotypic diagnosis and confirmed the prenatal prediction of lethality. We conclude that the combination of U/S and molecular genetic approach is helpful for establishing an accurate diagnosis of FGFR3-related skeletal dysplasias in utero and subsequently for appropriate genetic counselling and perinatal management., (Copyright © 2011 Wiley-Liss, Inc.)