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Featured Application: Few or no finishing systems are specifically available for 3D printable materials for permanent dental restorations. The generic systems tested in this study were generally able to give clinically acceptable results for roughness. Conversely, the outcome was poor for gloss, except for curing in a nitrogen chamber unit. The results suggest the need to develop finishing/polishing systems dedicated to this specific category of prosthetic materials. The object of the study was to assess the effect of different finishing and polishing systems on the roughness and gloss of a 3D-printed permanent restorative material. One 3D printable Permanent material was selected for the study. Squared-shaped specimens (14 mm2; 5 mm thickness) were obtained by designing and printing. Eighty specimens were produced and randomly assigned (n = 10) to 8 finishing and polishing methods: Sof-Lex™ Spiral Wheels (SW), Sof-Lex™ XT Pop-on Disc (SD), Identoflex Lucent no paste (Ln), Identoflex Lucent + paste (Lp), Resin Nitrogen polymerized (NG), Optiglaze (OG), Opti1Step (OS), and HiLusterPLUS (HL). Surface roughness and gloss were then measured by a roughness meter and a glossmeter, respectively. For roughness, statistically significant differences were found (p < 0.001), with NG(a) > SD(b) = OG(b) = Lp(b); Lp(b) = Ln(bc); Ln(bc) = OS(cd); OS(cd) = SW(de); and SW(de) = HL(e). For gloss, statistically significant differences were also identified (p < 0.001) with NG(a) > SD(b) > Lp(c) = OS(c) = OG(cd); OG(cd) = Ln(d) > HL(e) = SW(e). The nitrogen chamber polymerization showed better results for both roughness and gloss. Multi-step finishing/polishing systems were able to produce smoother surfaces than 1-step and 2-step systems. [ABSTRACT FROM AUTHOR]

Whole-exome sequencing (WES) in families with an unexplained tendency for venous thromboembolism (VTE) may favor detection of low-frequency variants in genes with known contribution to hemostasis or associated with VTE-related phenotypes. WES analysis in six family members, three of whom affected by documented VTE, filtered for MAF < 0.04 in 192 candidate genes, revealed 22 heterozygous (16 missense and six synonymous) variants in patients. Functional prediction by multi-component bioinformatics tools, implemented by a database/literature search, including ClinVar annotation and QTL analysis, prioritized 12 missense variants, three of which (CRP Leu61Pro, F2 Asn514Lys and NQO1 Arg139Trp) were present in all patients, and the frequent functional variants FGB Arg478Lys and IL1A Ala114Ser. Combinations of prioritized variants in each patient were used to infer functional protein interactions. Different interaction patterns, supported by high-quality evidence, included eight proteins intertwined in the "acute phase" (CRP, F2, SERPINA1 and IL1A) and/or in the "fibrinogen complex" (CRP, F2, PLAT, THBS1, VWF and FGB) significantly enriched terms. In a wide group of candidate genes, this approach highlighted six low-frequency variants (CRP Leu61Pro, F2 Asn514Lys, SERPINA1 Arg63Cys, THBS1 Asp901Glu, VWF Arg1399His and PLAT Arg164Trp), five of which were top ranked for predicted deleteriousness, which in different combinations may contribute to disease susceptibility in members of this family. [ABSTRACT FROM AUTHOR]

The aim of the study was to compare the translucency of CAD/CAM and printable composite materials for fixed dental prostheses (FDP). Eight A3 composite materials (7 CAD/CAM and 1 printable) for FPD were used to prepare a total of 150 specimens. CAD/CAM materials, all characterized by two different opacity levels, were: Tetric CAD (TEC) HT/MT; Shofu Block HC (SB) HT/LT; Cerasmart (CS) HT/LT; Brilliant Crios (BC) HT/LT; Grandio Bloc (GB) HT/LT; Lava Ultimate (LU) HT/LT, Katana Avencia (KAT) LT/OP. The printable system was Permanent Crown Resin. 1.0 mm-thick specimens were cut from commercial CAD/CAM blocks using a water-cooled diamond saw, or 3D printed. Measurements were performed using a benchtop spectrophotometer with an integrating sphere. Contrast Ratio (CR), Translucency Parameter (TP), and Translucency Parameter 00 (TP00) were calculated. One Way ANOVA followed by Tukey test for post hoc were performed for each of the translucency system. The tested materials exhibited a wide range of translucency values. CR ranged from 59 to 84, TP from 15.75 to 8.96, TP00 from 12.47 to 6.31. KAT(OP) and CS(HT) showed, respectively, the lowest and highest translucency for CR, TP and TP00. Due to the significant range of reported translucency values, clinicians should exercise caution when choosing the most appropriate material, especially considering factors such as substrate masking, and the necessary clinical thickness. [ABSTRACT FROM AUTHOR]

The ability of variants of the spliceosomal U1snRNA to rescue splicing has been proven in several human disease models, but not for nucleotide changes at the conserved GT nucleotide of 5′ splice sites (5′ss), frequent and associated with severe phenotypes. Here, we focused on variants at the 5′ss of F9 intron 3, leading to factor IX (FIX) deficiency (hemophilia B). Through minigene expression, we demonstrated that all changes induce complete exon 3 skipping, which explains the associated hemophilia B phenotype. Interestingly, engineered U1snRNAs remarkably increased the proportion of correct transcripts in the presence of the c.277+4A>G (∼60%) and also c.277+2T>C mutation (∼20%). Expression of splicing‐competent cDNA constructs indicated that the splicing rescue produces an appreciable increase of secreted FIX protein levels. These data provide the first experimental evidence that even part of variants at the conserved 5′ss +2T nucleotide can be rescued, thus expanding the applicability of this U1snRNA‐based approach. The ability of variants of the spliceosomal U1snRNA to rescue splicing has been proven in several human disease models, but not for nucleotide changes at the conserved GT nucleotide of 5′ splice sites (5′ss), frequent and associated with severe phenotypes. Through minigene expression of variants at the 5′ss of F9 intron 3 and splicing modulation by engineered U1snRNAs, we demonstrated that some nucleotide changes at the 5′ss +2T nucleotide can be rescued, thus expanding the applicability of this U1snRNA‐based approach. [ABSTRACT FROM AUTHOR]

Abstract: Pre‐peptide regions of secreted proteins display wide sequence variability, even among highly homologous proteins such as coagulation factors, and are intracellularly removed, thus potentially favoring secretion of wild‐type proteins upon suppression of nonsense mutations (translational readthrough). As models we selected F9 nonsense mutations with readthrough‐favorable features affecting the pre‐peptide and pro‐peptide regions of coagulation factor IX (FIX), which cause hemophilia B (HB). Only the p.Gly21Ter (c.61G > T) in the variable pre‐peptide hydrophobic core significantly responded (secretion, 4.1 ± 0.5% of wild‐type; coagulant activity, 4.0 ± 0.3%) to the readthrough‐inducer geneticin. Strikingly, for the p.Gly21Ter mutation, the resulting specific coagulant activity (0.96 ± 0.11) was compatible with normal function, thus suggesting secretion of FIX with wild‐type features upon readthrough and removal of pre‐peptide. Expression of the predicted readthrough‐deriving missense variants (Gly21Trp/Cys/Arg) revealed a preserved specific activity (ranging from 0.84 to 0.98), thus supporting our observation. Conversely, rescue of the p.Cys28Ter (c.84T > A) and p.Lys45Ter (c.133A > T) was prevented by constraints of adjacent cleavage sites, a finding consistent with the association of most missense mutations affecting these regions with severe or moderate HB. Overall, our data indicate that suppression of nonsense mutations in the pre‐peptide core preserves mature protein features, thus making this class of mutations preferred candidates for therapeutic readthrough. [ABSTRACT FROM AUTHOR]