Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.

Sis1 is an essential yeast Type II Hsp40 protein that assists cytosolic Hsp70 Ssa1 in the facilitation of processes that include translation initiation, the prevention of protein aggregation, and proteasomal protein degradation. An essential function of Sis1 and other Hsp40 proteins is the binding and delivery of non-native polypeptides to Hsp70. How Hsp40s function as molecular chaperones is unknown. The crystal structure of a Sis1 fragment that retains peptide-binding activity suggests that Type II Hsp40s utilize hydrophobic residues located in a solvent-exposed patch on carboxyl-terminal domain I to bind non-native polypeptides. To test this model, amino acid residues Val-184, Leu-186, Lys-199, Phe-201, Ile-203, and Phe-251, which form a depression in carboxyl-terminal domain I, were mutated, and the ability of Sis1 mutants to support cell viability and function as molecular chaperones was examined. We report that Lys-199, Phe-201, and Phe-251 are essential for cell viability and required for Sis1 polypeptide binding activity. Sis1 I203T could support normal cell growth, but when purified it exhibited severe defects in chaperone function. These data identify essential residues in Sis1 that function in polypeptide binding and help define the nature of the polypeptide-binding site in Type II Hsp40 proteins.

In the last two decades, many studies have focused on whether periodontitis is a risk factor for preterm birth (PTB). However, both epidemiological investigation and intervention trials have reached contradictory results from different studies. What explains the different findings, and how should future studies be conducted to better assess this risk factor? This article reviews recent epidemiological, animal, and in vitro studies as well as intervention trials that evaluate the link between periodontitis and PTB. Periodontitis may act as a distant reservoir of microbes and inflammatory mediators and contribute to the induction of PTB. Animal studies revealed that maternal infections with periodontal pathogens increase levels of circulating IL-1β, IL-6, IL-8, IL-17, and TNF-α and induce PTB. In vitro models showed that periodontal pathogens/byproducts induce COX-2, IL-8, IFN-γ, and TNF-α secretion and/or apoptosis in placental tissues/cells. The effectiveness of periodontal treatment to prevent PTB is influenced by the diagnostic criteria of periodontitis, microbial community composition, severity of periodontitis, treatment strategy, treatment efficiency, and the period of treatment during pregnancy. Although intervention trials reported contradictory results, oral health maintenance is an important part of preventive care that is both effective and safe throughout pregnancy and should be supported before and during pregnancy. As contradictory epidemiological and intervention studies continue to be published, two new ideas are proposed here: (1) severe and/or generalized periodontitis promotes PTB and (2) periodontitis only promotes PTB for pregnant women who are young or HIV-infected or have preeclampsia, pre-pregnancy obesity, or susceptible genotypes.

In dental clinic, unsatisfactory management of the dentin surface after dentin exposure often leads to the occurrence of dentin hypersensitivity and caries. Current approaches can occlude the tubules on the dentin surface to relieve dentin hypersensitivity; however, the blocked tubules are generally weak in combating daily tooth erosion and abrasion. Moreover, cariogenic bacteria, such as Streptococcus mutans, produce biofilm on the dentin surface, causing caries and compromising the tubules' sealing efficacy. To overcome this problem, the present study focused on establishing a versatile biomaterial, epigallocatechin-3-gallate-encapsulated nanohydroxyapatite/mesoporous silica nanoparticle (EGCG@nHAp@MSN), for therapeutic management of the dentin surface. The effectiveness of the biomaterial on dentinal tubule occlusion, including resistances against acid and abrasion, was evaluated by field-emission scanning electron microscopy (FESEM) and dentin permeability measurement. The inhibitory capability of the biomaterial on S. mutans biofilm formation was investigated by confocal laser scanning microscopy (CLSM), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony forming units (CFU) counts, and FESEM. Results demonstrated for the first time that the use of EGCG@nHAp@MSN on the dentin surface was capable of effectively occluding dentinal tubules, reducing dentin permeability, and achieving favorable acid- and abrasion-resistant stability. Furthermore, EGCG@nHAp@MSN held the capability to continuously release EGCG, Ca, and P, and significantly inhibit the formation and growth of S. mutans biofilm on the dentin surface. Thus, the development of EGCG@nHAp@MSN bridges the gap between multifunctional concept and dental clinical practice and is promising in providing dentists a therapeutic strategy for the management of the dentin surface to counter dentin hypersensitivity and caries.

Objective: To compare the diagnostic accuracy between cone-beam computed tomography (CBCT) and periapical radiography for detecting simulated external apical root resorption (EARR) in vitro. Materials and Methods: The study sample consisted of 160 single-rooted premolar teeth for simulating EARR of varying degrees according to four setups: no (intact teeth), mild (cavity of 1.0 mm in diameter and depth on root surface), moderate (0.4 mm, 0.8 mm, 1.2 mm, and 1.6 mm root shortening), and severe (2.4 mm, 2.8 mm, 3.2 mm, and 3.6 mm root shortening). Two groups of radiographic images were obtained via CBCT and periapical radiography. The absence or presence and the severity for all resorption lesions were evaluated blindly by two calibrated observers. Results: With the CBCT method, the rates of correct classification of no, mild, moderate, and severe EARR were 96.3%, 98.8%, 41.3%, and 87.5%, respectively; with the periapical radiography method, the rates were 82.5%, 41.3%, 68.8%, and 92.5%, respectively. Highly significant differences were found between the two imaging methods for detection of mild (P , .001), moderate (P , .001), and all EARR (P , .001). For detection of all EARR, the sensitivity and specificity values were 75.8% and 96.3% for CBCT, compared with 67.5% and 82.5% for periapical radiography. Conclusion: CBCT is a reliable diagnostic tool to detect simulated EARR, whereas periapical radiography underestimates it. However, if a periapical radiograph is already available to the diagnosis of EARR, CBCT should be used with extreme caution to avoid additional radiation exposure. (Angle Orthod. 2013;83:189-195.)