Biology subjects

Horst, J. A.

Publications and source records attributed to Horst, J. A..

4 recordsLinked to original sources

bioRxiv2018

Accurate informatic modeling of tooth enamel pellicle interactions by training substitution matrices with Mat4Pep

MotivationProtein-hydroxyapatite interactions govern the development and homeostasis of teeth and bone. Characterization would enable design of peptides to regenerate mineralized tissues and control attachments such as ligaments and dental plaque. Progress has been limited because no available methods produce robust data for assessing phase interfaces.\n\nResultsWe show that tooth enamel pellicle peptides contain subtle sequence similarities that encode hydroxyapatite binding mechanisms, by segregating pellicle peptides from control sequences using our previously developed substitution matrix-based peptide comparison protocol (Oren et al., 2007), with improvements. Sampling diverse matrices, adding biological control sequences, and optimizing matrix refinement algorithms improves discrimination from 0.81 to 0.99 AUC in leave-one-out experiments. Other contemporary methods fail on this problem. We find hydroxyapatite interaction sequence patterns by applying the resulting selected refined matrix (\"pellitrix\") to cluster the peptides and build subgroup alignments. We identify putative hydroxyapatite maturation domains by application to enamel biomineralization proteins and prioritize putative novel pellicle peptides identified by In stageTip (iST) mass spectrometry. The sequence comparison protocol outperforms other contemporary options for this small and heterogeneous group, and is generalized for application to any group of peptides.\n\nAvailabilitySoftware to apply this protocol is freely available at github.com/JeremyHorst/Mat4Pep and compbio.org/protinfo/ Mat4Pep.\n\nContactjahorst@gmail.com, ram@compbio.org.\n\nSupplementary informationAvailable at Bioinformatics online.

bioinformatics↗

bioRxiv2017

Silver fluoride as a treatment for the disease dental caries

The current paradigm of treatment for dental caries (tooth decay) in primary teeth is dangerous, fails to reach many children, and suffers high recurrence. Acceptance of the paradigm arises from a misperception that untreated caries in primary teeth is a threat to life. We show a linear relationship between age and deaths in the United States from 1999 through 2015 caused by dental caries, pulpal / periapical abscess, or facial cellulitis. The intercept of 6 years coincides with emergence of the first permanent tooth: it appears that caries in primary teeth is not a threat to life. Thus, treatment goals should be to avoid pain, which is not possible with operative dentistry, as it causes pain. Medical management of caries is a distinct treatment philosophy which employs topical minimally invasive therapies that treat the disease, and is not merely prevention. Silver diamine fluoride (SDF) is a central agent to enable effective non-invasive treatment. The announcement of FDA Breakthrough Therapy designation suggests that SDF will become the first FDA approved drug for treating the disease dental caries. Since our last review, 4 clinical trials have been completed, which inform an update to the application protocol and frequency regimen. Suggestions from these studies are to skip the rinsing step due to demonstration of safety and concern of diminished effectiveness by dilution, and to start patients with an intensive regimen of multiple applications over the first few weeks. Breakthroughs in elucidating the impact of SDF on tooth structure and the plaque microbiome inform potential opportunities for bioengineering and understanding caries arrest, respectively. Dentists have been surprised by preference of this treatment over traditional invasive approaches. Renewed interest in this old material has delivered progress to optimize the judicious use of SDF, and enable a revolution in caries management - particularly for primary teeth.\n\nONE SENTENCE SUMMARYAnesthesia is inappropriate for first-line treatment of early childhood caries now that safe topical treatments such as silver diamine fluoride are available.

pharmacology and toxicology↗

bioRxiv2017

Silver microwires from treating tooth decay with silver diamine fluoride

Silver diamine fluoride (SDF) is a brush-on treatment for tooth decay that stops 81% of cavitated caries lesions (dental cavities). Before this innovation, caries was treatable only with operative approaches (dental fillings). SDF-treated lesions harden and become resistant to further decay. We hypothesized that the hardening is due to reaction with silver, rather than classic fluoride-mediated remineralization, because infected dentin is not amenable to remineralization. Using synchrotron microCT with 1.3 m resolution, we observe filamentous densities up to 500 m in length and 0.25-7.0 m in diameter, formed in situ by applying SDF to caries lesions. We show that these \"microwires\" fill voids in the lesion caused by disease, and permeate through surrounding dentinal tubules. Using spectroscopy, we confirm that the chemical composition of the observed microwires is predominantly silver. To our knowledge, this represents the first structural microscale observations resulting from clinical SDF treatment. These novel observations hint at mechanistic explanations for the first clinical method to harden carious dentin besides remineralization. We hypothesize that SDF may not only achieve its antimicrobial functions by biochemical interactions, but also through its inherent ability to integrate into dentin.

pharmacology and toxicology↗

bioRxiv2017

Topical Silver Diamine Fluoride For Dental Caries Arrest In Preschool Children: A Randomized Controlled Trial

ObjectivesThe Stopping Cavities Trial investigated effectiveness and safety of 38% silver diamine fluoride in arresting caries lesions.\n\nMaterials and MethodsDouble-blind randomized placebo-controlled superiority trial with 2 parallel groups. Oregon preschools. 66 preschool children with [≥]1 lesion. 38% silver diamine fluoride or placebo (blue-tinted water), applied topically to the lesion. The primary endpoint was caries arrest (lesion inactivity, Nyvad criteria) 14-21 days post intervention. Dental plaque was collected from all children, and microbial composition was assessed by RNA sequencing from 2 lesions and 1 unaffected surface before treatment and at follow-up for 3 children from each group.\n\nResults and ConclusionMean fraction of arrested caries lesions in the silver diamine fluoride group was higher (0.72; 95% CI; 0.55, 0.84) than in the placebo group (0.05; 95% CI; 0.00, 0.16). Confirmatory analysis using generalized estimating equation log-linear regression, accounting for the number of treated surfaces and length of follow-up, indicated the fraction of arrested caries was significantly higher in the treatment group (relative risk, 17.3; 95% CI: 4.3 to 69.4). No harms were observed. RNA sequencing analysis identified no consistent changes in relative abundance of caries-associated microbes, nor emergence of antibiotic or metal resistance gene expression. Topical 38% silver diamine fluoride was effective and safe in arresting cavities in preschool children. The treatment is applicable to primary care practice and may reduce the burden of untreated tooth decay in the population.\n\nTrial RegistrationClinicalTrials.gov NCT02536040.\n\nClinical SignificanceIn this clinical trial, 72% of caries lesions were arrested by silver diamine fluoride, with no harms. Contrary to the presumed antibacterial mechanism, lesion bacterial composition changed negligibly. This simple topical treatment is applicable to primary care practice and may reduce the burden of untreated tooth decay in the population.

clinical trials↗