Accuracy of aMMP-8 point-of-care test in indicating periodontal treatment outcomes in stage III/IV periodontitis: A 24-week follow-up study.

OBJECTIVE: To analyse the correspondence between aMMP-8 PoC test results and the clinical endpoints of non-surgical periodontal treatment in stage III/IV periodontitis. BACKGROUND: The diagnostic success of the active-matrix metalloproteinase-8 (aMMP-8) point-of-care (PoC) test has been demonstrated in various studies, but the evidence of its accuracy following periodontal treatment is limited. MATERIALS AND METHODS: Altogether 42 stage III/IV grade C periodontitis patients were included in this prospective diagnostic study. Clinical periodontal indices were recorded, aMMP-8 PoC test was applied and mouthrinse was collected before and at 6, 12 and 24 weeks after non-surgical periodontal treatment. Quantitative aMMP-8 levels were determined with immunofluorometric assay (IFMA) for the verification of the PoC test results. The accuracy of the aMMP-8 PoC test was assessed using previously established clinical endpoints as references. RESULTS: Sensitivity and specificity of aMMP-8 PoC test to indicate clinical endpoints were ranged as follows: Sensitivity 71.4% at baseline, 39.3%-42.4% at week 6, 28.6%-32.4% at week 12 and 35.3%-42.9% at week 24; specificity 64.3%-80% at week 6, 40%-57.1% at week 12 and 56%-64.3% at week 24. CONCLUSIONS: The accuracy of aMMP-8 PoC test in identifying clinical endpoints after non-surgical periodontal treatment is reduced in relation to baseline. Individual healing patterns of each diseased pocket eventually limit the accuracy of the dichotomous aMMP-8 oral rinse test during the post-treatment period.

Periodontal microbiology and microbial etiology of periodontal diseases: Historical concepts and contemporary perspectives.

This narrative review summarizes the collective knowledge on periodontal microbiology, through a historical timeline that highlights the European contribution in the global field. The etiological concepts on periodontal disease culminate to the ecological plaque hypothesis and its dysbiosis-centered interpretation. Reference is made to anerobic microbiology and to the discovery of select periodontal pathogens and their virulence factors, as well as to biofilms. The evolution of contemporary molecular methods and high-throughput platforms is highlighted in appreciating the breadth and depth of the periodontal microbiome. Finally clinical microbiology is brought into perspective with the contribution of different microbial species in periodontal diagnosis, the combination of microbial and host biomarkers for this purpose, and the use of antimicrobials in the treatment of the disease.

Regulation of gingival keratinocyte monocyte chemoattractant protein-1-induced protein (MCPIP)-1 and mucosa-associated lymphoid tissue lymphoma translocation protein (MALT)-1 expressions by periodontal bacteria, lipopolysaccharide, and interleukin-1ß.

BACKGROUND: The aim of this study was to evaluate oral bacteria- and interleukin (IL)-1ß-induced protein and mRNA expression profiles of monocyte chemoattractant protein-1-induced protein (MCPIP)-1 and mucosa-associated lymphoid tissue lymphoma translocation protein (MALT)-1 in human gingival keratinocyte monolayers and organotypic oral mucosal models. METHODS: Human gingival keratinocyte (HMK) monolayers were incubated with Porphyromonas gingivalis, Fusobacterium nucleatum, P. gingivalis lipopolysaccharide (LPS) and IL-1ß. The protein levels of MCPIP-1 and MALT-1 were examined by immunoblots and mRNA levels by qPCR. MCPIP-1 and MALT-1 protein expression levels were also analyzed immunohistochemically using an organotypic oral mucosal model. One-way analysis of variance followed by Tukey correction was used in statistical analyses. RESULTS: In keratinocyte monolayers, MCPIP-1 protein expression was suppressed by F. nucleatum and MALT-1 protein expression was suppressed by F. nucleatum, P. gingivalis LPS and IL-1ß. P. gingivalis seemed to degrade MCPIP-1 and MALT-1 at all tested time points and degradation was inhibited when P. gingivalis was heat-killed. MCPIP-1 mRNA levels were increased by P. gingivalis, F. nucleatum, and IL-1ß, however, no changes were observed in MALT-1 mRNA levels. CONCLUSION: Gingival keratinocyte MCPIP-1 and MALT-1 mRNA and protein expression responses are regulated by infection and inflammatory mediators. These findings suggest that periodontitis-associated bacteria-induced modifications in MCPIP-1 and MALT-1 responses can be a part of periodontal disease pathogenesis.

Prevotella species as oral residents and infectious agents with potential impact on systemic conditions.

Oral Prevotella are known as anaerobic commensals on oral mucosae and in dental plaques from early life onwards, including pigmented P. melaninogenica, P. nigrescens, and P. pallens and non-pigmented Prevotella species. Many Prevotella species contribute to oral inflammatory processes, being frequent findings in dysbiotic biofilms of periodontal diseases (P. intermedia, P. nigrescens), cariotic lesions (P. denticola, Alloprevotella (formerly Prevotella) tannerae), endodontic infections (P. baroniae, P. oris, P. multisaccharivorax), and other clinically relevant oral conditions. Over the years, several novel species have been recovered from the oral cavity without knowledge of their clinical relevance. Within this wide genus, virulence properties and other characteristics like biofilm formation seemingly vary in a species- and strain-dependent manner, as shown for the P. intermedia group organisms (P. aurantiaca, P. intermedia, P. nigrescens, and P. pallens). Oral Prevotella species are identified in various non-oral infections and chronic pathological conditions. Here, we have updated the knowledge of the genus Prevotella and the role of Prevotella species as residents and infectious agents of the oral cavity, as well as their detection in non-oral infections, but also gathered information on their potential link to cancers of the head and neck, and other systemic disorders.

Editorial for the Special Issue: Oral Immunology and Periodontitis.

The two most common forms of oral infectious diseases are caries and periodontal diseases [...].

Periodontitis and peri-implantitis tissue levels of Treponema denticola-CTLP and its MMP-8 activating ability.

BACKGROUND AND AIMS: Chymotrypsin-like-proteinase of Treponema denticola (Td-CTLP) can stimulate the protein expression and activation of matrix metalloproteinase (MMP)-8 (or collagenase-2), a potent tissue destructive enzyme from gingival cells in vitro. The aims of this study were 1) to demonstrate the proMMP-8 (or latent MMP-8) activation by Td-CTLP in vitro and 2) to detect Td-CTLP and MMP-8 protein levels in the tissue samples of peri-implantitis and periodontitis patients. MATERIALS AND METHODS: proMMP-8 activation by Td-CTLP was analyzed by immunoblots. Tissue specimens were collected from 38 systemically healthy and non-smoking patients; 14 of whom had moderate to severe periodontitis, 10 of whom were suffering from peri-implantitis, and finally 14 of whom showed no sign of periodontal inflammation nor radiological bone decay (control group). The immune-expression levels of MMP-8 and Td-CTLP in the epithelium and the connective tissue were analyzed immunohistochemically. A pixel color-intensity analyze was performed with ImageJ software (version 1.46c; Rasband WS, National Institutes of Health, Bethesda, MD, USA) to obtain a comparable numeral score for each patient's epithelium and connective tissue MMP-8 and Td-CTLP enzyme level. RESULTS: Td-CTLP activated proMMP-8 in vitro by converting the 70-75 kDa proMMP-8 to 65 kDa active MMP-8. Also, lower molecular size 25-50 kDa parts of MMP-8 were formed. There was no statistically significant difference between the study groups in terms of their MMP-8 and Td-CTLP levels in the epithelium or in the connective tissue. CONCLUSION: Regarding the limits of this study, it can thus be said that the Td-CTLP enzyme can activate the host proMMP-8 enzyme. Tissue protein levels of MMP-8 and Td-CTLP do not seem to be changed in peri-implantitis and in periodontitis.

Regulation of hBD-2, hBD-3, hCAP18/LL37, and Proinflammatory Cytokine Secretion by Human Milk Oligosaccharides in an Organotypic Oral Mucosal Model.

Human milk oligosaccharides (HMOs), the third largest solid fraction in human milk, can modulate inflammation through Toll-like receptor signaling, but little is known about their immunomodulatory potential in the oral cavity. In this study, we determined whether the HMOs 2'-fucosyllactose (2'-FL) and 3-fucosyllactose (3-FL) regulate human-beta defensin (hBD)-2 and -3, cathelicidin (hCAP18/LL-37), and cytokine responses in human gingival cells using a three-dimensional oral mucosal culture model. The model was incubated with 0.1% or 1% 2'-FL and 3-FL, alone and in combination, for 5 or 24 h, and hBD-2, hBD-3, and hCAP18/LL-37 were analyzed by immunohistochemistry. The expression profiles of interleukin (IL)-1, IL-1RA, IL-8, and monocyte chemoattractant protein (MCP)-1 were determined by LUMINEX immunoassay. The combination of 1% 2'-FL and 1% 3-FL, and 1% 3-FL alone, for 24 h upregulated hBD-2 protein expression significantly (p < 0.001 and p = 0.016, respectively). No changes in the other antimicrobial peptides or proinflammatory cytokines were observed. Thus, 3-FL, alone and in combination with 2'-FL, stimulates oral mucosal secretion of hBD-2, without effecting a proinflammatory response when studied in an oral mucosal culture model.

Bacterial Cyclic Dinucleotides and the cGAS-cGAMP-STING Pathway: A Role in Periodontitis?

Host cells can recognize cytosolic double-stranded DNAs and endogenous second messengers as cyclic dinucleotides-including c-di-GMP, c-di-AMP, and cGAMP-of invading microbes via the critical and essential innate immune signaling adaptor molecule known as STING. This recognition activates the innate immune system and leads to the production of Type I interferons and proinflammatory cytokines. In this review, we (1) focus on the possible role of bacterial cyclic dinucleotides and the STING/TBK1/IRF3 pathway in the pathogenesis of periodontal disease and the regulation of periodontal immune response, and (2) review and discuss activators and inhibitors of the STING pathway as immune response regulators and their potential utility in the treatment of periodontitis. PubMed/Medline, Scopus, and Web of Science were searched with the terms "STING", "TBK 1", "IRF3", and "cGAS"-alone, or together with "periodontitis". Current studies produced evidence for using STING-pathway-targeting molecules as part of anticancer therapy, and as vaccine adjuvants against microbial infections; however, the role of the STING/TBK1/IRF3 pathway in periodontal disease pathogenesis is still undiscovered. Understanding the stimulation of the innate immune response by cyclic dinucleotides opens a new approach to host modulation therapies in periodontology.

Oral Prevotella Species and Their Connection to Events of Clinical Relevance in Gastrointestinal and Respiratory Tracts.

Prevotella is recognized as one of the core anaerobic genera in the oral microbiome. In addition, members of this genus belong to microbial communities of the gastrointestinal and respiratory tracts. Several novel Prevotella species, most of them of oral origin, have been described, but limited knowledge is still available of their clinical relevance. Prevotella melaninogenica is among the anaerobic commensals on oral mucosae from early months of life onward, and other early colonizing Prevotella species in the oral cavity include Prevotella nigrescens and Prevotella pallens. Oral Prevotella species get constant access to the gastrointestinal tract via saliva swallowing and to lower airways via microaspiration. At these extra-oral sites, they play a role as commensals but also as potentially harmful agents on mucosal surfaces. The aim of this narrative review is to give an updated overview on the involvement of oral Prevotella species in gastrointestinal and respiratory health and disease.

Activation of Gingival Fibroblasts by Bacterial Cyclic Dinucleotides and Lipopolysaccharide.

Human gingival fibroblasts (HGFs) recognize microbe-associated molecular patterns (MAMPs) and respond with inflammatory proteins. Simultaneous impacts of bacterial cyclic di-guanosine monophosphate (c-di-GMP), cyclic di-adenosine monophosphate (c-di-AMP), and lipopolysaccharide (LPS) on gingival keratinocytes have been previously demonstrated, but the effects of these MAMPs on other periodontal cell types, such as gingival fibroblasts, remain to be clarified. The present aim was to examine the independent and combined effects of these cyclic dinucleotides and LPS on interleukin (IL) and matrix metalloproteinase (MMP) response of HGFs. The cells were incubated with c-di-GMP and c-di-AMP, either in the presence or absence of Porphyromonas gingivalis LPS, for 2 h and 24 h. The levels of IL-8, -10, and -34, and MMP-1, -2, and -3 secreted were measured by the Luminex technique. LPS alone or together with cyclic dinucleotides elevated IL-8 levels. IL-10 levels were significantly increased in the presence of c-di-GMP and LPS after 2 h but disappeared after 24 h of incubation. Concurrent treatment of c-di-AMP and LPS elevated MMP-1 levels, whereas c-di-GMP with LPS suppressed MMP-2 levels but increased MMP-3 levels. To conclude, we produce evidence that cyclic dinucleotides interact with LPS-mediated early response of gingival fibroblasts, while late cellular response is mainly regulated by LPS.

Immunological and Microbiological Profiling of Cumulative Risk Score for Periodontitis.

The cumulative risk score (CRS) is a mathematical salivary diagnostic model to define an individual's risk of having periodontitis. In order to further validate this salivary biomarker, we investigated how periodontal bacteria, lipopolysaccharide (LPS), and systemic and local host immune responses relate to CRS. Subgingival plaque, saliva, and serum samples collected from 445 individuals were used in the analyses. Plaque levels of 28 microbial species, especially those of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Porphyromonas endodontalis, Prevotella intermedia, and Tannerella forsythia, and serum and salivary levels of IgA and IgG against these five species were determined. Additionally, LPS activity was measured. High CRS associated strongly with all IgA/IgG antibody and LPS levels in saliva, whereas in serum the associations were not that obvious. In the final logistic regression model, the best predictors of high CRS were saliva IgA burden against the five species (OR 7.04, 95% CI 2.25-22.0), IgG burden (3.79, 1.78-8.08), LPS (2.19, 1.38-3.47), and the sum of 17 subgingival Gram-negative species (6.19, 2.10-18.3). CRS is strongly associated with microbial biomarker species of periodontitis and salivary humoral immune responses against them.

An Oral Rinse Active Matrix Metalloproteinase-8 Point-of-Care Immunotest May Be Less Accurate in Patients with Crohn's Disease.

The diagnostic accuracy of point-of-care (PoC) applications may be compromised in individuals with additional inflammatory conditions. This cross-sectional study examined the performance of a commercial oral rinse active matrix metalloproteinase-8 (aMMP-8) PoC immunotest in individuals with (n = 47) and without Crohn's disease (CD) (n = 41). Oral rinse collected from the participants was analyzed by the PoC immunotest. Molecular forms and fragments of salivary MMP-8 were detected by western immunoblotting. The sensitivity of the immunotest for periodontitis was 60.0% in the CD group and 90.0% in the control group. The respective specificity was 75.0% and 80.0%. In both groups, clinical diagnosis of periodontitis exhibited a significant association with the immunotest results, however, the odds ratio (OR) was more than ten-fold in controls (OR 54.3, 95% CI: 3.1-953, p = 0.006) in comparison to CD patients (OR 5.2, 95% CI: 1.3-21.6, p = 0.022). According to Western immunoblot results, the immunotest MMP-8 positivity was not related to elevated levels of molecular forms and fragments of MMP-8 in the CD group, as in the control group. The diagnostic accuracy of the aMMP-8 PoC oral rinse immunotest is reduced in CD patients, which may be related to lower levels or undetectable complexes.

Regulatory effects of PRF and titanium surfaces on cellular adhesion, spread, and cytokine expressions of gingival keratinocytes.

Dental implant material has an impact on adhesion and spreading of oral mucosal cells on its surface. Platelet-rich fibrin (PRF), a second-generation platelet concentrate, can enhance cell proliferation and adhesion. The aim was to examine the regulatory effects of PRF and titanium surfaces on cellular adhesion, spread, and cytokine expressions of gingival keratinocytes. Human gingival keratinocytes were cultured on titanium grade 4, titanium grade 5 (Ti5), and HA discs at 37 °C in a CO2 incubator for 6 h and 24 h, using either elutes of titanium-PRF (T-PRF) or leukocyte and platelet-rich fibrin (L-PRF), or mammalian cell culture medium as growth media. Cell numbers were determined using a Cell Titer 96 assay. Interleukin (IL)-1ß, IL-1Ra, IL-8, monocyte chemoattractant protein (MCP)-1, and vascular endothelial growth factor (VEGF) expression levels were measured using the Luminex® xMAP™ technique, and cell adhesion and spread by scanning electron microscopy. Epithelial cell adhesion and spread was most prominent to Ti5 surfaces. L-PRF stimulated cell adhesion to HA surface. Both T-PRF and L-PRF activated the expressions of IL-1 ß, IL-8, IL-1Ra, MCP-1, and VEGF, T-PRF being the strongest activator. Titanium surface type has a regulatory role in epithelial cell adhesion and spread, while PRF type determines the cytokine response.

NFE2L2/NRF2, OGG1, and cytokine responses of human gingival keratinocytes against oxidative insults of various origin.

OBJECTIVE: Bacterial or tobacco-related insults induce oxidative stress in gingival keratinocytes. The aim of this study was to investigate anti-oxidative and cytokine responses of human gingival keratinocytes (HMK cells) against Porphyromonas gingivalis lipopolysaccharide (Pg LPS), nicotine, and 4-nitroquinoline N-oxide (4-NQO). MATERIALS AND METHODS: HMK cells were incubated with Pg LPS (1 µl/ml), nicotine (1.54 mM), and 4-NQO (1 µM) for 24 h. Intracellular and extracellular levels of interleukin (IL)-1ß, IL-1 receptor antagonist (IL-1Ra), IL-8, monocyte chemoattractant protein (MCP)-1, and vascular endothelial growth factor (VEGF) were measured with the Luminex® xMAP™ technique, and nuclear factor, erythroid 2 like 2 (NFE2L2/NRF2) and 8-oxoguanine DNA glycosylase (OGG1) with Western blots. Data were statistically analyzed by two-way ANOVA with Bonferroni correction. RESULTS: All tested oxidative stress inducers increased intracellular OGG1 levels, whereas only nicotine and 4-NQO induced NFE2L2/NRF2 levels. Nicotine, 4-NQO, and their combinational applications with Pg LPS induced the secretions of IL-1ß and IL-1Ra, while that of IL-8 was inhibited by the presence of Pg LPS. MCP-1 secretion was suppressed by nicotine, alone and together with Pg LPS, while 4-NQO activated its secretion. Treatment of HMK cells with Pg LPS, nicotine, 4-NQO, or their combinations did not affect VEGF levels. CONCLUSION: Pg LPS, nicotine, and 4-NQO induce oxidative stress and regulate anti-oxidative response and cytokine expressions in human gingival keratinocytes differently. These results may indicate that bacterial and tobacco-related insults regulate distinct pathways.

Molecular forms and fragments of salivary MMP-8 in relation to periodontitis.

AIM: To investigate the molecular forms of salivary matrix metalloproteinase (MMP)-8 in relation to periodontitis. MATERIALS AND METHODS: Molecular forms, degree of activation and fragmentation of neutrophilic and mesenchymal-type MMP-8 isoforms were analysed from salivary samples of 81 subjects with generalized periodontitis, 63 subjects with localized periodontitis and 79 subjects without pocket teeth, by using western-immunoblots with computer quantitation. In addition, human recombinant proMMP-8 was in vitro activated by Treponema denticola chymotrypsin-like protease (Td-CTLP), sodium hypochlorite (NaOCl, 1 mM, oxidant) or amino phenyl mercuric acetate (APMA, 1 mM). RESULTS: In saliva of periodontitis-affected individuals, MMP-8 is found in multiple forms, that is, complexes, active and pro-forms of neutrophilic and mesenchymal-type MMP-8, and especially 20-27 kDa fragments. The quantity of these fragments was elevated in both localized and generalized forms of periodontitis. Moreover, the tested activators (Td-CTLP, NaOCl and APMA) activated inactive proMMP-8, resulting in fragments of 20-27 kDa, in vitro, and salivary concentrations of T. denticola correlated significantly with salivary levels of fragmented MMP-8. CONCLUSION: The present results indicate that during the development and progression of periodontitis, MMP-8 appears as activated and fragmented, and treponemal proteases most likely play role in this cascade.

Salivary biomarkers in association with periodontal parameters and the periodontitis risk haplotype.

Genetic factors play a role in periodontitis. Here we examined whether the risk haplotype of MHC class III region BAT1-NFKBIL1-LTA and lymphotoxin-α polymorphisms associate with salivary biomarkers of periodontal disease. A total of 455 individuals with detailed clinical and radiographic periodontal health data were included in the study. A 610 K genotyping chip and a Sequenom platform were used in genotyping analyses. Phospholipid transfer protein activity, concentrations of lymphotoxin-α, IL-8 and myeloperoxidase, and a cumulative risk score (combining Porphyromonas gingivalis, IL-1ß and matrix metalloproteinase-8) were examined in saliva samples. Elevated IL-8 and myeloperoxidase concentrations and cumulative risk scores associated with advanced tooth loss, deepened periodontal pockets and signs of periodontal inflammation. In multiple logistic regression models adjusted for periodontal parameters and risk factors, myeloperoxidase concentration (odds ratio (OR); 1.37, P = 0.007) associated with increased odds for having the risk haplotype and lymphotoxin-α concentration with its genetic variants rs2857708, rs2009658 and rs2844482. In conclusion, salivary levels of IL-8, myeloperoxidase and cumulative risk scores associate with periodontal inflammation and tissue destruction, while those of myeloperoxidase and lymphotoxin-α associate with genetic factors as well.

Proteomic analysis of RAW macrophages treated with cGAMP or c-di-GMP reveals differentially activated cellular pathways.

Global and quantitative analysis of the proteome help to reveal how host cells sense invading bacteria and respond to bacterial signaling molecules. Here, we performed label free quantitative proteomic analysis of RAW macrophages treated with host-derived cGAMP and bacterial-derived c-di-GMP, in an attempt to identify cellular pathways impacted by these dinucleotides and determine if the host responds differentially to these two cyclic dinucleotides. We identified a total of 3811 proteins of which abundances of 404 proteins in cGAMP and 236 proteins in c-di-GMP treated cells were significantly different compared to the control. Many of the proteins that were strongly and commonly upregulated, such as interferon-induced proteins 47, 202 and 204 (Ifi47, Ifi202, Ifi204), ubiquitin-activating enzyme E7 (Uba7), interferon-induced protein with tetratricopeptide repeats 1, 2 or 3 (Ifit1, Ifit2, Ifit3), ubiquitin-like protein ISG15 (ISG15), might be due to the fact that both dinucleotides promote the production of interferons, which induce the expression of many proteins. However, there were also other proteins that were differentially affected by cGAMP or c-di-GMP treatment, including probable ATP-dependent RNA helicase DHX58 (Dhx58), nuclear autoantigen Sp-100 (Sp100), MARCKS-related protein (Marcksl1) and antigen peptide transporter 2 (Tap2). This is probably due to the differential levels of IFNs produced by the dinucleotides or may indicate that non-STING activation might also contribute to the host's response to c-di-GMP and cGAMP. Interestingly Trex1, a nuclease that degrades DNA (an activator of cGAS to produce cGAMP), was upregulated (3.22 fold) upon cGAMP treatment, hinting at a possible feedback loop to regulate cGAMP synthesis. These results lay a foundation for future studies to better characterize and understand the complex c-di-GMP and cGAMP signaling network.

Effects of Xylitol and Sucrose Mint Products on Streptococcus mutans Colonization in a Dental Simulator Model.

Few laboratory methods exist for evaluating the cariogenicity of food ingredients. In this study, a dental simulator was used to determine the effects of commercial sucrose and xylitol mint products on the adherence and planktonic growth of Streptococcus mutans. Solutions (3% w/v) of sucrose, xylitol, sucrose mints, xylitol mints, xylitol with 0.02% peppermint oil (PO), and 0.02% PO alone were used to test the levels of planktonic and adhered S. mutans. A dental simulator with continuous artificial saliva flow, constant temperature, and mixing was used as a test environment and hydroxyapatite (HA) discs were implemented into the model to simulate the tooth surface. Bacterial content was quantified by qPCR. Compared with the artificial saliva alone, sucrose and sucrose mints increased the numbers of HA-attached S. mutans, whereas xylitol decreased them. Similarly, planktonic S. mutans quantities rose with sucrose and declined with xylitol and xylitol mints. Versus sucrose mints, xylitol mints significantly reduced the counts of HA-bound and planktonic S. mutans. Similar results were observed with the main ingredients of both types of mints separately. PO-supplemented artificial saliva did not influence the numbers of S. mutans that attached to HA or planktonic S. mutans compared with artificial saliva control. In our dental simulator model, xylitol reduced the counts of adhering and planktonic S.mutans. The mints behaved similarly as their pure, main ingredients-sucrose or xylitol, respectively. PO, which has been suggested to have antimicrobial properties, did not influence S. mutans colonization.

Cyclic Dinucleotides in Oral Bacteria and in Oral Biofilms.

Oral cavity acts as a reservoir of bacterial pathogens for systemic infections and several oral microorganisms have been linked to systemic diseases. Quorum sensing and cyclic dinucleotides, two "decision-making" signaling systems, communicate to regulate physiological process in bacteria. Discovery of cyclic dinucleotides has a long history, but the progress in our understanding of how cyclic dinucleotides regulate bacterial lifestyle is relatively new. Oral microorganisms form some of the most intricate biofilms, yet c-di-GMP, and c-di-AMP signaling have been rarely studied in oral biofilms. Recent studies demonstrated that, with the aid of bacterial messenger molecules and their analogs, it is possible to activate host innate and adaptive immune responses and epithelial integrity with a dose that is relevant to inhibit bacterial virulence mechanisms, such as fimbriae and exopolysaccharide production, biofilm formation, and host cell invasion. The aim of this perspective article is to present available information on cyclic dinucleotides in oral bacteria and in oral biofilms. Moreover, technologies that can be used to detect cyclic dinucleotides in oral biofilms are described. Finally, directions for future research are highlighted.

Personalized medicine beyond genomics: alternative futures in big data-proteomics, environtome and the social proteome.

No field in science and medicine today remains untouched by Big Data, and psychiatry is no exception. Proteomics is a Big Data technology and a next generation biomarker, supporting novel system diagnostics and therapeutics in psychiatry. Proteomics technology is, in fact, much older than genomics and dates to the 1970s, well before the launch of the international Human Genome Project. While the genome has long been framed as the master or "elite" executive molecule in cell biology, the proteome by contrast is humble. Yet the proteome is critical for life-it ensures the daily functioning of cells and whole organisms. In short, proteins are the blue-collar workers of biology, the down-to-earth molecules that we cannot live without. Since 2010, proteomics has found renewed meaning and international attention with the launch of the Human Proteome Project and the growing interest in Big Data technologies such as proteomics. This article presents an interdisciplinary technology foresight analysis and conceptualizes the terms "environtome" and "social proteome". We define "environtome" as the entire complement of elements external to the human host, from microbiome, ambient temperature and weather conditions to government innovation policies, stock market dynamics, human values, political power and social norms that collectively shape the human host spatially and temporally. The "social proteome" is the subset of the environtome that influences the transition of proteomics technology to innovative applications in society. The social proteome encompasses, for example, new reimbursement schemes and business innovation models for proteomics diagnostics that depart from the "once-a-life-time" genotypic tests and the anticipated hype attendant to context and time sensitive proteomics tests. Building on the "nesting principle" for governance of complex systems as discussed by Elinor Ostrom, we propose here a 3-tiered organizational architecture for Big Data science such as proteomics. The proposed nested governance structure is comprised of (a) scientists, (b) ethicists, and (c) scholars in the nascent field of "ethics-of-ethics", and aims to cultivate a robust social proteome for personalized medicine. Ostrom often noted that such nested governance designs offer assurance that political power embedded in innovation processes is distributed evenly and is not concentrated disproportionately in a single overbearing stakeholder or person. We agree with this assessment and conclude by underscoring the synergistic value of social and biological proteomes to realize the full potentials of proteomics science for personalized medicine in psychiatry in the present era of Big Data.