Age-associated changes in innate immunity and their impacts on inflammatory disease.

Periodontal disease arises from excessive host inflammatory responses to the tooth-associated microbial biofilm, known as dental plaque. Severity ranges from superficial inflammation of the gingivae (gingivitis) to extensive destruction of connective tissue and bone (periodontitis) leading to tooth loss. In its severe form, periodontitis affects 10 - 15% of the total human population to the extent that they will lose half their teeth by age 50. Periodontitis, a prevalent chronic disease with an impact on systemic health, such as atherosclerosis and Alzheimer\u27s disease, is critically dependent on neutrophils. Although conventional periodontal treatment may reverse destructive inflammation, a subset of patients develops recurrent disease for reasons that are not clear, thus necessitating better understanding of the underlying immunopathology. Therefore, there is a compelling need to elucidate pathogenic mechanisms, which may be targeted for novel therapeutic intervention strategies in periodontal disease. Developmental endothelial locus-1 (Del-1) was recently identified as a novel endothelial-derived inhibitor of neutrophil extravasation. However, whether Oel-1 regulates the local tissue-specific inflammatory response and controls chronic inflammatory diseases has not been addressed yet. Upon aging, normal mice displayed increased disease accompanied by diminished Oel-1 expression. Consistent with a protective role for Oel-1 in periodontitis, Del-1-1- mice developed spontaneous inflammatory periodontal bone loss characterized by excessive local neutrophil infiltration and interleukin (IL)-17 expression. The disease was reversed in Del-1-1- mice with additional genetic deficiencies in the LFA-1 integrin or the IL-17 receptor. Strikingly, local administration of Oel-1 suppressed neutrophil infiltration and IL-17 expression in the periodontal tissue. We, therefore, concluded that Oel-1 is required for tissue homeostasis by regulating LFA-1-dependent neutrophil trafficking, inhibiting IL-17-mediated pathology, and may be a promising novel therapeutic for the treatment of inflammatory diseases. In conclusion, we showed that Oel-1, a novel inhibitor of integrindependent neutrophil adhesion, regulates local tissue-specific inflammation and controls chronic inflammatory disease. Oel-1 inhibits LFA-1-dependent neutrophil recruitment and IL-17-mediated pathology and may be a promising novel therapeutic for inflammatory diseases

A gene encoding a SHINE1/WAX INDUCER1 transcription factor controls cuticular wax in barley

All land plants seal their above ground body parts with a lipid-rich hydrophobic barrier called the cuticle to protect themselves from dehydration and other terrestrial threats. Mutational studies in several model species have identified multiple loci regulating cuticular metabolism and development. Of particular importance are the eceriferum (cer) mutants characterized by a loss of cuticular wax. Some barley cer mutants, including cer-x, show defects in the distinctive β-diketone-enriched wax bloom on reproductive stage leaf sheaths, stems, and spikes. We exploited extensive allelic populations, near-isogenic lines, and powerful genotyping platforms to identify variation in the HvWAX INDUCER1 (HvWIN1) gene, encoding a SHINE transcription factor, as underlying cer-x. Comparing the cer-x allelic glossy sheath4.l Bowman Near Isogenic Line BW407 to cv. Bowman revealed an increased cuticular permeability in tissues showing reduced accumulation of β-diketones and altered cuticular metabolic gene expression in BW407. Analyses across the barley pangenome and hundreds of exome-capture datasets revealed high sequence conservation of HvWIN1 and two non-synonymous variants exclusive to the cultivated germplasm. Taken together, we suggest that variation in HvWIN1 controls multiple cuticular features in barley

<i>APETALA2</i> functions as a temporal factor together with <i>BLADE-ON-PETIOLE2</i> and <i>MADS29</i> to control flower and grain development in barley

Cereal grain develops from fertilised florets. Alterations in floret and grain development greatly influence grain yield and quality. Despite this, little is known about the underlying genetic control of these processes, especially in key temperate cereals such as barley and wheat. Using a combination of near-isogenic mutant comparisons, gene editing and genetic analyses, we reveal that HvAPETALA2 (HvAP2) controls floret organ identity, floret boundaries, and maternal tissue differentiation and elimination during grain development. These new roles of HvAP2 correlate with changes in grain size and HvAP2-dependent expression of specific HvMADS-box genes, including the B-sister gene, HvMADS29 Consistent with this, gene editing demonstrates that HvMADS29 shares roles with HvAP2 in maternal tissue differentiation. We also discovered that a gain-of-function HvAP2 allele masks changes in floret organ identity and grain size due to loss of barley LAXATUM.A/ BLADE-ON-PETIOLE2 (HvBOP2) gene function. Taken together, we reveal novel, pleiotropic roles and regulatory interactions for an APETALA2-like gene controlling floret and grain development in a temperate cereal.Jennifer R. Shoesmith, Charles Ugochukwu Solomon, Xiujuan Yang, Laura G. Wilkinson, Scott Sheldrick, Ewan van Eijden ... et al

Atomically dispersed Pt-N-4 sites as efficient and selective electrocatalysts for the chlorine evolution reaction

Chlorine evolution reaction (CER) is a critical anode reaction in chlor-alkali electrolysis. Although precious metal-based mixed metal oxides (MMOs) have been widely used as CER catalysts, they suffer from the concomitant generation of oxygen during the CER. Herein, we demonstrate that atomically dispersed Pt-N-4 sites doped on a carbon nanotube (Pt-1/CNT) can catalyse the CER with excellent activity and selectivity. The Pt-1/CNT catalyst shows superior CER activity to a Pt nanoparticle-based catalyst and a commercial Ru/Ir-based MMO catalyst. Notably, Pt-1/CNT exhibits near 100% CER selectivity even in acidic media, with low Cl- concentrations (0.1M), as well as in neutral media, whereas the MMO catalyst shows substantially lower CER selectivity. In situ electrochemical X-ray absorption spectroscopy reveals the direct adsorption of Cl- on Pt-N-4 sites during the CER. Density functional theory calculations suggest the PtN4C12 site as the most plausible active site structure for the CER

Conserved signalling components coordinate epidermal patterning and cuticle deposition in barley

Faced with terrestrial threats, land plants seal their aerial surfaces with a lipid-rich cuticle. To breathe, plants interrupt their cuticles with adjustable epidermal pores, called stomata, that regulate gas exchange, and develop other specialised epidermal cells such as defensive hairs. Mechanisms coordinating epidermal features remain poorly understood. Addressing this, we studied two loci whose allelic variation causes both cuticular wax-deficiency and misarranged stomata in barley, identifying the underlying genes, Cer-g/ HvYDA1, encoding a YODA-like (YDA) MAPKKK, and Cer-s/ HvBRX-Solo, encoding a single BREVIS-RADIX (BRX) domain protein. Both genes control cuticular integrity, the spacing and identity of epidermal cells, and barley’s distinctive epicuticular wax blooms, as well as stomatal patterning in elevated CO(2) conditions. Genetic analyses revealed epistatic and modifying relationships between HvYDA1 and HvBRX-Solo, intimating that their products participate in interacting pathway(s) linking epidermal patterning with cuticular properties in barley. This may represent a mechanism for coordinating multiple adaptive features of the land plant epidermis in a cultivated cereal

Efficacy of lateral bone augmentation prior to implant placement: A systematic review and meta-analysis

AIM The aim of the current systematic review was to critically appraise evidence from randomized and prospective non-randomized comparative clinical trials about the efficacy of lateral bone augmentation prior to implant placement and their outcome regarding bone-width gain. MATERIAL AND METHODS Eight databases were searched until May 2018 for randomized and prospective non-randomized comparative trials on lateral bone augmentation prior to implant placement. After elimination of duplicate studies, data extraction and risk-of-bias assessment according to the Cochrane guidelines, random-effects meta-analyses of Mean Differences (MD) or Relative Risks (RR) and their 95% CIs were performed, followed by subgroup, meta-regression, and sensitivity analyses. RESULTS A total of 25 trials (16 randomized / 9 non-randomized) were identified, which included a total of 553 patients (42.2% male; mean age of 43.9 years). In these included studies and populations, various modalities for primary lateral bone augmentation rendered implant placement feasible. Bone width gain was significantly inversely associated with baseline bone width (pooled effect: -0.35 mm/mm; 95% CI: -0.63 to -0.07 mm; p=0.01). % graft resorption demonstrated a correlation with patient age (36% /year, 95% CI: -0.62 to -0.11 mm; p=0.01). The presence of xenograft added to autogenous graft led to less resorption compared to autograft alone (MD: 1.06 mm; 95% CI: 0.21 to 1.92 mm; p=0.01). Barrier membrane did not yield significant difference in terms of bone width gain (MD: -0.33 mm; 95% CI: -2.24 to 1.58 mm; p>0.05) and graft resorption (MD: 0.84 mm; 95% CI: -1.42 to 3.09 mm; p>0.05). CONCLUSIONS Initially smaller bone dimension favors larger bone width gain, which indicates that a severe lateral bone deficiency can be effectively augmented applying primary lateral bone augmentation. Patients' age and recipient site (maxilla or mandible) seems to influence graft resorption. The addition of a xenograft can be helpful for reducing graft resorption. This article is protected by copyright. All rights reserved

Sphingosine Kinase-1 Is Required for Toll Mediated β-Defensin 2 Induction in Human Oral Keratinocytes

Host defense against invading pathogens is triggered by various receptors including toll-like receptors (TLRs). Activation of TLRs is a pivotal step in the initiation of innate, inflammatory, and antimicrobial defense mechanisms. Human beta-defensin 2 (HBD-2) is a cationic antimicrobial peptide secreted upon gram-negative bacterial perturbation in many cells. Stimulation of various TLRs has been shown to induce HBD-2 in oral keratinocytes, yet the underlying cellular mechanisms of this induction are poorly understood.Here we demonstrate that HBD-2 induction is mediated by the Sphingosine kinase-1 (Sphk-1) and augmented by the inhibition of Glycogen Synthase Kinase-3beta (GSK-3beta) via the Phosphoinositide 3-kinase (PI3K) dependent pathway. HBD-2 secretion was dose dependently inhibited by a pharmacological inhibitor of Sphk-1. Interestingly, inhibition of GSK-3beta by SB 216763 or by RNA interference, augmented HBD-2 induction. Overexpression of Sphk-1 with concomitant inhibition of GSK-3beta enhanced the induction of beta-defensin-2 in oral keratinocytes. Ectopic expression of constitutively active GSK-3beta (S9A) abrogated HBD-2 whereas kinase inactive GSK-3beta (R85A) induced higher amounts of HBD-2.These data implicate Sphk-1 in HBD-2 regulation in oral keratinocytes which also involves the activation of PI3K, AKT, GSK-3beta and ERK 1/2. Thus we reveal the intricate relationship and pathways of toll-signaling molecules regulating HBD-2 which may have therapeutic potential

A bacterial glycan core linked to surface (S)-layer proteins modulates host immunity through Th17 suppression

Tannerella forsythia is a pathogen implicated in periodontitis, an inflammatory disease of the tooth-supporting tissues often leading to tooth loss. This key periodontal pathogen is decorated with a unique glycan core O-glycosidically linked to the bacterium's proteinaceous surface (S)-layer lattice and other glycoproteins. Herein, we show that the terminal motif of this glycan core acts to modulate dendritic cell effector functions to suppress T-helper (Th)17 responses. In contrast to the wild-type bacterial strain, infection with a mutant strain lacking the complete S-layer glycan core induced robust Th17 and reduced periodontal bone loss in mice. Our findings demonstrate that surface glycosylation of this pathogen may act to ensure its persistence in the host likely through suppression of Th17 responses. In addition, our data suggest that the bacterium then induces the Toll-like receptor 2–Th2 inflammatory axis that has previously been shown to cause bone destruction. Our study provides a biological basis for pathogenesis and opens opportunities in exploiting bacterial glycans as therapeutic targets against periodontitis and a range of other infectious diseases

Tobacco Upregulates P. gingivalis Fimbrial Proteins Which Induce TLR2 Hyposensitivity

Tobacco smokers are more susceptible to periodontitis than non-smokers but exhibit reduced signs of clinical inflammation. The underlying mechanisms are unknown. We have previously shown that cigarette smoke extract (CSE) represents an environmental stress to which P. gingivalis adapts by altering the expression of several virulence factors - including major and minor fimbrial antigens (FimA and Mfa1, respectively) and capsule - concomitant with a reduced pro-inflammatory potential of intact P. gingivalis.We hypothesized that CSE-regulation of capsule and fimbrial genes is reflected at the ultrastructural and functional levels, alters the nature of host-pathogen interactions, and contributes to the reduced pro- inflammatory potential of smoke exposed P. gingivalis. CSE induced ultrastructural alterations were determined by electron microscopy, confirmed by Western blot and physiological consequences studied in open-flow biofilms. Inflammatory profiling of specific CSE-dysregulated proteins, rFimA and rMfa1, was determined by quantifying cytokine induction in primary human innate and OBA-9 cells. CSE up-regulates P. gingivalis FimA at the protein level, suppresses the production of capsular polysaccharides at the ultrastructural level, and creates conditions that promote biofilm formation. We further show that while FimA is recognized by TLR2/6, it has only minimal inflammatory activity in several cell types. Furthermore, FimA stimulation chronically abrogates the pro-inflammatory response to subsequent TLR2 stimulation by other TLR-2-specific agonists (Pam3CSK4, FSL, Mfa1) in an IkappaBalpha- and IRAK-1-dependent manner.These studies provide some of the first information to explain, mechanistically, how tobacco smoke changes the P. gingivalis phenotype in a manner likely to promote P. gingivalis colonization and infection while simultaneously reducing the host response to this major mucosal pathogen