Human height is a representative phenotype to elucidate genetic architecture. However, the majority of large studies have been performed in European population. To investigate the rare and ...low-frequency variants associated with height, we construct a reference panel (N = 3,541) for genotype imputation by integrating the whole-genome sequence data from 1,037 Japanese with that of the 1000 Genomes Project, and perform a genome-wide association study in 191,787 Japanese. We report 573 height-associated variants, including 22 rare and 42 low-frequency variants. These 64 variants explain 1.7% of the phenotypic variance. Furthermore, a gene-based analysis identifies two genes with multiple height-increasing rare and low-frequency nonsynonymous variants (SLC27A3 and CYP26B1; P
< 2.5 × 10
). Our analysis shows a general tendency of the effect sizes of rare variants towards increasing height, which is contrary to findings among Europeans, suggesting that height-associated rare variants are under different selection pressure in Japanese and European populations.
Prevotella intermedia, a Gram-negative oral anaerobic bacterium, is frequently isolated from the periodontal pockets of patients with chronic periodontitis. In recent years, the involvement of the ...bacterium in respiratory tract infections as well as in oral infections has been revealed. P. intermedia possesses several potent virulence factors, such as cysteine proteinase interpain A encoded by the
gene. The genome of P. intermedia carries genes of the type IX secretion system (T9SS), which enables the translocation of virulence factors across the outer membrane in several pathogens belonging to the phylum
; however, it is still unclear whether the T9SS is functional in this microorganism. Recently, we performed targeted mutagenesis in the strain OMA14 of P. intermedia. Here, we successfully obtained mutants deficient in
and the T9SS component genes
and
. None of the mutants exhibited protease activity of interpain A. The
and
mutants, but not the
mutant, showed defects in colony pigmentation, hemagglutination, and biofilm formation. We also obtained a complemented strain for the
gene that recovered all the above abilities. These results indicate that T9SS functions in P. intermedia and that interpain A is one of the T9SS cargo proteins.
The virulence factors of periodontal pathogens such as Prevotella intermedia have not been elucidated. Using our established procedure, we succeeded in generating type IX secretion system mutants and gene complementation strains that might transfer virulence factors to the bacterial surface. The generated strains clearly indicate that T9SS in P. intermedia is essential for colonial pigmentation, hemagglutination, and biofilm formation. These results indicated that interpain A is a T9SS cargo protein.
The type IX secretion system (T9SS) was originally discovered in Porphyromonas gingivalis, one of the pathogenic bacteria associated with periodontal disease and is now known to be present in many ...members of the phylum Bacteroidetes. The T9SS secretes a number of potent virulence factors, including the highly hydrolytic proteases called gingipains, across the outer membrane in P. gingivalis. To understand the entire machinery of T9SS, an exhaustive search for T9SS‐related genes in P. gingivalis using the mariner family transposon (Tn) and Tn‐seq analysis was performed. Seven hundred and two Tn insertion sites in Tn mutants with no colony pigmentation that is associated with Lys‐gingipain (Kgp) defectiveness were determined, and it was found that the Tn was inserted in the kgp gene and 54 T9SS‐related candidate genes. Thirty‐three out of the 54 genes were already known as T9SS‐related genes. Furthermore, deletion mutant analysis of the remaining 21 genes revealed that they were not related to the T9SS. The 33 T9SS‐related genes include a gene for PGN_0297, which was found to be associated with the T9SS components PorK and PorN. A PGN_0297 gene deletion mutant was constructed, and it was found that the mutant showed no colony pigmentation, hemagglutination or gingipain activities, indicating that PGN_0297 was an essential component of the T9SS. The 33 genes did not include the six genes (gppX, omp17, porY, rfa, sigP and wzx) that were also reported as T9SS‐related genes. gppX deletion and insertion mutants were constructed, and it was found that they did not show deficiency in the T9SS.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
To understand the genetics of type 2 diabetes in people of Japanese ancestry, we conducted A meta-analysis of four genome-wide association studies (GWAS; 36,614 cases and 155,150 controls of Japanese ...ancestry). We identified 88 type 2 diabetes-associated loci (P < 5.0 × 10
) with 115 independent signals (P < 5.0 × 10
), of which 28 loci with 30 signals were novel. Twenty-eight missense variants were in linkage disequilibrium (r
> 0.6) with the lead variants. Among the 28 missense variants, three previously unreported variants had distinct minor allele frequency (MAF) spectra between people of Japanese and European ancestry (MAF
> 0.05 versus MAF
< 0.01), including missense variants in genes related to pancreatic acinar cells (GP2) and insulin secretion (GLP1R). Transethnic comparisons of the molecular pathways identified from the GWAS results highlight both ethnically shared and heterogeneous effects of a series of pathways on type 2 diabetes (for example, monogenic diabetes and beta cells).
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Porphyromonas gingivalis is a major pathogen of periodontal diseases, including periodontitis. We have investigated the effect of P. gingivalis infection on the PI3K/Akt (protein kinase B) signaling ...pathway in gingival epithelial cells. Here, we found that live P. gingivalis, but not heat-killed P. gingivalis, reduced Akt phosphorylation at both Thr-308 and Ser-473, which implies a decrease in Akt activity. Actually, PI3K, which is upstream of Akt, was also inactivated by P. gingivalis. Furthermore, glycogen synthase kinase 3α/β, mammalian target of rapamycin, and Bad, which are downstream proteins in the PI3K/Akt cascade, were also dephosphorylated, a phenomenon consistent with Akt inactivation by P. gingivalis. However, these events did not require direct interaction between bacteria and host cells and were independent of P. gingivalis invasion into the cells. The use of gingipain-specific inhibitors and a gingipain-deficient P. gingivalis mutant KDP136 revealed that the gingipains and their protease activities were essential for the inactivation of PI3K and Akt. The associations between the PI3K regulatory subunit p85α and membrane proteins were disrupted by wild-type P. gingivalis. Moreover, PDK1 translocation to the plasma membrane was reduced by wild-type P. gingivalis, but not KDP136, indicating little production of phosphatidylinositol 3,4,5-triphosphate by PI3K. Therefore, it is likely that PI3K failed to transmit homeostatic extracellular stimuli to intracellular signaling pathways by gingipains. Taken together, our findings indicate that P. gingivalis attenuates the PI3K/Akt signaling pathway via the proteolytic effects of gingipains, resulting in the dysregulation of PI3K/Akt-dependent cellular functions and the destruction of epithelial barriers.
Background: The significance of gingipains on the PI3K/Akt signaling pathway is poorly understood.
Results: The inactivation of PI3K and Akt was induced by P. gingivalis, which was associated with gingipains.
Conclusion: Gingipains are critical for suppressing the PI3K/Akt signaling pathway via extracellular proteolysis independent of P. gingivalis invasion.
Significance: This study shows the first evidence that the gingipains negatively regulate the PI3K/Akt signaling pathway.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Descriptive epidemiology is dened as epidemiological studies and activities with descriptive components that are much stronger than their analytic components or that fall within the descriptive area ...of the descriptive-analytic spectrum. Descriptive epidemiology deals with the occurrence of disease, in terms of both geographical comparisons and descriptions of temporal trends.
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FFLJ, NUK, ODKLJ, UL, UM, UPUK
Colony spreading of Flavobacterium johnsoniae is shown to include gliding motility using the cell surface adhesin SprB, and is drastically affected by agar and glucose concentrations. Wild-type (WT) ...and ΔsprB mutant cells formed nonspreading colonies on soft agar, but spreading dendritic colonies on soft agar containing glucose. In the presence of glucose, an initial cell growth-dependent phase was followed by a secondary SprB-independent, gliding motility-dependent phase. The branching pattern of a ΔsprB colony was less complex than the pattern formed by the WT. Mesoscopic and microstructural information was obtained by atmospheric scanning electron microscopy (ASEM) and transmission EM, respectively. In the growth-dependent phase of WT colonies, dendritic tips spread rapidly by the movement of individual cells. In the following SprB-independent phase, leading tips were extended outwards by the movement of dynamic windmill-like rolling centers, and the lipoproteins were expressed more abundantly. Dark spots in WT cells during the growth-dependent spreading phase were not observed in the SprB-independent phase. Various mutations showed that the lipoproteins and the motility machinery were necessary for SprB-independent spreading. Overall, SprB-independent colony spreading is influenced by the lipoproteins, some of which are involved in the gliding machinery, and medium conditions, which together determine the nutrient-seeking behavior.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Adhesive pili (or fimbriae) in bacteria are classified into five types, among which type V pili have been most recently described. Type V pili differ from other pili types with respect to transport ...mechanism, structure, and pilin synthesis. Genes of type V pili are restricted to the phylum Bacteroidetes. Protein subunits that compose type V pili are transported to the cell surface as lipoprotein precursors and then polymerized into a pilus through a strand-exchange mechanism, which is demonstrated by several experiments, including palmitic acid labeling and Cys-Cys cross-linking analysis. Here, we describe the use of these methods to analyze type V pili.
Biogenesis of Type V pili Shoji, Mikio; Shibata, Satoshi; Sueyoshi, Takayuki ...
Microbiology and immunology,
October 2020, Volume:
64, Issue:
10
Journal Article
Peer reviewed
Open access
Pili or fimbriae, which are filamentous structures present on the surface of bacteria, were purified from a periodontal pathogen, Porphyromonas gingivalis, in 1980s. The protein component of pili ...(stalk pilin), which is its major component, was named FimA; it has a molecular weight of approximately 41 kDa. Because the molecular weight of the pilin from P. gingivalis is twice that of pilins from other bacterial pili, the P. gingivalis Fim pili were suggested to be formed via a novel mechanism. In earlier studies, we reported that the FimA pilin is secreted on the cell surface as a lipoprotein precursor, and the subsequent N‐terminal processing of the FimA precursor by arginine‐specific proteases is necessary for Fim pili formation. The crystal structures of FimA and its related proteins were determined recently, which show that Fim pili are formed by a protease‐mediated strand‐exchange mechanism. The most recent study conducted by us, wherein we performed cryoelectron microscopy of the pilus structure, provided evidence in support of this mechanism. As the P. gingivalis Fim pili are formed through novel transport and assembly mechanisms, such pili are now designated as Type V pili. Surface lipoproteins, including the anchor pilin FimB of Fim pili that are present on the outer membrane, have been detected in certain Gram‐negative bacteria. Here, we describe the assembly mechanisms of pili, including those of Type V and other pili, as well as the lipoprotein transport mechanisms.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Although associations between oral health and pneumonia have been reported in previous studies, particularly in the institutionalized elderly, few prospective studies have investigated the ...association between oral condition and pneumonia among community-dwelling people and whether the findings among inpatients or patients in nursing homes are applicable to the general population is still unclear. The oral bacteria propagated in the periodontal regions may drop into the lung and increase the risk of pneumonia. We, therefore, investigated the association of tooth loss with mortality from pneumonia in a cohort study of Japanese dentists. Members of the Japan Dental Association (JDA) participated in the LEMONADE (Longitudinal Evaluation of Multi-phasic, Odontological and Nutritional Associations in Dentists) Study. From 2001 to 2006, they completed a baseline questionnaire on lifestyle and health factors including the number of teeth lost (excluding third molars). We followed 19,775 participants (mean age ± standard deviation, 51.4 ± 11.7 years; 1,573 women 8.0% and 18,202 men 92.0%) for mortality from pneumonia (ICD-10, J12-J18). Mortality data were collected via the fraternal insurance program of the JDA. The hazard ratios (HRs) were estimated with adjustment for sex, age, body mass index, smoking status, physical activity and diabetes history. During the median follow-up period of 9.5 years, we documented 68 deaths from pneumonia. Participants who were edentulous at baseline were at significantly increased risk of mortality from pneumonia. The multivariable-adjusted HRs were 2.07 (95% confidence interval CI, 1.09-3.95) for the edentulous and 1.60 (95% CI, 0.83-3.10) for loss of 15-27 teeth relative to loss of 0-14 teeth (trend p = 0.026). The HR per one tooth loss was also significant; 1.031 (95% CI, 1.004-1.060). In conclusion, a large number of teeth lost may indicate an increased risk of mortality from pneumonia in community-dwelling populations.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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