Interaction between Bacteriophage DMS3 and Host CRISPR Region Inhibits Group Behaviors of Pseudomonas aeruginosa

Bacteriophage infection has profound effects on bacterial biology. Clustered regular interspaced short palindromic repeats (CRISPRs) and cas (CRISPR-associated) genes are found in most archaea and many bacteria and have been reported to play a role in resistance to bacteriophage infection. We observed that lysogenic infection of Pseudomonas aeruginosa PA14 with bacteriophage DMS3 inhibits biofilm formation and swarming motility, both important bacterial group behaviors. This inhibition requires the CRISPR region in the host. Mutation or deletion of five of the six cas genes and one of the two CRISPRs in this region restored biofilm formation and swarming to DMS3 lysogenized strains. Our observations suggest a role for CRISPR regions in modifying the effects of lysogeny on P. aeruginosa

Relationship between number of contacts between previous dropouts with type 2 diabetes and health care professionals on glycaemic control : A cohort study in public primary health care

Aim: Previous study findings have shown that more frequent contacts with the diabetes care team predict better diabetes control. It is unknown whether this is true also for previous dropouts with type 2 diabetes (T2D). The aim of this study was to evaluate if those previous dropouts with T2D who succeeded to improve their glycaemic control had more frequent contacts with health care professionals in the public primary diabetes health care system than those dropouts who did not show improvement. Methods: In this "real life" retrospective cohort study, we identified 115 dropouts with T2D who were contacted by trained diabetes nurses and who returned to a public T2D-care system. Those previous dropouts who had baseline haemoglobin A(1c) >= 53 mmoVmol (7%) and had a reduction in HbA(1c) >= 6 mmol/mol (0.5%) during the follow-up were compared with those with unsatisfactory change in HbA(1c) (baseline HbA(1c) >= 53 mmoVmol and change Results: Previous dropouts showing improvement had more visits to the diabetes nurse (p = 0.003) and other nurses (p <0.001) than those with no improvement or those with satisfactory glycaemic control. Telephone calls not focusing on diabetes (p <0.001) were also more frequent among previous dropouts with improvement than among the others. Conclusions: Especially previous dropouts with T2D who had poor glycaemic control, may benefit from more frequent contacts including visits and telephone calls. Recalling dropouts does not seem to lead to overuse of the T2D care-system by those recalled patients whose glycaemic control does not require special care. (C) 2019 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.Peer reviewe

SIRT6 polymorphism rs117385980 is associated with longevity and healthy aging in Finnish men

Background: Sirtuin-6 (SIRT6) is involved in various crucial cellular pathways, being a key regulator of telomere structure, DNA repair, metabolism, transcriptional control and the NF-kappa B pathway. Sirt6 knock-out mice have been reported to develop typical features of aging and senescence at the age of 2-3 weeks and die within 4 weeks. The aim of this study was to investigate whether sequence variations of SIRT6 are associated with aging and longevity in Finnish men. Methods: The sample of this study consisted of 43 longer-living and healthy males and 92 male control subjects who have died of natural causes at an average age of 66,6 (+/- 4,1) years and who belonged to the Helsinki Birth Cohort Study (HBCS). Single nucleotide polymorphisms (SNPs) in the exons and their surroundings of the SIRT6 were studied using direct PCR sequencing. Results: The SNP rs117385980 (C > T), situated 23 bases downstream of the exon 2 exon/intron border was found in heterozygous form in 1/43 longer-living healthy men (Minor allele frequency (MAF) 0,0116) and in 9/92 controls (MAF 0,0489). To replicate this finding, we studied a group of 63 healthy men at an average age of 83 years from the Helsinki Businessmen Study (HBS)-cohort. The heterozygosity of the same SNP was seen in 2/63 men from the HBS-cohort (MAF 0,0159). Fisher exact test was performed in our two combined study samples. The P-value for all samples combined was 0.07 and the odds ratio 3.53 (95% confidence interval 0.96-13.4). Conclusions: These results suggest an inverse association between the T allele of rs117385980 and longevity. The result needs to be confirmed in a larger study. It remains to be determined whether rs117385980 itself has an effect or if it is a mere genetic marker for some other yet undiscovered sequence variant causing a functional effect.Peer reviewe

The C-type lectin receptor SIGNR3 binds to fungi present in commensal microbiota and influences immune regulation in experimental colitis

Inflammatory bowel disease is a condition of acute and chronic inflammation of the gut. An important factor contributing to pathogenesis is a dysregulated mucosal immunity against commensal bacteria and fungi. Host pattern- recognition receptors (PRRs) sense commensals in the gut and are involved in maintaining the balance between controlled responses to pathogens and overwhelming innate immune activation. C-type lectin receptors (CLRs) are PRRs recognizing glycan structures on pathogens and self-antigens. Here we examined the role of the murine CLR specific intracellular adhesion molecule-3 grabbing non-integrin homolog-related 3 (SIGNR3) in the recognition of commensals and its involvement in intestinal immunity. SIGNR3 is the closest murine homolog of the human dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) receptor recognizing similar carbohydrate ligands such as terminal fucose or high-mannose glycans. We discovered that SIGNR3 recognizes fungi present in the commensal microbiota. To analyze whether this interaction impacts the intestinal immunity against microbiota, the dextran sulfate sodium-induced colitis model was employed. SIGNR3(-/-) mice exhibited an increased weight loss associated with more severe colitis symptoms compared to wild-type control mice. The increased inflammation in SIGNR3(-/-) mice was accompanied by a higher level of TNF-α in colon. Our findings demonstrate for the first time that SIGNR3 recognizes intestinal fungi and has an immune regulatory role in colitis

Polygenic Risk Score of SERPINA6/SERPINA1 Associates with Diurnal and Stress-Induced HPA Axis Activity in Children

Purpose: Corticosteroid-binding globulin (CBG) transports glucocorticoids in blood. Variation in genes SERPINA6 encoding for CBG, SERPINA2 and SERPINAI (serpin family A member 6, 2, and 1) have been shown to influence morning plasma cortisol and CBG in adults. However, association of this genetic variation with diurnal and stress-induced salivary cortisol remain unknown. This study aims to investigate the effect of genetic variation in SERPINA6/2/1 loci on diurnal and stress-induced salivary cortisol in children. Methods: We studied 186, 8-year-old children with genome-wide genotyping. We generated weighted polygenic risk score (PRS) based on 6 genome-wide significant SNPs (rs11621961, rs11629171, rs7161521, rs2749527, rs3762132, rs4900229) derived from the CORNET meta-analyses. Salivary cortisol was measured across one day and in response to the Trier Social Stress Test for Children (TSST-C). Results: Mixed models, adjusted for covariates, showed that the PRS x sampling time interactions associated with diurnal (P <0.001) and stress-induced (P = 0.009) salivary cortisol. In the high PRS group (dichotomized at median) the diurnal salivary cortisol pattern decreased less from awakening to bedtime than in the low PRS group (standardized estimates of sampling time -0.64 vs. -0.73, P <0.0001 for both estimates). In response to stress, salivary cortisol increased in the high PRS group while it remained unchanged in the low PRS group (standardized estimates of sampling time 0.12, P = 0.015 vs. -0.06, P = 0.16). These results were mainly driven by minor alleles of rs7161521 (SERPINA6) and rs4900229 (SERPINAI). Conclusions: Genetic variation in SERPINA6/2/1loci may underpin higher hypothalamic-pituitary-adrenocortical axis activity in children.Peer reviewe

Mucin 4 and matrix metalloproteinase 7 as novel salivary biomarkers for periodontitis

Aim: Periodontitis is a chronic inflammatory disease, characterized by irreversible destruction of tooth-supporting tissue including alveolar bone. We recently reported mucin 4 ( MUC4) and matrix metalloproteinase 7 (MMP7) as highly associated with periodontitis in gingival tissue biopsies. The aim of this study was to further investigate the levels of MUC4 and MMP7 in saliva and gingival crevicular fluid (GCF) samples of patients with periodontitis. Materials and Methods: Saliva and GCF samples were collected from periodontitis patients and healthy controls. The levels of MUC4, MMP7, and total protein concentrations were analysed using ELISA or Bradford assay. Results: MUC4 levels were significantly lower in saliva and GCF from periodontitis patients relative to healthy controls. MMP7 levels were significantly higher in saliva and GCF from periodontitis patients. Multivariate analysis revealed that MUC4 was significantly associated with periodontitis after adjusting for age and smoking habits and, moreover, that the combination of MUC4 and MMP7 accurately discriminated periodontitis from healthy controls. Conclusions: MUC4 and MMP7 may be utilized as possible novel biomarkers for periodontitis.Peer reviewe

Contacting dropouts from type 2 diabetes care in public primary health care : description of the patient population

Objective: To characterize dropouts from type-2 diabetes (T2D) care in communal primary health care. Design: An observational study. Setting: In a Finnish city, patients with T2D who had not contacted the public primary health care system during the past 12 months were identified with a computer based search and contacted by a trained diabetes nurse. Subjects: Dropouts from T2D treatment. Main outcome measures: Demographic factors, laboratory parameters, examinations, medications, and comorbidities. Results: Of the patients with T2D, 10% (n=356) were dropouts and 60% of them were men. Median HbA(1c) was 6.5 (QR for 25% and 75%: 6.0, 7.7) %, (45 [42,61] mmol/mol). Of the dropouts, 14% had HbA(1c)9.0% (75mmol/mol), and these patients were younger than the other dropouts (mean age 54.4 [SD 10.8] years vs. 60.6 [9.4] years, p Conclusions: Ten percent of T2D patients were dropouts of whom those with a poor glycaemic control were younger than the other dropouts. BP and LDL cholesterol concentrations were non-optimal among the majority of the dropouts. Metformin was prescribed less frequently to the dropouts than is usual for T2D patients. The comorbidities were equally common among the dropouts as among the other T2D patients.Peer reviewe

Heterozygous TYROBP deletion (PLOSLFIN) is not a strong risk factor for cognitive impairment

Biallelic loss-of-function mutations in TYROBP and TREM2 cause a rare disease that resembles early-onset frontotemporal dementia with bone lesions called polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). Some PLOSL-causing variants in TREM2 have also been associated with Alzheimer's disease when heterozygous. Here, we studied the PLOSLFIN TYROBP deletion that covers 4 of the gene's 5 exons. We genotyped 3220 older Finns (mean age 79, range 58-104) and found 11 deletion carriers (mean age 78, range 60-94). The carrier prevalence was 0.0034 (1 in 293) that matches previous findings in younger cohorts suggesting no significant early mortality. By comparing Mini-Mental State Examination (MMSE) scores and diagnoses of dementia, we did not find any significant differences between TYROBP deletion carriers and noncarriers (all p-values >0.5). Neuropathological analysis of 2 deletion carriers (aged 89 and 94 years) demonstrated only minimal beta amyloid pathology (Consortium to Establish a Registry for Alzheimer's Disease (CERAD) score 0). Collectively these results suggest that heterozygous carriership of the TYROBP deletion is not a major risk factor of cognitive impairment. (C) 2017 Elsevier Inc. All rights reserved.Peer reviewe