Molecular characterization of the UV-response in Caenorhabditis elegans

The Structural Maintenance of Chromosomes (SMC) proteins form distinct complexes that maintain genome stability during chromosome segregation, homologous recombination (HR), and DNA replication. Using a forward genetic screen, we identified two alleles of smc-5 that exacerbate UV-sensitivity in C. elegans. Germ cells of smc-5 defective animals show reduced proliferation, sensitivity to perturbed replication and accumulation of RAD-51 foci that indicate the activation of HR. Mutations in the translesion synthesis polymerase polh-1 act synergistically with smc-5 mutations in provoking genome instability after UV-induced DNA damage. In contrast, the DNA damage accumulation and UV-sensitivity in smc-5 mutant strains are suppressed by mutations in the C. elegans BRCA1/BARD1 homologues, brc-1 and brd-1. We propose that SMC-5/6 promotes replication fork stability and facilitates recombination-dependent repair when the BRC-1/BRD-1 complex initiates HR at stalled replication forks. Our data suggest that BRC-1/BRD-1 can both, promote and antagonize genome stability depending on whether HR is initiated during DSB repair or during replication stalling. In addition, we characterized the pool of small regulatory RNAs that respond to UV irradiation in young C. elegans. Deep sequencing identified miRNAs that were regulated differentially after treatment with UV light and revealed novel miRNAs. We validated upregulation of mir-2214*, mir-235, mir-71 and mir-238 as well as suppression of mir-1830, let-7, mir-2211, mir-48 and lin-4. However, analysis of mutants and GFP-reporter strains indicated that lin-4 and let-7 are dispensable for resistance to UV and that promoter activity is not changed after irradiation. Combining literature research and bioinformatical approaches we found that UV-regulated miRNAs are associated with growth and development. Also, we provide evidence that miRNAs alter MAPK kinase signaling, control nucleotide excision repair and the proteasome in response to UV irradiation

Towards a harmonized European surveillance for dietary and physical activity indicators in young and adult populations

Background The Policy Evaluation Network proposes a consolidated approach to measure comparable health indicators across European health surveillance systems to evaluate effectiveness of policy action. Methods In a stepwise approach, questionnaire items used by the systems for measuring diet and physical activity data to describe health indicators were identified based on their validity, reliability, and suitability to monitor achievement of health recommendations. They were collated to unified questionnaire modules and discussed bilaterally with representatives of these systems to explore barriers and facilitators for implementation. Also, establishment of a methodological competence platform was proposed, in which the surveillance and monitoring systems agree on the priorities and common quality standards for the harmonization process and to coordinate the integration of questionnaire modules into existing systems. Results In total, seven questionnaire modules were developed, of which two diet and two physical activity modules were proposed for implementation. Each module allows measurement of data reflecting only partial aspects of national and WHO recommendations related to diet and physical activity. Main barriers were the requirements of systems to monitor temporal trends and to minimize costs. Main facilitator for implementation was the systems’ use of questionnaire items that were comparable to the unified modules. Representatives agreed to participate in a methodological competence platform. Conclusion We successfully took first steps in the realization of the roadmap towards a harmonization of European surveillance by introducing unified questionnaire modules allowing the collection of comparable health indicators and by initiating the establishment of a competence platform to guide this process

Age-Specific Quantification of Overweight/Obesity Risk Factors From Infancy to Adolescence and Differences by Educational Level of Parents

Objectives: To explore the age-dependent associations between 26 risk factors and BMI in early life, and differences by parental educational level.Methods: Data of 10,310 children (24,155 measurements) aged 2–16 years participating in a multi-centre European cohort from 2007 to 2014 were utilized. Trajectories of overweight/obesity risk factors and their age-specific associations with BMI were estimated using polynomial mixed-effects models.Results: Exposure to most unfavourable factors was higher in the low/medium compared to the high education group, e.g., for PC/TV time (12.6 vs. 10.6 h/week). Trajectories of various risk factors markedly changed at an age of 9–11 years. Having a family history of obesity, maternal BMI, pregnancy weight gain and birth weight were positively associated with BMI trajectories throughout childhood/adolescence in both education groups; associations of behavioural factors with BMI were small. Parental unemployment and migrant background were positively associated with BMI in the low/medium education group.Conclusion: Associations of risk factors with BMI trajectories did not essentially differ by parental education except for social vulnerabilities. The age period of 9–11 years may be a sensitive period for adopting unfavourable behaviours

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG