A meta-analysis of brain DNA methylation across sex, age and Alzheimer’s disease points for accelerated epigenetic aging in neurodegeneration

AbstractAlzheimer’s disease (AD) is characterized by specific alterations of brain DNA methylation (DNAm) patterns. Age and sex, two major risk factors for AD, are also known to largely affect the epigenetic profiles in the brain, but their contribution to AD-associated DNAm changes has been poorly investigated. In this study we considered publicly available DNAm datasets of 4 brain regions (temporal, frontal, entorhinal cortex and cerebellum) from healthy adult subjects and AD patients, and performed a meta-analysis to identify sex-, age- and AD-associated epigenetic profiles. We showed that DNAm differences between males and females tend to be shared between the 4 brain regions, while aging differently affects cortical regions compared to cerebellum. We found that the proportion of sex-dependent probes whose methylation changes also during aging is higher than expected, but that differences between males and females tend to be maintained, with only few probes showing sex-by-age interaction. We did not find significant overlaps between AD- and sex-associated probes, nor disease-by-sex interaction effects. On the contrary, we found that AD-related epigenetic modifications are significantly enriched in probes whose DNAm changes with age and that there is a high concordance between the direction of changes (hyper or hypo-methylation) in aging and AD, supporting accelerated epigenetic aging in the disease.In conclusion, we demonstrated that age-associated, but not sex-associated DNAm concurs to the epigenetic deregulation observed in AD, providing new insight on how advanced age enables neurodegeneration.</jats:p

Phenotypic and genotypic antibiotic resistance profiles of Escherichia coli O157 from cattle and slaughterhouse wastewater isolates

Gencay, Yilmaz Emre/0000-0002-2154-9663WOS: 000354724300054The aims of this study were to determine the minimal inhibition concentration of 20 different antibiotics on cattle and slaughterhouse wastewater Escherichia coli O157, including both Shiga toxigenic E. coli O157 (STEC O157) and non-Shiga toxigenic strains (non-STEC O157) by the Epsilometer test, and to determine the antibiotic resistance gene profiles of the isolates by PCR. A total of 102 cattle and slaughterhouse wastewater E. coli O157 isolates including 96 E. coli O157:H7(+) (81 non-sorbitol fermenting [NSF] STEC O157:H7, 12 NSF non-STEC O157:H7, and three sorbitol fermenting [SF] non-STEC O157:H7) and six non-STEC O157:H7(-) isolated from 744 cattle and slaughterhouse wastewater samples collected within a 2-year period were assessed. Of 93 NSF E. coli O157:H7 isolates, 19 were resistant to tetracycline and sulfamethoxazole, 14 to trimethoprim, 13 to cefoxitin, 11 to streptomycin, 10 to ampicillin, eight to chloramphenicol, six to cephalothin, four to cefaclor, four to aztreonam, and four to nalidixic acid. In six of the E. coli O157:H7(-) isolates, tetracycline resistance was detected while five of them were also resistant to ampicillin, sulfamethoxazole, and trimethoprim. In PCR analysis, 26.0 % (25/96) of the NSF E. coli O157:H7(+) and all of the E. coli O157:H7(-) isolates harbored one or more antibiotic resistance genes. While tetA, tetB, tetC, strA, strB, and sulI genes were detected from a number of the isolates, tetD, tetE, tetG, cmlA, floR, sulII, aadA, and ampC genes were not detected in any of the isolates. Results suggest a high antibiotic resistance in E. coli O157:H7(+)/H7(-) cattle and wastewater isolates. The majority of our resistant isolates, antibacterial resistance genes did not correlate with observed phenotypic resistance. Other resistance traits and regulatory factors that mediate antibiotic resistance should be included in further antimicrobial resistance investigations.Scientific and Technological Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [110R013]This study was supported by The Scientific and Technological Research Council of Turkey (TUBITAK, project no: 110R013)

Identification of a novel locus associated with skin colour in African-admixed populations

Skin pigmentation is a complex trait that varies largely among populations. Most genome-wide association studies of this trait have been performed in Europeans and Asians. We aimed to uncover genes influencing skin colour in African-admixed individuals. We performed a genome-wide association study of melanin levels in 285 Hispanic/Latino individuals from Puerto Rico, analyzing 14 million genetic variants. A total of 82 variants with p-value ≤1 × 10(−5) were followed up in 373 African Americans. Fourteen single nucleotide polymorphisms were replicated, of which nine were associated with skin colour at genome-wide significance in a meta-analysis across the two studies. These results validated the association of two previously known skin pigmentation genes, SLC24A5 (minimum p = 2.62 × 10(−14), rs1426654) and SLC45A2 (minimum p = 9.71 × 10(−10), rs16891982), and revealed the intergenic region of BEND7 and PRPF18 as a novel locus associated with this trait (minimum p = 4.58 × 10(−9), rs6602666). The most significant variant within this region is common among African-descent populations but not among Europeans or Native Americans. Our findings support the advantages of analyzing African-admixed populations to discover new genes influencing skin pigmentation