A BS TRACT: Background: The gut microbiome and its metabolites can impact brain health and are altered in Parkinson's disease (PD) patients. It has been recently demonstrated that PD patients have reduced fecal levels of the potent epigenetic modulator butyrate and its bacterial producers.Objectives: Here, we investigate whether the changes in the gut microbiome and associated metabolites are related to PD symptoms and epigenetic markers in leucocytes and neurons. Methods: Stool, whole blood samples, and clinical data were collected from 55 PD patients and 55 controls. We performed DNA methylation analysis on whole blood samples and analyzed the results in relation to fecal shortchain fatty acid concentrations and microbiota composition. In another cohort, prefrontal cortex neurons were isolated from control and PD brains. We identified genome-wide DNA methylation by targeted bisulfite sequencing. Results: We show that lower fecal butyrate and reduced counts of genera Roseburia, Romboutsia, and Prevotella are related to depressive symptoms in PD patients. Genes containing butyrate-associated methylation sites include PD risk genes and significantly overlap with sites epigenetically altered in PD blood leucocytes, predominantly neutrophils, and in brain neurons, relative to controls. Moreover, butyrate-associated methylated-DNA regions in PD overlap with those altered in gastrointestinal (GI), autoimmune, and psychiatric diseases. Conclusions: Decreased levels of bacterially produced butyrate are related to epigenetic changes in leucocytes and neurons from PD patients and to the severity of their depressive symptoms. PD shares common butyratedependent epigenetic changes with certain GI and psychiatric disorders, which could be relevant for their epidemiological relation.

Sunlight-associated melanomas carry a unique C-to-T mutation signature. UVB radiation induces cyclobutane pyrimidine dimers (CPDs) as the major form of DNA damage, but the mechanism of how CPDs cause mutations is unclear. To map CPDs at single-base resolution genome wide, we developed the circle damage sequencing (circle-damage-seq) method. In human cells, CPDs form preferentially in a tetranucleotide sequence context (5′-Py-T<>Py-T/A), but this alone does not explain the tumor mutation patterns. To test whether mutations arise at CPDs by cytosine deamination, we specifically mapped UVB-induced cytosine-deaminated CPDs. Transcription start sites (TSSs) were protected from CPDs and deaminated CPDs, but both lesions were enriched immediately upstream of the TSS, suggesting a mutation-promoting role of bound transcription factors. Most importantly, the genomic dinucleotide and trinucleotide sequence specificity of deaminated CPDs matched the prominent mutation signature of melanomas. Our data identify the cytosine-deaminated CPD as the leading premutagenic lesion responsible for mutations in melanomas.

BackgroundIn Korea, the breastfeeding (BF) rate of infants aged 6 months or more is drastically decreasing, and this phenomenon is particularly worrisome for the future health of the population. The present study aimed to identify an antenatal strategy for initiation and continuation of human BF, and to identify how Baby-Friendly Hospitals (BFHs) may positively influence the intention to breastfeed.MethodsA total of 414 pregnant Korean antenatal women were surveyed using questionnaires to determine current knowledge of the benefits of human breast milk, whether they planned to breastfeed after delivery, to continue BF after reinstatement in the workforce, are willing to abide by rooming-in care for infants, and plan to give birth at BFHs.ResultsWe found that planning room-in care, greater awareness of BF benefits for infant and mother, participation in antenatal education programs, and provision of BF facilities in the workplace were positively associated with plans for exclusive breastfeeding (EBF) and longer BF duration. The mothers who planned to give birth at BFHs also desired to breastfeed immediately after birth, implement in-room care, continue BF at their workplace, participate in antenatal BF educational programs, and were more aware of the benefits of BF.ConclusionIf the beneficial effects of BFHs were well known to individuals, these would enhance the success rate of BF in Korea. Antenatal education and consequent acquisition of better knowledge of the benefits of BF are important for increasing the rate of BF practices.

The antibody to hepatitis B surface antigen (anti-HBs) seropositivity rate after 3 doses of hepatitis B virus (HBV) vaccination during infancy period is known to be higher than 90%. However, a considerable number of vaccines do not form protective anti-HBs or chronologic decrease of anti-HBs. We retrospectively collected data of HBV serologic test results in 20,738 individuals from 2000 to 2015. After exclusion criteria were applied, 19,072 individuals were included. We analyzed the anti-HBs seropositivity rate, anti-HBs disappearance rate, anti-HBs positive seroconversion rate after receiving a booster vaccine, and the difference in anti-HBs positivity between the 2 groups; group A (born before 2005, while both recombinant vaccines and plasma-derived vaccines were used) and group B (born after 2005, when only recombinant vaccines were used by national regulation). The anti-HBs seropositivity rate was 55.8%, but there was a significant difference in the rate of seropositivity for anti-HBs between the group A and B (53.0% vs. 78.1%, P < 0.001). There was no significant age-adjusted difference in the mean seropositivity rate between the 2 groups (P = 0.058). In addition, the anti-HBs positivity rate was significantly lower in the group A as compared with the group B during infancy (83.1% vs. 92.1%, P < 0.001). A total of 1,106 anti-HBs-positive subjects underwent serologic tests more than twice. Of these, 217 subjects (19.6%) showed anti-HBs disappearance. After booster vaccinations, 87.4% (83/95) achieved seroconversion from seronegative to seropositive. Our results highlight the importance of lifelong protection against HBV and the possible necessity of booster vaccination after adolescent period.

An open challenge in human genetics is to better understand the systems-level impact of genotype variation on developmental cognition. To characterize the genetic underpinnings of peri-adolescent cognition, we performed genotype–phenotype and systems analysis for binarized accuracy in nine cognitive tasks from the Philadelphia Neurodevelopmental Cohort (~2,200 individuals of European continental ancestry aged 8–21 years). We report a region of genome-wide significance within the 3′ end of the Fibulin-1 gene (P = 4.6 × 10−8), associated with accuracy in nonverbal reasoning, a heritable form of complex reasoning ability. Diffusion tensor imaging data from a subset of these participants identified a significant association of white matter fractional anisotropy with FBLN1 genotypes (P &lt; 0.025); poor performers show an increase in the C and A allele for rs77601382 and rs5765534, respectively, which is associated with increased fractional anisotropy. Integration of published human brain-specific ’omic maps, including single-cell transcriptomes of the developing human brain, shows that FBLN1 demonstrates greatest expression in the fetal brain, as a marker of intermediate progenitor cells, demonstrates negligible expression in the adolescent and adult human brain, and demonstrates increased expression in the brain in schizophrenia. Collectively these findings warrant further study of this gene and genetic locus in cognition, neurodevelopment, and disease. Separately, genotype-pathway analysis identified an enrichment of variants associated with working memory accuracy in pathways related to development and to autonomic nervous system dysfunction. Top-ranking pathway genes include those genetically associated with diseases with working memory deficits, such as schizophrenia and Parkinson’s disease. This work advances the “molecules-to-behavior” view of cognition and provides a framework for using systems-level organization of data for other biomedical domains.