Biology subjects

Stone, J.

Publications and source records attributed to Stone, J..

5 recordsLinked to original sources

bioRxiv2018

Associations between environmental breast cancer risk factors and DNA methylation-based risk-predicting measures

BackgroundGenome-wide average DNA methylation (GWAM) and epigenetic age acceleration have been suggested to predict breast cancer risk. We aimed to investigate the relationships between these putative risk-predicting measures and environmental breast cancer risk factors.\n\nMethodsUsing the Illumina HumanMethylation450K assay methylation data, we calculated GWAM and epigenetic age acceleration for 132 female twin pairs and their 215 sisters. Linear regression was used to estimate associations between these risk-predicting measures and multiple breast cancer risk factors. Within-pair analysis was performed for the 132 twin pairs.\n\nResultsGWAM was negatively associated with number of live births, and positively with age at first live birth (both P<0.05). Epigenetic age acceleration was positively associated with body mass index (BMI), smoking, alcohol drinking and age at menarche, and negatively with age at first live birth (all P<0.05), and the associations with BMI, alcohol drinking and age at first live birth remained in the within-pair analysis.\n\nConclusionsThis exploratory study shows that lifestyle and hormone-related breast cancer risk factors are associated with DNA methylation-based measures that could predict breast cancer risk. The associations of epigenetic age acceleration with BMI, alcohol drinking and age at first live birth are unlikely to be due to familial confounding.

epidemiology↗

bioRxiv2018

The expansion in lymphoid organs of IL-4+ BATF+ T follicular helper cells is linked to IgG4 class switching in vivo

Distinct TFH subsets that influence specific class-switching events are assumed to exist, but the accumulation of isotype-specific TFH subsets in secondary and tertiary lymphoid organs has not been hitherto demonstrated. IL-4 expressing TFH cells are surprisingly sparse in human secondary lymphoid organs. In sharp contrast, in IgG4-related disease (IgG4-RD), a disorder characterized by polarized Ig class switching, most TFH cells in tertiary and secondary lymphoid organs make IL-4. Human IL-4+ TFH cells do not express GATA-3 but express nuclear BATF, and the transcriptomes of IL-4 secreting TFH cells differ both from PD1hi TFH cells that do not secrete IL-4 and IL4-secreting non-TFH cells. Unlike IgG4-RD, IL-4+ TFH cells are rarely found in tertiary lymphoid organs in Sjogrens syndrome, a disorder in which IgG4 is not elevated. The proportion of CD4+IL-4+BATF+ T cells as well as of CD4+IL-4+CXCR5+ T cells in IgG4-RD tissues correlates tightly with tissue IgG4 plasma cell numbers and plasma IgG4 levels in patients but not with the total plasma levels of other isotypes. These data describe a disease-related TFH sub-population in human tertiary and secondary lymphoid organs that is linked to IgG4 class switching.

immunology↗

bioRxiv2017

Inference about causation between body mass index and DNA methylation in blood from a twin family study

BackgroundSeveral studies have reported DNA methylation in blood to be associated with body mass index (BMI), but only a few have investigated causal aspects of the association. We used a twin family design to assess this association at two life points and applied a novel analytical approach to investigate the evidence for causality.\n\nMethodsThe methylation profile of DNA from peripheral blood was measured for 479 Australian women (mean age 56 years) from 130 twin families. Linear regression was used to estimate the associations of methylation at ~410 000 cytosine-guanine dinucleotides (CpG), and of the average methylation at ~20 000 genes, with current BMI, BMI at age 18-21 years, and the change between the two (BMI change). A novel regression-based methodology for twins, Inference about Causation through Examination of Familial Confounding (ICE FALCON), was used to assess causation.\n\nResultsAt 5% false discovery rate, nine, six and 12 CpGs at 24 loci were associated with current BMI, BMI at age 18-21 years and BMI change, respectively. The average methylation of BHLHE40 and SOCS3 loci was associated with current BMI, and of PHGDH locus was associated with BMI change. From the ICE FALCON analyses with BMI as the predictor and methylation as the outcome, a womans methylation level was associated with her co-twins BMI, and the association disappeared conditioning on her own BMI, consistent with BMI causing methylation. To the contrary, using methylation as the predictor and BMI as the outcome, a womans BMI was not associated with her co-twins methylation level, consistent with methylation not causing BMI.\n\nConclusionFor middle-aged women, peripheral blood DNA methylation at several genomic locations is associated with current BMI, BMI at age 18-21 years and BMI change. Our study suggests that BMI has a causal effect on peripheral blood DNA methylation.

epidemiology↗

bioRxiv2017

Hunters or gardeners?Linking community structure and function of trap-associated microbes to the nutrient acquisition strategy of a carnivorous plant

All higher eukaryotes live in a relationship with diverse microorganisms which colonize their bodily surfaces; plants are no exception. However, we still lack a satisfactory understanding of how these loosely associated microbiomes with immense diversity and functional potential interact with their hosts or how these interactions shape processes within populations and ecosystems. There is considerable similarity between microbial communities colonizing plant surfaces such as roots, and those of the animal gut. This often overlooked parallel allows us to look at microbial as well as host ecophysiology from a fresh perspective. The traps of carnivorous plants are sophisticated digestive organs and interface environments between the supply and the demand for nutrients. We selected the miniature ecosystem in the traps of aquatic carnivorous Utricularia plants as our model system. By assessing the trap-associated microbial community structure, diversity, function, as well as the nutrient recycling potential of bacterivory, we gained insight into the nutrient acquisition strategies of the Utricularia hosts. We conclude that trap ecophysiological function is in many aspects highly analogous to that of the herbivore gut and centers around complex microbial consortia, which act synergistically to covert complex organic matter, often of algal origin, into a source of nutrients for the plants.

microbiology↗

bioRxiv2017

Unbiased Strain-Typing of Arbovirus Directly from Mosquitoes Using Nanopore Sequencing: A Field-forward Biosurveillance Protocol

The future of infectious disease surveillance and outbreak response is trending towards smaller hand-held solutions for point-of-need pathogen detection.1-4 Although recent advances have paved the way for these technologies to include sequencing of pathogens directly from clinical samples, the ability to carry out unbiased sequencing for pathogen discovery and subtyping directly from environmental samples has yet to be demonstrated with hand-held platforms.5 Products such as the two3 qPCR system from Biomeme Inc., as well as the MinION from Oxford Nanopore Technologies, have generated renewed prospects for point-of-need diagnostics and near real-time environmental testing and characterization of viral and microbial pathogens. Here, samples of Culex cedecei mosquitoes collected in Southern Florida, USA were tested for Venezuelan Equine Encephalitis Virus (VEEV), a previously-weaponized arthropod-borne RNA-virus capable of causing acute and fatal encephalitis in animal and human hosts. A single 20-mosquito pool tested positive for VEEV by real-time reverse transcription quantitative PCR (RT-qPCR) on the Biomeme two3. The virus-positive sample was then subjected to unbiased metatranscriptome sequencing on the MinION and determined to contain Everglades Virus (EVEV), a strain of VEEV transmitted exclusively by Culex cedecei in South Florida. The result was confirmed on \"gold standard\" thermocyclers and sequencing machines, and comparison to nanopore results is discussed. Our results demonstrate, for the first time, the use of unbiased sequence-based detection and subtyping of a high-consequence biothreat pathogen directly from an environmental sample using field-forward hardware and protocols. The further development and validation of methods designed for field-based diagnostic metagenomics and pathogen discovery, such as those suitable for use in mobile \"pocket laboratories\", will address a growing demand for public health teams to carry out their mission where it is most urgent: at the point-of-need.6

genomics↗