Genome-Wide Methylation Profiling in 229 Patients With Crohn's Disease Requiring Intestinal Resection:Epigenetic Analysis of the Trial of Prevention of Post-operative Crohn's Disease (TOPPIC)

Background & AimsDNA methylation alterations may provide important insights into gene-environment interaction in cancer, aging, and complex diseases, such as inflammatory bowel disease (IBD). We aim first to determine whether the circulating DNA methylome in patients requiring surgery may predict Crohn’s disease (CD) recurrence following intestinal resection; and second to compare the circulating methylome seen in patients with established CD with that we had reported in a series of inception cohorts.MethodsTOPPIC was a placebo-controlled, randomized controlled trial of 6-mercaptopurine at 29 UK centers in patients with CD undergoing ileocolic resection between 2008 and 2012. Genomic DNA was extracted from whole blood samples from 229 of the 240 patients taken before intestinal surgery and analyzed using 450KHumanMethylation and Infinium Omni Express Exome arrays (Illumina, San Diego, CA). Coprimary objectives were to determine whether methylation alterations may predict clinical disease recurrence; and to assess whether the epigenetic alterations previously reported in newly diagnosed IBD were present in the patients with CD recruited into the TOPPIC study. Differential methylation and variance analysis was performed comparing patients with and without clinical evidence of recurrence. Secondary analyses included investigation of methylation associations with smoking, genotype (MeQTLs), and chronologic age. Validation of our previously published case-control observation of the methylome was performed using historical control data (CD, n = 123; Control, n = 198).ResultsCD recurrence in patients following surgery is associated with 5 differentially methylated positions (Holm P < .05), including probes mapping to WHSC1 (P = 4.1 × 10-9, Holm P = .002) and EFNA3 (P = 4.9 × 10-8, Holm P = .02). Five differentially variable positions are demonstrated in the group of patients with evidence of disease recurrence including a probe mapping to MAD1L1 (P = 6.4 × 10-5). DNA methylation clock analyses demonstrated significant age acceleration in CD compared with control subjects (GrimAge + 2 years; 95% confidence interval, 1.2–2.7 years), with some evidence for accelerated aging in patients with CD with disease recurrence following surgery (GrimAge +1.04 years; 95% confidence interval, -0.04 to 2.22). Significant methylation differences between CD cases and control subjects were seen by comparing this cohort in conjunction with previously published control data, including validation of our previously described differentially methylated positions (RPS6KA2 P = 1.2 × 10-19, SBNO2 = 1.2 × 10-11) and regions (TXK [false discovery rate, P = 3.6 × 10-14], WRAP73 [false discovery rate, P = 1.9 × 10-9], VMP1 [false discovery rate, P = 1.7 × 10-7], and ITGB2 [false discovery rate, P = 1.4 × 10-7]).ConclusionsWe demonstrate differential methylation and differentially variable methylation in patients developing clinical recurrence within 3 years of surgery. Moreover, we report replication of the CD-associated methylome, previously characterized only in adult and pediatric inception cohorts, in patients with medically refractory disease needing surgery

Observational quantification of three-dimensional anisotropies and scalings of space plasma turbulence at kinetic scales

A statistical survey of spectral anisotropy of space plasma turbulence is performed using five years measurements from MMS in the magnetosheath. By measuring the five-point second-order structure functions of the magnetic field, we have for the first time quantified the three-dimensional anisotropies and scalings at sub-ion-scales ($<$ 100 km). In the local reference frame $(\hat L_{\perp}, \hat l_{\perp}, \hat l_{\parallel})$ defined with respect to local mean magnetic field $\boldsymbol {B}_0$ (Chen et al. 2012), the "statistical eddies" are found to be mostly elongated along $\boldsymbol {B}_0$ and shortened in the direction perpendicular to both $\boldsymbol {B}_0$ and local field fluctuations. From several $d_i$ (ion inertial length) toward $\sim$ 0.05 $d_i$, the ratio between eddies' parallel and perpendicular lengths features a trend of rise then fall, whereas the anisotropy in the perpendicular plane appears scale-invariant. Specifically, the anisotropy relations for the total magnetic field at 0.1-1.0 $d_i$ are obtained as $l_{\parallel} \simeq 2.44 \cdot l_{\perp}^{0.71}$, and $L_{\perp} \simeq 1.58 \cdot l_{\perp}^{1.08}$, respectively. Our results provide new observational evidence to compare with phenomenological models and numerical simulations, which may help to better understand the nature of kinetic scale turbulence.Comment: Accepte

Development of a customised data management system for a COVID-19-adapted colorectal cancer pathway

Objectives A customised data management system was required for a rapidly implemented COVID-19-adapted colorectal cancer pathway in order to mitigate the risks of delayed and missed diagnoses during the pandemic. We assessed its performance and robustness.Methods A system was developed using Microsoft Excel (2007) to retain the spreadsheets’ intuitiveness of direct data entry. Visual Basic for Applications (VBA) was used to construct a user-friendly interface to enhance efficiency of data entry and segregate the data for operational tasks.Results Large data segregation was possible using VBA macros. Data validation and conditional formatting minimised data entry errors. Computation by the COUNT function facilitated live data monitoring.Conclusion It is possible to rapidly implement a makeshift database system with clinicians’ regular input. Large-volume data management using a spreadsheet system is possible with appropriate data definition and VBA-programmed data segregation. The described concept is applicable to any data management system construction requiring speed and flexibility in a resource-limited situation

Chromatin structure and evolution in the human genome

<p>Abstract</p> <p>Background</p> <p>Evolutionary rates are not constant across the human genome but genes in close proximity have been shown to experience similar levels of divergence and selection. The higher-order organisation of chromosomes has often been invoked to explain such phenomena but previously there has been insufficient data on chromosome structure to investigate this rigorously. Using the results of a recent genome-wide analysis of open and closed human chromatin structures we have investigated the global association between divergence, selection and chromatin structure for the first time.</p> <p>Results</p> <p>In this study we have shown that, paradoxically, synonymous site divergence (dS) at non-CpG sites is highest in regions of open chromatin, primarily as a result of an increased number of transitions, while the rates of other traditional measures of mutation (intergenic, intronic and ancient repeat divergence as well as SNP density) are highest in closed regions of the genome. Analysis of human-chimpanzee divergence across intron-exon boundaries indicates that although genes in relatively open chromatin generally display little selection at their synonymous sites, those in closed regions show markedly lower divergence at their fourfold degenerate sites than in neighbouring introns and intergenic regions. Exclusion of known Exonic Splice Enhancer hexamers has little affect on the divergence observed at fourfold degenerate sites across chromatin categories; however, we show that closed chromatin is enriched with certain classes of ncRNA genes whose RNA secondary structure may be particularly important.</p> <p>Conclusion</p> <p>We conclude that, overall, non-CpG mutation rates are lowest in open regions of the genome and that regions of the genome with a closed chromatin structure have the highest background mutation rate. This might reflect lower rates of DNA damage or enhanced DNA repair processes in regions of open chromatin. Our results also indicate that dS is a poor measure of mutation rates, particularly when used in closed regions of the genome, as genes in closed regions generally display relatively strong levels of selection at their synonymous sites.</p

Unveiling Dust-enshrouded Star Formation in the Early Universe: a Sub-mm Survey of the Hubble Deep Field

The advent of sensitive sub-mm array cameras now allows a proper census of dust-enshrouded massive star-formation in very distant galaxies, previously hidden activity to which even the faintest optical images are insensitive. We present the deepest sub-mm survey of the sky to date, taken with the SCUBA camera on the James Clerk Maxwell Telescope and centred on the Hubble Deep Field. The high source density found in this image implies that the survey is confusion-limited below a flux density of 2 mJy. However, within the central 80 arcsec radius independent analyses yield 5 reproducible sources with S(850um) > 2 mJy which simulations indicate can be ascribed to individual galaxies. We give positions and flux densities for these, and furthermore show using multi-frequency photometric data that the brightest sources in our map lie at redshifts z~3. These results lead to integral source counts which are completely inconsistent with a no-evolution model, and imply that massive star-formation activity continues at redshifts > 2. The combined brightness of the 5 most secure sources in our map is sufficient to account for 30 - 50% of the previously unresolved sub-mm background, and we estimate statistically that the entire background is resolved at about the 0.3 mJy level. Finally we discuss possible optical identifications and redshift estimates for the brightest sources. One source appears to be associated with an extreme starburst galaxy at z~1, whilst the remaining four appear to lie in the redshift range 2 < z < 4. This implies a star-formation density over this redshift range that is at least five times higher than that inferred from the ultraviolet output of HDF galaxies.Comment: 19 pages, 6 figures (to appear as a Nature Article

A Submillimetre Survey of the Hubble Deep Field: Unveiling Dust-Enshrouded Star Formation in the Early Universe

The advent of sensitive sub-mm array cameras now allows a proper census of dust-enshrouded massive star-formation in very distant galaxies, previously hidden activity to which even the deepest optical images are insensitive. We present the deepest sub-mm survey, taken with the SCUBA camera on the James Clerk Maxwell Telescope (JCMT) and centred on the Hubble Deep Field (HDF). The high source density on this image implies that the survey is confusion-limited below a flux density of 2 mJy. However within the central 80 arcsec radius independent analyses yield 5 reproducible sources with S(850um) > 2 mJy which simulations indicate can be ascribed to individual galaxies. These data lead to integral source counts which are completely inconsistent with a no evolution model, whilst the combined brightness of the 5 most secure sources in our map is sufficient to account for 30-50% of the previously unresolved sub-mm background, and statistically the entire background is resolved at about the 0.3 mJy level. Four of the five brightest sources appear to be associated with galaxies which lie in the redshift range 2 < z < 4. With the caveat that this is a small sample of sources detected in a small survey area, these submm data imply a star-formation density over this redshift range that is at least five times higher than that inferred from the rest-frame ultraviolet output of HDF galaxies.Comment: to appear in the proceedings of `The Birth of Galaxies', Xth Rencontres de Blois, 4 pages, 1 postscript figure, uses blois.sty (included

Beyond the Clinic: Maximum Free-Living Stepping as a Potential Measure of Physical Performance

Measures of physical performance captured within a clinical setting are commonly used as a surrogate for underlying health or disease risk within an individual. By measuring physical behaviour within a free-living setting, we may be able to better quantify physical performance. In our study, we outline an approach to measure maximum free-living step count using a body-worn sensor as an indicator of physical performance. We then use this approach to characterise the maximum step count over a range of window durations within a population of older adults to identify a preferred duration over which to measure the maximum step count. We found that while almost all individuals (97%) undertook at least one instance of continuous stepping longer than two minutes, a sizeable minority of individuals (31%) had no periods of continuous stepping longer than six minutes. We suggest that the maximum step count measured over a six-minute period may be too sensitive to the adults' lack of opportunity to undertake prolonged periods of stepping, and a two-minute window could provide a more representative measure of physical performance