Identifying cancer subtypes in glioblastoma by combining genomic, transcriptomic and epigenomic data

We present a nonparametric Bayesian method for disease subtype discovery in multi-dimensional cancer data. Our method can simultaneously analyse a wide range of data types, allowing for both agreement and disagreement between their underlying clustering structure. It includes feature selection and infers the most likely number of disease subtypes, given the data. We apply the method to 277 glioblastoma samples from The Cancer Genome Atlas, for which there are gene expression, copy number variation, methylation and microRNA data. We identify 8 distinct consensus subtypes and study their prognostic value for death, new tumour events, progression and recurrence. The consensus subtypes are prognostic of tumour recurrence (log-rank p-value of $3.6 \times 10^{-4}$ after correction for multiple hypothesis tests). This is driven principally by the methylation data (log-rank p-value of $2.0 \times 10^{-3}$) but the effect is strengthened by the other 3 data types, demonstrating the value of integrating multiple data types. Of particular note is a subtype of 47 patients characterised by very low levels of methylation. This subtype has very low rates of tumour recurrence and no new events in 10 years of follow up. We also identify a small gene expression subtype of 6 patients that shows particularly poor survival outcomes. Additionally, we note a consensus subtype that showly a highly distinctive data signature and suggest that it is therefore a biologically distinct subtype of glioblastoma. The code is available from https://sites.google.com/site/multipledatafusion/

Transposon mutagenesis in a hyper-invasive clinical isolate of Campylobacter jejuni reveals a number of genes with potential roles in invasion.

Transposon mutagenesis has been applied to a hyper-invasive clinical isolate of Campylobacter jejuni, 01/51. A random transposon mutant library was screened in an in vitro assay of invasion and 26 mutants with a significant reduction in invasion were identified. Given that the invasion potential of C. jejuni is relatively poor compared to other enteric pathogens, the use of a hyper-invasive strain was advantageous as it greatly facilitated the identification of mutants with reduced invasion. The location of the transposon insertion in 23 of these mutants has been determined; all but three of the insertions are in genes also present in the genome-sequenced strain NCTC 11168. Eight of the mutants contain transposon insertions in one region of the genome (approximately 14 kb), which when compared with the genome of NCTC 11168 overlaps with one of the previously reported plasticity regions and is likely to be involved in genomic variation between strains. Further characterization of one of the mutants within this region has identified a gene that might be involved in adhesion to host cells.

Tandem repeats upstream of the Arabidopsis endogene SDC recruit non-CG DNA methylation and initiate siRNA spreading.

Plants use siRNAs to target cytosine DNA methylation to both symmetrical CG and nonsymmetrical (CHG and CHH) sequence contexts. DNA methylation and siRNA clusters most frequently overlap with transposons in the Arabidopsis thaliana genome. However, a significant number of protein-coding genes also show promoter DNA methylation, and this can be used to silence their expression. Loss of the majority of non-CG DNA methylation in drm1 drm2 cmt3 triple mutants leads to developmental phenotypes. We identified the gene responsible for these phenotypes as SUPPRESSOR OF drm1 drm2 cmt3 (SDC), which encodes an F-box protein and possesses seven promoter tandem repeats. The SDC repeats show a unique silencing requirement for non-CG DNA methylation directed redundantly by histone methylation and siRNAs, and display spreading of siRNAs and methylation beyond the repeated region. In addition to revealing the complexity of DNA methylation control in A. thaliana, SDC has important implications for how plant genomes utilize gene silencing to repress endogenous genes.

Reynolds number effects on scalar dissipation rate transport and its modeling in turbulent premixed combustion

The effects of turbulent Reynolds number, Ret, on the transport of scalar dissipation rate of reaction progress variable in the context of Reynolds averaged Navier-Stokes simulations have been analyzed using three-dimensional simplified chemistry-based direct numerical simulation (DNS) data of freely propagating turbulent premixed flames with different values of Ret. Scaling arguments have been used to explain the effects of Ret on the turbulent transport, scalar-turbulence interaction, and the combined reaction and molecular dissipation terms. Suitable modifications to the models for these terms have been proposed to account for Ret effects, and the model parameters include explicit Ret dependence. These expressions approach expected asymptotic limits for large values of Ret. However, turbulent Reynolds number Ret does not seem to have any major effects on the modeling of the term arising from density variation. Copyright © Taylor and Francis Group, LLC.

Updated correlation between aircraft smoke number and black carbon concentration

Aircraft emissions of black carbon (BC) contribute to anthropogenic climate forcing and degrade air quality. The smoke number (SN) is the current regulatory measure of aircraft particulate matter emissions and quantifies exhaust plume visibility. Several correlations between SN and the exhaust mass concentration of BC (CBC) have been developed, based on measurements relevant to older aircraft engines. These form the basis of the current standard method used to estimate aircraft BC emissions (First Order Approximation version 3 [FOA3]) for the purposes of environmental impact analyses. In this study, BC with a geometric mean diameter (GMD) of 20, 30, and 60 nm and filter diameters of 19 and 35 mm are used to investigate the effect of particle size and sampling variability on SN measurements. For BC with 20 and 30 nm GMD, corresponding to BC emitted by modern aircraft engines, a smaller SN results from a given CBC than is the case for BC with 60 nm GMD, which is more typical of older engines. An updated correlation between CBC and SNthat accounts for typical size of BC emitted by modern aircraft is proposed. An uncertainty of ±25% accounts for variation in GMD in the range 20-30 nm and for the range of filter diameters. The SN-CBC correlation currently used in FOA3 underestimates by a factor of 2.5-3 for SN <15, implying that current estimates of aircraft BC emissions derived from SN are underestimated by the same factor. Copyright © American Association for Aerosol Research.

Experimental study of the effects of temperature variation on droplet size and wetness fraction in a low-pressure model steam turbine

The three-stage low-pressure model steam turbine at the Institute of Thermal Turbomachinery and Machinery Laboratory (ITSM) was used to study the impact of three different steam inlet temperatures on the homogeneous condensation process and the resulting wetness topology. The droplet spectrum as well as the particle number concentration were measured in front of the last stage using an optical-pneumatic probe. At design load, condensation starts inside the stator of the second stage. A change in the steam inlet temperature is able to shift the location of condensation onset within the blade row up- or downstream and even into adjoining blade passages, which leads to significantly different local droplet sizes and wetness fractions due to different local expansion rates. The measured results are compared to steady three-dimensional computational fluid dynamics calculations. The predicted nucleation zones could be largely confirmed by the measurements. Although the trend of measured and calculated droplet size across the span is satisfactory, there are considerable differences between the measured and computed droplet spectrum and wetness fractions. © IMechE 2013 Reprints and permissions: sagepub.co.uk/ journalsPermissions.nav.