Epigenome-wide methylation profile of chronic kidney disease-derived arterial DNA uncovers novel pathways in disease-associated cardiovascular pathology

Chronic kidney disease (CKD) related cardiovascular disease (CVD) is characterized by vascular remodelling with well-established structural and functional changes in the vascular wall such as arterial stiffness, matrix deposition, and calcification. These phenotypic changes resemble pathology seen in ageing, and are likely to be mediated by sustained alterations in gene expression, which may be caused by epigenetic changes such as tissue-specific DNA methylation. We aimed to investigate tissue specific changes in DNA methylation that occur in CKD-related CVD. Genome-wide DNA methylation changes were examined in bisulphite converted genomic DNA isolated from the vascular media of CKD and healthy arteries. Methylation-specific PCR was used to validate the array data, and the association between DNA methylation and gene and protein expression was examined. The DNA methylation age was compared to the chronological age in both cases and controls. Three hundred and nineteen differentially methylated regions (DMR) were identified spread across the genome. Pathway analysis revealed that DMRs associated with genes were involved in embryonic and vascular development, and signalling pathways such as TGFβ and FGF. Expression of top differentially methylated gene HOXA5 showed a significant negative correlation with DNA methylation. Interestingly, DNA methylation age and chronological age were highly correlated, but there was no evidence of accelerated age-related DNA methylation in the arteries of CKD patients. In conclusion, we demonstrated that differential DNA methylation in the arterial tissue of CKD patients represents a potential mediator of arterial pathology and may be used to uncover novel pathways in the genesis of CKD-associated complications

Detection of Large Scale Structure in a B<17m Galaxy Redshift Survey

We report on results from the Durham/UKST Galaxy Redshift Survey where we have found large scale ``cellular'' features in the galaxy distribution. These have spatial 2-point correlation function power significantly in excess of the predictions of the standard cold dark matter cosmological model1, supporting the previous observational results from the APM survey2,3. At smaller scales, the 1-D pairwise galaxy velocity dispersion is measured to be 387+96−62 kms−1 which is also inconsistent with the prediction of the standard cold dark matter model1. Finally, the survey has produced the most significant detection yet of large scale redshift space distortions due to dynamical infall of galaxies4. An estimate of Ω0.6/b=0.55±0.12 is obtained which is consistent either with a low density Universe or a critical density Universe where galaxies are biased tracers of the mass.preprin

Swift observations of V404 Cyg during the 2015 outburst: X-ray outflows from super-Eddington accretion

The black hole (BH) binary V404 Cyg entered the outburst phase in 2015 June after 26 yr of X-ray quiescence, and with its behaviour broke the outburst evolution pattern typical of most BH binaries. We observed the entire outburst with the Swift satellite and performed time-resolved spectroscopy of its most active phase, obtaining over a thousand spectra with exposures from tens to hundreds of seconds. All the spectra can be fitted with an absorbed power-law model, which most of the time required the presence of a partial covering. A blueshifted iron-Ka line appears in 10 per cent of the spectra together with the signature of high column densities, and about 20 per cent of the spectra seem to show signatures of reflection. None of the spectra showed the unambiguous presence of soft disc-blackbody emission, while the observed bolometric flux exceeded the Eddington value in 3 per cent of the spectra. Our results can be explained assuming that the inner part of the accretion flow is inflated into a slim disc that both hides the innermost (and brightest) regions of the flow, and produces a cold, clumpy, high-density outflow that introduces the high absorption and fast spectral variability observed. We argue that the BH in V404 Cyg might have been accreting erratically or even continuously at Eddington/super-Eddington rates - thus sustaining a surrounding slim disc - while being partly or completely obscured by the inflated disc and its outflow. Hence, the largest flares produced by the source might not be accretion-driven events, but instead the effects of the unveiling of the extremely bright source hidden within the system

Analytic philosophy for biomedical research: the imperative of applying yesterday's timeless messages to today's impasses

The mantra that "the best way to predict the future is to invent it" (attributed to the computer scientist Alan Kay) exemplifies some of the expectations from the technical and innovative sides of biomedical research at present. However, for technical advancements to make real impacts both on patient health and genuine scientific understanding, quite a number of lingering challenges facing the entire spectrum from protein biology all the way to randomized controlled trials should start to be overcome. The proposal in this chapter is that philosophy is essential in this process. By reviewing select examples from the history of science and philosophy, disciplines which were indistinguishable until the mid-nineteenth century, I argue that progress toward the many impasses in biomedicine can be achieved by emphasizing theoretical work (in the true sense of the word 'theory') as a vital foundation for experimental biology. Furthermore, a philosophical biology program that could provide a framework for theoretical investigations is outlined

Swift Multiwavelength Follow-up of LVC S200224ca and the Implications for Binary Black Hole Mergers

On 2020 February 24, during their third observing run ("O3"), the Laser Interferometer Gravitational-wave Observatory and Virgo Collaboration detected S200224ca: a candidate gravitational wave (GW) event produced by a binary black hole (BBH) merger. This event was one of the best-localized compact binary coalescences detected in O3 (with 50%/90% error regions of 13/72 deg2), and so the Neil Gehrels Swift Observatory performed rapid near-UV/X-ray follow-up observations. Swift-XRT and UVOT covered approximately 79.2% and 62.4% (respectively) of the GW error region, making S200224ca the BBH event most thoroughly followed-up in near-UV (u-band) and X-ray to date. No likely EM counterparts to the GW event were found by the Swift BAT, XRT, or UVOT, nor by other observatories. Here, we report on the results of our searches for an EM counterpart, both in the BAT data near the time of the merger, and in follow-up UVOT/XRT observations. We also discuss the upper limits we can place on EM radiation from S200224ca, as well as the implications these limits have on the physics of BBH mergers. Namely, we place a shallow upper limit on the dimensionless BH charge, $\hat{q}\lt 1.4\times {10}^{-4}$, and an upper limit on the isotropic-equivalent energy of a blast wave E < 4.1 × 1051 erg (assuming typical GRB parameters)

Swift-XRT follow-up of gravitational wave triggers during the third aLIGO/Virgo observing run

The Neil Gehrels Swift Observatory followed up 18 gravitational wave (GW) triggers from the LIGO/Virgo collaboration during the O3 observing run in 2019/2020, performing approximately 6500 pointings in total. Of these events, four were finally classified (if real) as binary black hole (BH) triggers, six as binary neutron star (NS) events, two each of NSBH and Mass Gap triggers, one an unmodelled (Burst) trigger, and the remaining three were subsequently retracted. Thus far, four of these O3 triggers have been formally confirmed as real gravitational wave events. While no likely electromagnetic counterparts to any of these GW events have been identified in the X-ray data (to an average upper limit of 3.60 x 10^{-12} erg cm^{-2} s^{-1} over 0.3-10 keV), or at other wavelengths, we present a summary of all the Swift-XRT observations performed during O3, together with typical upper limits for each trigger observed. The majority of X-ray sources detected during O3 were previously uncatalogued; while some of these will be new (transient) sources, others are simply too faint to have been detected by earlier survey missions such as ROSAT. The all-sky survey currently being performed by eROSITA will be a very useful comparison for future observing runs, reducing the number of apparent candidate X-ray counterparts by up to 95 per cent

The Relationship of DNA Methylation with Age, Gender and Genotype in Twins and Healthy Controls

Cytosine-5 methylation within CpG dinucleotides is a potentially important mechanism of epigenetic influence on human traits and disease. In addition to influences of age and gender, genetic control of DNA methylation levels has recently been described. We used whole blood genomic DNA in a twin set (23 MZ twin-pairs and 23 DZ twin-pairs, N = 92) as well as healthy controls (N = 96) to investigate heritability and relationship with age and gender of selected DNA methylation profiles using readily commercially available GoldenGate bead array technology. Despite the inability to detect meaningful methylation differences in the majority of CpG loci due to tissue type and locus selection issues, we found replicable significant associations of DNA methylation with age and gender. We identified associations of genetically heritable single nucleotide polymorphisms with large differences in DNA methylation levels near the polymorphism (cis effects) as well as associations with much smaller differences in DNA methylation levels elsewhere in the human genome (trans effects). Our results demonstrate the feasibility of array-based approaches in studies of DNA methylation and highlight the vast differences between individual loci. The identification of CpG loci of which DNA methylation levels are under genetic control or are related to age or gender will facilitate further studies into the role of DNA methylation and disease

Bayesian Computation with Intractable Likelihoods

This article surveys computational methods for posterior inference with intractable likelihoods, that is where the likelihood function is unavailable in closed form, or where evaluation of the likelihood is infeasible. We review recent developments in pseudo-marginal methods, approximate Bayesian computation (ABC), the exchange algorithm, thermodynamic integration, and composite likelihood, paying particular attention to advancements in scalability for large datasets. We also mention R and MATLAB source code for implementations of these algorithms, where they are available.Comment: arXiv admin note: text overlap with arXiv:1503.0806

Visualizing Interactions along the Escherichia coli Twin-Arginine Translocation Pathway Using Protein Fragment Complementation

The twin-arginine translocation (Tat) pathway is well known for its ability to export fully folded substrate proteins out of the cytoplasm of Gram-negative and Gram-positive bacteria. Studies of this mechanism in Escherichia coli have identified numerous transient protein-protein interactions that guide export-competent proteins through the Tat pathway. To visualize these interactions, we have adapted bimolecular fluorescence complementation (BiFC) to detect protein-protein interactions along the Tat pathway of living cells. Fragments of the yellow fluorescent protein (YFP) were fused to soluble and transmembrane factors that participate in the translocation process including Tat substrates, Tat-specific proofreading chaperones and the integral membrane proteins TatABC that form the translocase. Fluorescence analysis of these YFP chimeras revealed a wide range of interactions such as the one between the Tat substrate dimethyl sulfoxide reductase (DmsA) and its dedicated proofreading chaperone DmsD. In addition, BiFC analysis illuminated homo- and hetero-oligomeric complexes of the TatA, TatB and TatC integral membrane proteins that were consistent with the current model of translocase assembly. In the case of TatBC assemblies, we provide the first evidence that these complexes are co-localized at the cell poles. Finally, we used this BiFC approach to capture interactions between the putative Tat receptor complex formed by TatBC and the DmsA substrate or its dedicated chaperone DmsD. Our results demonstrate that BiFC is a powerful approach for studying cytoplasmic and inner membrane interactions underlying bacterial secretory pathways