The Hidden Effects of Parasites in a Changing Ocean

Trematode parasites are a fascinating group of species which occur in almost all types of marine habitat and infect many ecologically and commercially important marine organisms. They possess complex life histories that involve multiple host species, often radically change morphology as they move between hosts, and can dramatically alter the performance of infected organisms.As with all marine organisms, trematodes are affected by human-mediated changes to the global oceans – for example, warmer temperatures, less available oxygen, increased seawater acidity.Of course, given the complex nature of host–parasite interactions, the effects of such changes to the marine environment could have equally complex consequences for disease dynamics. The potential for such substantial change to the role of trematode parasites caused by a changing marine environment can best be understood by following a single parasite species through a complete life cycle

Extracellular Calcium-Sensing Receptor Inhibition of Intestinal EpithelialTNF Signaling Requires CaSR-Mediated Wnt5a/Ror2 Interaction

Tumor necrosis factor alpha (TNFα) and its receptor TNFR1 play a central role in the development of colitis-associated colon cancer. To understand a role for the extracellular calcium-sensing receptor (CaSR) and its non-canonical Wnt mediators, Wnt5a/Ror2, we used reductionistic systems. We added lipopolysaccharide (LPS) to mouse peritoneal macrophages, RAW264.7 cells, a murine macrophage cell line, and 18Co colonic myofibroblasts, to stimulate TNFα secretion and then activated endogenous CaSR. CaSR activation inhibited TNFα secretion, which in RAW264.7 cells knockdown of CaSR by short-interfering RNA (siRNA) duplex reversed. LPS-stimulated NFκB promoter activity in RAW264.7 cells was inhibited by CaSR activation with Ca2+ or other polyvalent CaSR agonists. Reducing CaSR expression with siRNA duplex prevented this inhibition. Following LPS addition to CaSR–HEK cells or RAW264.7 macrophages, CaSR stimulation deneddylated Cullin1. Wnt5a added to HT-29 cells which overexpressed Ror2 or T84 monolayers treated with 3 mM Ca2+ reduced TNFR1 protein expression ∼70%. TNFα/INFγ addition to high resistance T84 monolayers reduced transepithelial resistance 50% within 4 h. CaSR activation (3 mM Ca2+) together with rhWnt5a (200 ng/ml) prevented this reduction while Wnt3a addition had no effect. LPS-stimulated TNFα secretion from RAW264.7 cells was not effected by rhWnt5a but increased 10-fold by Wnt3a. Together our results suggest that following LPS challenge, CaSR activation will inhibit NFκB activity and reduce TNFα secretion from macrophages and stroma while Wnt5a/Ror2 engagement on intestinal epithelia reduces TNFR1 expression, allowing TNFα signaling to be titrated. Our results also suggest that canonical Wnt signaling may enhance TLR4 stimulation of TNFα secretion from murine macrophages

A Stochastic Model for the Luminosity Fluctuations of Accreting Black Holes

In this work we have developed a new stochastic model for the fluctuations in lightcurves of accreting black holes. The model is based on a linear combination of stochastic processes and is also the solution to the linear diffusion equation perturbed by a spatially correlated noise field. This allows flexible modeling of the power spectral density (PSD), and we derive the likelihood function for the process, enabling one to estimate the parameters of the process, including break frequencies in the PSD. Our statistical technique is computationally efficient, unbiased by aliasing and red noise leak, and fully accounts for irregular sampling and measurement errors. We show that our stochastic model provides a good approximation to the X-ray lightcurves of galactic black holes, and the optical and X-ray lightcurves of AGN. We use the estimated time scales of our stochastic model to recover the correlation between characteristic time scale of the high frequency X-ray fluctuations and black hole mass for AGN, including two new `detections' of the time scale for Fairall 9 and NGC 5548. We find a tight anti-correlation between the black hole mass and the amplitude of the driving noise field, which is proportional to the amplitude of the high frequency X-ray PSD, and we estimate that this parameter gives black hole mass estimates to within ~ 0.2 dex precision, potentially the most accurate method for AGN yet. We also find evidence that ~ 13% of AGN optical PSDs fall off flatter than 1 / f^2, and, similar to previous work, find that the optical fluctuations are more suppressed on short time scales compared to the X-rays, but are larger on long time scales, suggesting the optical fluctuations are not solely due to reprocessing of X-rays.Comment: 22 pages, 10 figures, resubmitted to match accepted version, in press at Ap

Kepler Observations of Rapid Optical Variability in Active Galactic Nuclei

Over three quarters in 2010-2011, Kepler monitored optical emission from four active galactic nuclei (AGN) with ~30 min sampling, >90% duty cycle, and <~0.1% repeatability. These data determined the AGN optical fluctuation power spectral density functions (PSDs) over a wide range in temporal frequency. Fits to these PSDs yielded power law slopes of -2.6 to -3.3, much steeper than typically seen in the X-rays. We find evidence that individual AGN exhibit intrinsically different PSD slopes. The steep PSD fits are a challenge to recent AGN variability models but seem consistent with first order MRI theoretical calculations of accretion disk fluctuations.Comment: Accepted by Astrophysical Journal Letters, 31 Oct 201

SYSTEMS-2: a randomised phase II study of radiotherapy dose escalation for pain control in malignant pleural mesothelioma

SYSTEMS-2 is a randomised study of radiotherapy dose escalation for pain control in 112 patients with malignant pleural mesothelioma (MPM). Standard palliative (20Gy/5#) or dose escalated treatment (36Gy/6#) will be delivered using advanced radiotherapy techniques and pain responses will be compared at week 5. Data will guide optimal palliative radiotherapy in MPM

Geographical distance and reduced access to palliative radiotherapy: Systematic Review and Meta-Analysis

Background. Palliative radiotherapy (PRT) is an effective way of reducing symptoms caused by advanced incurable cancer. Several studies have investigated factors that contribute to inequalities in access to PRT; distance to a radiotherapy centre has been identified as one potential barrier.Aim. To assess whether there is an association between distance to a radiotherapy centre and utilisation rates of PRT in adults with cancer.Methods. A systematic review and meta-analysis protocol was registered in the PROSPERO database (CRD42020190772). MEDLINE, EMBASE, CINAHL and APA-PsycINFO were searched for relevant papers up to 28 February 2021.Results. Twenty-one studies were included. Twelve studies focused on whether patients with incurable cancer received PRT, as part of their treatment package. Pooled results reported that living ≥50 km vs <50 km from the radiotherapy centre was associated with a reduced likelihood of receiving PRT (OR 0.84 (95%CI 0.80, 0.88)). Nine focused on distance from the radiotherapy centre and compared single-fraction (SF) versus multiple-fraction PRT, indicating that patients living further away were more likely to receive SF. Pooled results comparing ≥50 km versus <50 km showed increased odds of receiving SF for those living ≥50 km (OR 1.48 (95%CI 1.26,1.75)).Conclusion. Patients living further away from radiotherapy centres were less likely to receive PRT and those who received PRT were more likely to receive SF PRT, providing some evidence of inequalities in access to PRT treatment based on proximity to centres providing radiotherapy. Further research is needed to understand whether these inequalities are influenced by clinical referral patterns or by patients unwilling or unable to travel longer distances