Ecosystem uptake and transfer of Sellafield-derived radiocarbon (14C). Part 1. The Irish Sea

Ecosystem uptake and transfer processes of Sellafield-derived radiocarbon (14C) within the Irish Sea were examined. Highly variable activities in sediment, seawater and biota indicate complex 14C dispersal and uptake dynamics. All east basin biota exhibited 14C enrichments above ambient background while most west basin biota had 14C activities close to background, although four organisms including two slow-moving species were significantly enriched. The western Irish Sea gyre is a suggested pathway for transfer of 14C to the west basin and retention therein. Despite ongoing Sellafield 14C discharges, organic sediments near Sellafield were significantly less enriched than associated benthic organisms. Rapid scavenging of labile, 14C-enriched organic material by organisms and mixing to depth of 14C-enriched detritus arriving at the sediment/water interface are proposed mechanisms to explain this. All commercially important fish, crustaceans and molluscs showed 14C enrichments above background; however, the radiation dose from their consumption is extremely low and radiologically insignificant

Structure and Metal Binding Properties of ZnuA, a Periplasmic Zinc Transporter from \u3cem\u3eEscherichia coli\u3c/em\u3e

ZnuA is the periplasmic Zn2+-binding protein associated with the high-affinity ATP-binding cassette ZnuABC transporter from Escherichia coli. Although several structures of ZnuA and its homologs have been determined, details regarding metal ion stoichiometry, affinity, and specificity as well as the mechanism of metal uptake and transfer remain unclear. The crystal structures of E. coli ZnuA (Eco-ZnuA) in the apo, Zn2+-bound, and Co2+-bound forms have been determined. ZnZnuA binds at least two metal ions. The first, observed previously in other structures, is coordinated tetrahedrally by Glu59, His60, His143, and His207. Replacement of Zn2+ with Co2+ results in almost identical coordination geometry at this site. The second metal binding site involves His224 and several yet to be identified residues from the His-rich loop that is unique to Zn2+ periplasmic metal binding receptors. Electron paramagnetic resonance and X-ray absorption spectroscopic data on CoZnuA provide additional insight into possible residues involved in this second site. The second site is also detected by metal analysis and circular dichroism (CD) titrations. Eco-ZnuA binds Zn2+ (estimated K d \u3c 20 nM), Co2+, Ni2+, Cu2+, Cu+, and Cd2+, but not Mn2+. Finally, conformational changes upon metal binding observed in the crystal structures together with fluorescence and CD data indicate that only Zn2+ substantially stabilizes ZnuA and might facilitate recognition of ZnuB and subsequent metal transfer

Comparison of aggregate and individual participant data approaches to meta-analysis of randomised trials : An observational study

BACKGROUND: It remains unclear when standard systematic reviews and meta-analyses that rely on published aggregate data (AD) can provide robust clinical conclusions. We aimed to compare the results from a large cohort of systematic reviews and meta-analyses based on individual participant data (IPD) with meta-analyses of published AD, to establish when the latter are most likely to be reliable and when the IPD approach might be required. METHODS AND FINDINGS: We used 18 cancer systematic reviews that included IPD meta-analyses: all of those completed and published by the Meta-analysis Group of the MRC Clinical Trials Unit from 1991 to 2010. We extracted or estimated hazard ratios (HRs) and standard errors (SEs) for survival from trial reports and compared these with IPD equivalents at both the trial and meta-analysis level. We also extracted or estimated the number of events. We used paired t tests to assess whether HRs and SEs from published AD differed on average from those from IPD. We assessed agreement, and whether this was associated with trial or meta-analysis characteristics, using the approach of Bland and Altman. The 18 systematic reviews comprised 238 unique trials or trial comparisons, including 37,082 participants. A HR and SE could be generated for 127 trials, representing 53% of the trials and approximately 79% of eligible participants. On average, trial HRs derived from published AD were slightly more in favour of the research interventions than those from IPD (HRAD to HRIPD ratio = 0.95, p = 0.007), but the limits of agreement show that for individual trials, the HRs could deviate substantially. These limits narrowed with an increasing number of participants (p < 0.001) or a greater number (p < 0.001) or proportion (p < 0.001) of events in the AD. On average, meta-analysis HRs from published AD slightly tended to favour the research interventions whether based on fixed-effect (HRAD to HRIPD ratio = 0.97, p = 0.088) or random-effects (HRAD to HRIPD ratio = 0.96, p = 0.044) models, but the limits of agreement show that for individual meta-analyses, agreement was much more variable. These limits tended to narrow with an increasing number (p = 0.077) or proportion of events (p = 0.11) in the AD. However, even when the information size of the AD was large, individual meta-analysis HRs could still differ from their IPD equivalents by a relative 10% in favour of the research intervention to 5% in favour of control. We utilised the results to construct a decision tree for assessing whether an AD meta-analysis includes sufficient information, and when estimates of effects are most likely to be reliable. A lack of power at the meta-analysis level may have prevented us identifying additional factors associated with the reliability of AD meta-analyses, and we cannot be sure that our results are generalisable to all outcomes and effect measures. CONCLUSIONS: In this study we found that HRs from published AD were most likely to agree with those from IPD when the information size was large. Based on these findings, we provide guidance for determining systematically when standard AD meta-analysis will likely generate robust clinical conclusions, and when the IPD approach will add considerable value

HO-3867, a STAT3 inhibitor induces apoptosis by inactivation of STAT3 activity in BRCA1-mutated ovarian cancer cells

BRCA1 plays an important role in DNA damage and repair, homologous recombination, cell-cycle regulation and apoptosis. BRCA-mutated ovarian cancer often presents at an advanced stage, however, tend to have better response to platinum-based chemotherapy as compared with sporadic cases of epithelial ovarian cancer (EOC). In spite of this, most patients will develop a recurrence and eventually succumb to the disease. Preclinical studies are currently investigating natural compounds and their analogs for tumor-directed targets in ovarian cancer. The aim of this study is to investigate whether the STAT3 inhibitor HO-3867, a novel curcumin analog, has a therapeutic effect on BRCA1-mutated ovarian cancer. Our novel agent, HO-3867 and a commercial STAT3 inhibitor, STATTIC, significantly inhibited BRCA-mutated ovarian cancer cells in vitro in a dose- and time-dependent manner. BRCA-mutated ovarian cancer cells treated with HO-3867 exhibited a significant degree of apoptosis with elevated levels of cleaved caspase-3, caspase-7 and PARP. HO-3867 treatment induced more reactive oxygen species (ROS) in BRCA-mutated cells compared with wild-type cells, however, there was no increased ROS when benign ovarian surface epithelial cells were treated with HO-3867. BRCA1-mutated cancer cells had higher expression of Tyrosine-phosphorylated STAT3 (pTyr705) as compared with other STAT proteins. Furthermore, treatment of these cells with HO-3867 resulted in decreased expression of pTyr705 and its downstream targets cyclin D1, Bcl-2 and survivin. In addition, overexpression of STAT3 cDNA provided resistance to HO-3867-induced apoptosis. Our results show that HO-3867, a potent STAT3 inhibitor, may have a role as a biologically targeted agent for BRCA1-mutated cancers either as an adjunct to cytotoxic chemotherapy or as a single agent

Using individual participant data to improve network meta-analysis projects.

A network meta-analysis combines the evidence from existing randomised trials about the comparative efficacy of multiple treatments. It allows direct and indirect evidence about each comparison to be included in the same analysis, and provides a coherent framework to compare and rank treatments. A traditional network meta-analysis uses aggregate data (eg, treatment effect estimates and standard errors) obtained from publications or trial investigators. An alternative approach is to obtain, check, harmonise and meta-analyse the individual participant data (IPD) from each trial. In this article, we describe potential advantages of IPD for network meta-analysis projects, emphasising five key benefits: (1) improving the quality and scope of information available for inclusion in the meta-analysis, (2) examining and plotting distributions of covariates across trials (eg, for potential effect modifiers), (3) standardising and improving the analysis of each trial, (4) adjusting for prognostic factors to allow a network meta-analysis of conditional treatment effects and (5) including treatment-covariate interactions (effect modifiers) to allow relative treatment effects to vary by participant-level covariate values (eg, age, baseline depression score). A running theme of all these benefits is that they help examine and reduce heterogeneity (differences in the true treatment effect between trials) and inconsistency (differences in the true treatment effect between direct and indirect evidence) in the network. As a consequence, an IPD network meta-analysis has the potential for more precise, reliable and informative results for clinical practice and even allows treatment comparisons to be made for individual patients and targeted populations conditional on their particular characteristics

An Experimental comparison of two solar photovoltaic thermal (PVT) energy conversion system for production of heat and power

Abstract Two solar photovoltaic-thermal (PVT) energy conversion systems are described and their performance tested under laboratory conditions. One of these was a simple Flat Plate (FP-PVT) design, with headers and risers for heat removal the other a fixed linear axis Compound Parabolic Concentrating solar PVT (CPC-PVT) energy conversion system with a heat-pipe for removal of solar gain. Both had a low iron glass cover for high transmissivity of solar radiation, and polycrystalline silicon solar photovoltaic cells adhered to the absorber. Heat loss coefficient for the FP-PVT collector was measured as 4.1W/m 2 /K and 3.5W/m 2 /K for the CPC-PVT solar collector. These solar collectors were tested under steady state conditions using the solar simulator facility at the University of Ulster&apos;s Centre for Sustainable Technologies. The FP-PVT and the CPC-PVT had a combined efficiency of 66.8% and 53.4% respectively producing both heat and power

Direct Mesoproterozoic connection of the Congo and Kalahari cratons in proto-Africa : Strange attractors across supercontinental cycles

Peer reviewe

Ecosystem uptake and transfer of Sellafield-derived radiocarbon (14C) part 2 : the west of Scotland

Ecosystem uptake and transfer of Sellafield-derived radiocarbon (14C) were examined within the West of Scotland marine environment. The dissolved inorganic carbon component of seawater, enriched in14C, is transported to the West of Scotland where it is transferred through the marine food web. Benthic and pelagic biota with variable life-spans living in the North Channel and Clyde Sea show comparable14C activities. This suggests that mixing of14C within the Irish Sea results in a relatively constant northwards dispersal of activity. Benthic species in the Firth of Lorn have similar14C enrichments, demonstrating that Irish Sea residual water is the dominant source to this area. Measured14C activities in biota show some similarity to western Irish Sea activities, indicating that dispersion to the West of Scotland is significant with respect to the fate of Sellafield14C releases. Activities measured in commercially important species do not pose any significant radiological risk