A pivotal role for NF-κB in the macrophage inflammatory response to the myeloperoxidase oxidant hypothiocyanous acid

© 2018 Elsevier Inc. Atherosclerosis is characterised by the infiltration of macrophages at sites of inflammation within the vessel wall and the release of myeloperoxidase (MPO), which forms hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN). HOCl is a damaging oxidant implicated in the development of atherosclerosis. Preferential formation of HOSCN occurs under conditions where thiocyanate ions are elevated, as is the case in smokers. HOSCN reacts selectively with thiols, which can result in more enzyme inactivation and damage than HOCl at susceptible sites, which may contribute to atherosclerosis in smokers. In this study, we show that exposure of macrophages to HOSCN results in a time- and dose-dependent increase in the mRNA expression and release of pro-inflammatory cytokines and chemokines, including monocyte chemotactic protein 1, tumour necrosis factor alpha, and interleukins 6, 8 and 1β. At high oxidant concentrations (>200 μM), a significant loss of cellular thiols and increased cell death is observed. HOSCN-induced cytokine/chemokine expression and cell death were decreased on pharmacological inhibition of nuclear factor kappa B. These data highlight a pathway by which HOSCN could promote inflammation and the development of atherosclerosis, in the presence of supra-physiological levels of the precursor thiocyanate, which are achievable by cigarette smoking

Stable kilohertz rate molecular beam laser ablation sources

A stable kilohertz (kHz) rate laser ablation/desorption supersonic molecular beam source for use in kHz rate laser experiments was discussed. The source was based based upon strong nonresonant interaction of a dithering laser focus with a rotating and translating solid rod. The kHz laser ablation of a high temperature refractory metal (niobium) for use in studied of metal clusters was also demonstrated. The kHz laser desorption and jet cooling of an involatile biomolecule (the DNA based guanine) for use in spectroscopic and dynamical studies was described.open151

Atmospheric CO2 and d13C-CO2 reconstruction of the little ice age from antarctic ice cores

The decrease of atmospheric CO2 concentration recorded in Antarctic ice around 1600 AD is one of the most significant atmospheric changes to have occurred during the last millennia, before the onset of the industrial period.Together with the temperature decrease, the CO2 drop has been used to derive the sensitivity of carbon stores to climate. However, the cause of it is still under debate because models are not yet able to reproduce either its magnitude, or its timing. Here we present new measurements of the CO2 concentration decrease recorded in an ice core from a medium accumulation rate site in Antarctica (DML). We show that the new record is compatible(differences <2 ppm) with the CO2 record from the high accumulation rate DSS site on Law Dome (East Antarctica), when the different age distributions are taken into account. We have also measured the d13C-CO2 change in DML ice, filling a gap around 1600 AD in the DSS d13C record. We use a double deconvolution of the CO2 and d13C records together to provide quantitative evidence that the CO2 decrease was caused by a change in the net flux to the terrestrial biosphere. Finally, we provide a new interpretation of a published record showing increasing atmospheric carbonyl sulphide during the CO2 decrease, suggesting that cooler LIA climate affected terrestrial biospheric fluxes. Altogether our findings support the hypothesis that reduced soil heterotrophic respiration is likely to have given the most significant contribution to the LIA CO2 decrease implying a positive CO2-climate feedback. © 2015, Authors

A co-registration investigation of inter-word spacing and parafoveal preview: Eye movements and fixation-related potentials

Participants’ eye movements (EMs) and EEG signal were simultaneously recorded to examine foveal and parafoveal processing during sentence reading. All the words in the sentence were manipulated for inter-word spacing (intact spaces vs. spaces replaced by a random letter) and parafoveal preview (identical preview vs. random letter string preview). We observed disruption for unspaced text and invalid preview conditions in both EMs and fixation-related potentials (FRPs). Unspaced and invalid preview conditions received longer reading times than spaced and valid preview conditions. In addition, the FRP data showed that unspaced previews disrupted reading in earlier time windows of analysis, compared to string preview conditions. Moreover, the effect of parafoveal preview was greater for spaced relative to unspaced conditions, in both EMs and FRPs. These findings replicate well-established preview effects, provide novel insight into the neural correlates of reading with and without inter-word spacing and suggest that spatial selection precedes lexical processing

Genetic Diversity in New Members of the Reticulocyte Binding Protein Family in Thai Plasmodium vivax Isolates

Background Plasmodium vivax merozoites specifically invade reticulocytes. Until recently, two reticulocyte-binding proteins (Pvrbp1 and Pvrbp2) expressed at the apical pole of the P. vivax merozoite were considered to be involved in reticulocyte recognition. The genome sequence recently obtained for the Salvador I (Sal-I) strain of P. vivax revealed additional genes in this family, and in particular Pvrbp2a, Pvrbp2b (Pvrbp2 has been renamed as Pvrbp2c) and two pseudogenes Pvrbp2d and Pvrbp3. It had been previously found that Pvrbp2c is substantially more polymorphic than Pvrbp1. The primary goal of this study was to ascertain the level of polymorphism of these new genes. Methodology/Principal Findings The sequence of the Pvrbp2a, Pvrbp2b, Pvrbp2d and Pvrbp3 genes were obtained by amplification/cloning using DNA purified from four isolates collected from patients that acquired the infection in the four cardinal regions of Thailand (west, north, south and east). An additional seven isolates from western Thailand were analyzed for gene copy number variation. There were significant polymorphisms exhibited by these genes (compared to the reference Sal-I strain) with the ratio of mutations leading to a non-synonymous or synonymous amino acid change close to 3∶1 for Pvrbp2a and Pvrbp2b. Although the degree of polymorphism exhibited by these two genes was higher than that of Pvrbp1, it did not reach the exceptional diversity noted for Pvrbp2c. It was interesting to note that variations in the copy number of Pvrbp2a and Pvrbp2b occurred in some isolates. Conclusions/Significance The evolution of different members of the Pvrbp2 family and their relatively high degree of polymorphism suggests that the proteins encoded by these genes are important for parasite survival and are under immune selection. Our data also shows that there are highly conserved regions in rbp2a and rbp2b, which might provide suitable targets for future vaccine development against the blood stage of P. vivax

A programme to spread eGFR graph surveillance for the early identification, support and treatment of people with progressive chronic kidney disease (ASSIST-CKD): protocol for the stepped wedge implementation and evaluation of an intervention to reduce late presentation for renal replacement therapy

Background Patients who start renal replacement therapy (RRT) for End-Stage Kidney Disease (ESKD) without having had timely access to specialist renal services have poor outcomes. At one NHS Trust in England, a community-wide CKD management system has led to a decline in the incident rate of RRT and the lowest percentage of patients presenting within 90 days of starting RRT in the UK. We describe the protocol for a quality improvement project to scale up and evaluate this innovation. Methods The intervention is based upon an off-line database that integrates laboratory results from blood samples taken in all settings stored under different identifying labels relating to the same patient. Graphs of estimated glomerular filtration rate (eGFR) over time are generated for patients 65 years with an incoming eGFR <40 ml/min/1.73 m2. Graphs where kidney function is deteriorating are flagged by a laboratory scientist and details sent to the primary care doctor (GP) with a prompt that further action may be needed. We will evaluate the impact of implementing this intervention across a large population served by a number of UK renal centres using a mixed methods approach. We are following a stepped-wedge design. The order of implementation among participating centres will be randomly allocated. Implementation will proceed with unidirectional steps from control group to intervention group until all centres are generating graphs of eGFR over time. The primary outcome for the quantitative evaluation is the proportion of patients referred to specialist renal services within 90 days of commencing RRT, using data collected routinely by the UK Renal Registry. The qualitative evaluation will investigate facilitators and barriers to adoption and spread of the intervention. It will include: semi-structured interviews with laboratory staff, renal centre staff and service commissioners; an online survey of GPs receiving the intervention; and focus groups of primary care staff. Discussion Late presentation to nephrology for patients with ESKD is a source of potentially avoidable harm. This protocol describes a robust quantitative and qualitative evaluation of a quality improvement intervention to reduce late presentation and improve the outcomes for patients with ESKD

Historical greenhouse gas concentrations for climate modelling (CMIP6)

Atmospheric greenhouse gas (GHG) concentrations are at unprecedented, record-high levels compared to the last 800 000 years. Those elevated GHG concentrations warm the planet and – partially offset by net cooling effects by aerosols – are largely responsible for the observed warming over the past 150 years. An accurate representation of GHG concentrations is hence important to understand and model recent climate change. So far, community efforts to create composite datasets of GHG concentrations with seasonal and latitudinal information have focused on marine boundary layer conditions and recent trends since the 1980s. Here, we provide consolidated datasets of historical atmospheric concentrations (mole fractions) of 43 GHGs to be used in the Climate Model Intercomparison Project – Phase 6 (CMIP6) experiments. The presented datasets are based on AGAGE and NOAA networks, firn and ice core data, and archived air data, and a large set of published studies. In contrast to previous intercomparisons, the new datasets are latitudinally resolved and include seasonality. We focus on the period 1850–2014 for historical CMIP6 runs, but data are also provided for the last 2000 years. We provide consolidated datasets in various spatiotemporal resolutions for carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O), as well as 40 other GHGs, namely 17 ozone-depleting substances, 11 hydrofluorocarbons (HFCs), 9 perfluorocarbons (PFCs), sulfur hexafluoride (SF6), nitrogen trifluoride (NF3) and sulfuryl fluoride (SO2F2). In addition, we provide three equivalence species that aggregate concentrations of GHGs other than CO2, CH4 and N2O, weighted by their radiative forcing efficiencies. For the year 1850, which is used for pre-industrial control runs, we estimate annual global-mean surface concentrations of CO2 at 284.3 ppm, CH4 at 808.2 ppb and N2O at 273.0 ppb. The data are available at https://esgfnode.llnl.gov/search/input4mips/ and http://www.climatecollege.unimelb.edu.au/cmip6. While the minimum CMIP6 recommendation is to use the global- and annual-mean time series, modelling groups can also choose our monthly and latitudinally resolved concentrations, which imply a stronger radiative forcing in the Northern Hemisphere winter (due to the latitudinal gradient and seasonality)

Does Manual Therapy Provide Additional Benefit To Breathing Retraining In The Management Of Dysfunctional Breathing? A Randomised Controlled Trial

Purpose: Dysfunctional breathing (DB) is associated with an abnormal breathing pattern, unexplained breathlessness and significant patient morbidity. Treatment involves breathing retraining through respiratory physiotherapy. Recently, manual therapy (MT) has also been used, but no evidence exists to validate its use. This study sought to investigate whether MT produces additional benefit when compared with breathing retraining alone in patients with DB. Methods: Sixty subjects with primary DB were randomised into either breathing retraining (standard treatment; n¼30) or breathing retraining plus MT (intervention; n¼30) group. Both the groups received standardised respiratory physiotherapy, which included: DB education, breathing retraining, home regimen, and audio disc. Intervention group subjects additionally received MT following further assessment. Data from 57 subjects were analysed. Results: At baseline, standard treatment group subjects were statistically younger (41.7 + 13.5 versus 50.8 + 13.0 years; p¼0.001) with higher Nijmegen scores (38.6 + 9.5 versus 31.5 + 6.9; p¼0.001). However, no significant difference was found between the groups for primary outcome Nijmegen score (95% CI ( 1.1, 6.6) p¼0.162), or any secondary outcomes (Hospital Anxiety & Depression Score, spirometry or exercise tolerance). Conclusion: Breathing retraining is currently the mainstay of treatment for patients with DB. The results of this study suggest MT provides no additional benefit in this patient group.Juliana Burgess, Dr Robert Wilson, Royal Brompton & Harefield NHS Foundation Trust, and Dr Andy Jones fo