Adaptive remodeling of the bacterial proteome by specific ribosomal modification regulates Pseudomonas infection and niche colonisation

Post-transcriptional control of protein abundance is a highly important, underexplored regulatory process by which organisms respond to their environments. Here we describe an important and previously unidentified regulatory pathway involving the ribosomal modification protein RimK, its regulator proteins RimA and RimB, and the widespread bacterial second messenger cyclic-di-GMP (cdG). Disruption of rimK affects motility and surface attachment in pathogenic and commensal Pseudomonas species, with rimK deletion significantly compromising rhizosphere colonisation by the commensal soil bacterium P. fluorescens, and plant infection by the pathogens P. syringae and P. aeruginosa. RimK functions as an ATP-dependent glutamyl ligase, adding glutamate residues to the C-terminus of ribosomal protein RpsF and inducing specific effects on both ribosome protein complement and function. Deletion of rimK in P. fluorescens leads to markedly reduced levels of multiple ribosomal proteins, and also of the key translational regulator Hfq. In turn, reduced Hfq levels induce specific downstream proteomic changes, with significant increases in multiple ABC transporters, stress response proteins and non-ribosomal peptide synthetases seen for both ΔrimK and Δhfq mutants. The activity of RimK is itself controlled by interactions with RimA, RimB and cdG. We propose that control of RimK activity represents a novel regulatory mechanism that dynamically influences interactions between bacteria and their hosts; translating environmental pressures into dynamic ribosomal changes, and consequently to an adaptive remodeling of the bacterial proteome

The impact of care pathways for exacerbation of Chronic Obstructive Pulmonary Disease: rationale and design of a cluster randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Hospital treatment of chronic obstructive pulmonary disease (COPD) frequently does not follow published evidences. This lack of adherence can contribute to the high morbidity, mortality and readmissions rates. The European Quality of Care Pathway (EQCP) study on acute exacerbations of COPD (NTC00962468) is undertaken to determine how care pathways (CP) as complex intervention for hospital treatment of COPD affects care variability, adherence to evidence based key interventions and clinical outcomes.</p> <p>Methods</p> <p>An international cluster Randomized Controlled Trial (cRCT) will be performed in Belgium, Italy, Ireland and Portugal. Based on the power analysis, a sample of 40 hospital teams and 398 patients will be included in the study. In the control arm of the study, usual care will be provided. The experimental teams will implement a CP as complex intervention which will include three active components: a formative evaluation of the quality and organization of care, a set of evidence based key interventions, and support on the development and implementation of the CP. The main outcome will be six-month readmission rate. As a secondary endpoint a set of clinical outcome and performance indicators (including care process evaluation and team functioning indicators) will be measured in both groups.</p> <p>Discussion</p> <p>The EQCP study is the first international cRCT on care pathways. The design of the EQCP project is both a research study and a quality improvement project and will include a realistic evaluation framework including process analysis to further understand why and when CP can really work.</p> <p>Trial Registration number</p> <p><b>NCT00962468</b></p

Isotope Analysis Reveals Foraging Area Dichotomy for Atlantic Leatherback Turtles

Background: The leatherback turtle (Dermochelys coriacea) has undergone a dramatic decline over the last 25 years, and this is believed to be primarily the result of mortality associated with fisheries bycatch followed by egg and nesting female harvest. Atlantic leatherback turtles undertake long migrations across ocean basins from subtropical and tropical nesting beaches to productive frontal areas. Migration between two nesting seasons can last 2 or 3 years, a time period termed the remigration interval (RI). Recent satellite transmitter data revealed that Atlantic leatherbacks follow two major dispersion patterns after nesting season, through the North Gulf Stream area or more eastward across the North Equatorial Current. However, information on the whole RI is lacking, precluding the accurate identification of feeding areas where conservation measures may need to be applied. Methodology/Principal Findings: Using stable isotopes as dietary tracers we determined the characteristics of feeding grounds of leatherback females nesting in French Guiana. During migration, 3-year RI females differed from 2-year RI females in their isotope values, implying differences in their choice of feeding habitats (offshore vs. more coastal) and foraging latitude (North Atlantic vs. West African coasts, respectively). Egg-yolk and blood isotope values are correlated in nesting females, indicating that egg analysis is a useful tool for assessing isotope values in these turtles, including adults when not available. Conclusions/Significance: Our results complement previous data on turtle movements during the first year following the nesting season, integrating the diet consumed during the year before nesting. We suggest that the French Guiana leatherback population segregates into two distinct isotopic groupings, and highlight the urgent need to determine the feeding habitats of the turtle in the Atlantic in order to protect this species from incidental take by commercial fisheries. Our results also emphasize the use of eggs, a less-invasive sampling material than blood, to assess isotopic data and feeding habits for adult female leatherbacks

Liverpool telescope 2: a new robotic facility for rapid transient follow-up

The Liverpool Telescope is one of the world's premier facilities for time domain astronomy. The time domain landscape is set to radically change in the coming decade, with surveys such as LSST providing huge numbers of transient detections on a nightly basis; transient detections across the electromagnetic spectrum from other facilities such as SVOM, SKA and CTA; and the era of `multi-messenger astronomy', wherein events are detected via non-electromagnetic means, such as gravitational wave emission. We describe here our plans for Liverpool Telescope 2: a new robotic telescope designed to capitalise on this new era of time domain astronomy. LT2 will be a 4-metre class facility co-located with the LT at the Observatorio del Roque de Los Muchachos on the Canary island of La Palma. The telescope will be designed for extremely rapid response: the aim is that the telescope will take data within 30 seconds of the receipt of a trigger from another facility. The motivation for this is twofold: firstly it will make it a world-leading facility for the study of fast fading transients and explosive phenomena discovered at early times. Secondly, it will enable large-scale programmes of low-to-intermediate resolution spectral classification of transients to be performed with great efficiency. In the target-rich environment of the LSST era, minimising acquisition overheads will be key to maximising the science gains from any follow-up programme. The telescope will have a diverse instrument suite which is simultaneously mounted for automatic changes, but it is envisaged that the primary instrument will be an intermediate resolution, optical/infrared spectrograph for scientific exploitation of transients discovered with the next generation of synoptic survey facilities. In this paper we outline the core science drivers for the telescope, and the requirements for the optical and mechanical design

Regulation of microRNA biogenesis and turnover by animals and their viruses

Item does not contain fulltextMicroRNAs (miRNAs) are a ubiquitous component of gene regulatory networks that modulate the precise amounts of proteins expressed in a cell. Despite their small size, miRNA genes contain various recognition elements that enable specificity in when, where and to what extent they are expressed. The importance of precise control of miRNA expression is underscored by functional studies in model organisms and by the association between miRNA mis-expression and disease. In the last decade, identification of the pathways by which miRNAs are produced, matured and turned-over has revealed many aspects of their biogenesis that are subject to regulation. Studies in viral systems have revealed a range of mechanisms by which viruses target these pathways through viral proteins or non-coding RNAs in order to regulate cellular gene expression. In parallel, a field of study has evolved around the activation and suppression of antiviral RNA interference (RNAi) by viruses. Virus encoded suppressors of RNAi can impact miRNA biogenesis in cases where miRNA and small interfering RNA pathways converge. Here we review the literature on the mechanisms by which miRNA biogenesis and turnover are regulated in animals and the diverse strategies that viruses use to subvert or inhibit these processes

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Biocompatible Choline-Based Deep Eutectic Solvents Enable One-Pot Production of Cellulosic Ethanol

Previous configurations of biomass conversion technologies based on the use of ionic liquids (ILs) suffer from problems such as high operating costs and large amounts of water used. There have been recent efforts toward process intensification and integration to realize a one-pot approach for biofuel production using certain ILs, but these typically still require pH adjustment and/or dilution after pretreatment and before saccharification and fermentation. Deep eutectic solvents (DESs) were investigated as an alternative to ILs to address these challenges, and the results obtained suggest that certain DESs are compatible with hydrolytic enzymes and common biofuel producing microorganisms such as Saccharomyces cerevisiae. Among the DESs investigated, choline chloride/glycerol (Ch12) achieved the highest rates of lignin extraction and pretreatment efficiency in terms of sugar yields (&gt;80%) after enzymatic hydrolysis. Most importantly, the DES-Ch12-based "one-pot" biomass conversion process does not require any pH adjustment before commencing with saccharification and fermentation. Degradation compounds generated from polysaccharides (e.g., furfural) and lignin (e.g., ferulic acid) during biomass conversion were characterized and evaluated for their potential inhibitory effect on yeast growth and biofuel production. We conclude that this DES can be used to achieve biofuel (e.g., ethanol) production with a theoretical yield of 77.5% based on the initial glucan present in the biomass in a consolidated one-pot process configuration, redefining biomass conversion using DESs