Intrinsic antimicrobial resistance determinants in the superbug Pseudomonas aeruginosa

Antimicrobial-resistant bacteria pose a serious threat in the clinic. This is particularly true for opportunistic pathogens that possess high intrinsic resistance. Though many studies have focused on understanding the acquisition of bacterial resistance upon exposure to antimicrobials, the mechanisms controlling intrinsic resistance are not well understood. In this study, we subjected the model opportunistic superbug Pseudomonas aeruginosa to 14 antimicrobials under highly controlled conditions and assessed its response using expression-and fitness-based genomic approaches. Our results reveal that gene expression changes and mutant fitness in response to sub-MIC antimicrobials do not correlate on a genomewide scale, indicating that gene expression is not a good predictor of fitness determinants. In general, fewer fitness determinants were identified for antiseptics and disinfectants than for antibiotics. Analysis of gene expression and fitness data together allowed the prediction of antagonistic interactions between antimicrobials and insight into the molecular mechanisms controlling these interactions. IMPORTANCE Infections involving multidrug-resistant pathogens are difficult to treat because the therapeutic options are limited. These infections impose a significant financial burden on infected patients and on health care systems. Despite years of antimicrobial resistance research, we lack a comprehensive understanding of the intrinsic mechanisms controlling antimicrobial resistance. This work uses two fine-scale genomic approaches to identify genetic loci important for antimicrobial resistance of the opportunistic pathogen Pseudomonas aeruginosa. Our results reveal that antibiotics have more resistance determinants than antiseptics/disinfectants and that gene expression upon exposure to antimicrobials is not a good predictor of these resistance determinants. In addition, we show that when used together, genomewide gene expression and fitness profiling can provide mechanistic insights into multidrug resistance mechanisms.open

Evidence for Circumpolar Distribution of Planktonic Archaea in the Southern Ocean

Surveys using rRNA-targeted probes specific for the 3 domains of life (Eucarya, Archaea, and Bacteria) indicated the presence, and at times high abundance, of archaeal rRNA in a variety of water masses surrounding Antarctica. Hybridization signals of archaeal rRNA contributed significantly to that of total picoplankton rRNA both north and south of the Polar Front in Drake Passage. Late winter surface water populations collected around the South Shetland Islands also yielded relatively high archaeal rRNA hybridization signals, approaching 10% or greater of the total rRNA. Summer samples collected in the western region of the Antarctic Peninsula and at McMurdo Sound in the Ross Sea region of Antarctica yielded lower amounts of archaeal rRNA in the surface waters, and higher levels of archaeal rRNA at depth (150 to 500 m). The hybridization data were compared to biological, chemical, and hydrographic information when possible. In surface waters, archaeal rRNA and chlorophyll a varied inversely. The data presented here further supports the hypothesis that planktonic archaea are a common, widespread and likely ecologically important component of Antarctic picoplankton assemblages. The presence of these archaea in circumpolar deep water suggests a conduit for their circumpolar transport around Antarctica via the Antarctic Circumpolar Current, as well as their export to the deep sea, or to intermediate waters of the South Atlantic via mixing at the polar front

NIMBUS: The Near-Infrared Multi-Band Ultraprecise Spectroimager for SOFIA

We present a new and innovative near-infrared multi-band ultraprecise spectroimager (NIMBUS) for SOFIA. This design is capable of characterizing a large sample of extrasolar planet atmospheres by measuring elemental and molecular abundances during primary transit and occultation. This wide-field spectroimager would also provide new insights into Trans-Neptunian Objects (TNO), Solar System occultations, brown dwarf atmospheres, carbon chemistry in globular clusters, chemical gradients in nearby galaxies, and galaxy photometric redshifts. NIMBUS would be the premier ultraprecise spectroimager by taking advantage of the SOFIA observatory and state of the art infrared technologies. This optical design splits the beam into eight separate spectral bandpasses, centered around key molecular bands from 1 to 4 microns. Each spectral channel has a wide field of view for simultaneous observations of a reference star that can decorrelate time-variable atmospheric and optical assembly effects, allowing the instrument to achieve ultraprecise calibration for imaging and photometry for a wide variety of astrophysical sources. NIMBUS produces the same data products as a low-resolution integral field spectrograph over a large spectral bandpass, but this design obviates many of the problems that preclude high-precision measurements with traditional slit and integral field spectrographs. This instrument concept is currently not funded for development.Comment: 14 pages, 9 figures, SPIE Astronomical Telescopes and Instrumentation 201

Algorithm to Diagnose Leaks or Blockages Downstream of the Secondary Air Injection Reaction (SAIR) Pressure Sensor

A control module and method for an exhaust system of an engine can include a secondary air intake (SAI) pressure module that monitors SAI pressure. An accumulation module can accumulate an SAI string length based on the monitored SAI pressure. A calculation module can determine an average SAI string length based on the accumulated SAI string length. A determination module can determine an operating characteristic of the vehicle exhaust based on the average SAI string length

Long-Term Corticosteroid-Sparing Immunosuppression for Cardiac Sarcoidosis.

Background Long-term corticosteroid therapy is the standard of care for treatment of cardiac sarcoidosis (CS). The efficacy of long-term corticosteroid-sparing immunosuppression in CS is unknown. The goal of this study was to assess the efficacy of methotrexate with or without adalimumab for long-term disease suppression in CS, and to assess recurrence and adverse event rates after immunosuppression discontinuation. Methods and Results Retrospective chart review identified treatment-naive CS patients at a single academic medical center who received corticosteroid-sparing maintenance therapy. Demographics, cardiac uptake of 18-fluorodeoxyglucose, and adverse cardiac events were compared before and during treatment and between those with persistent or interrupted immunosuppression. Twenty-eight CS patients were followed for a mean 4.1 (SD 1.5) years. Twenty-five patients received 4 to 8 weeks of high-dose prednisone (>30 mg/day), followed by taper and maintenance therapy with methotrexate±low-dose prednisone (low-dose prednisone, <10 mg/day). Adalimumab was added in 19 patients with persistently active CS or in those with intolerance to methotrexate. Methotrexate±low-dose prednisone resulted in initial reduction (88%) or elimination (60%) of 18-fluorodeoxyglucose uptake, and patients receiving adalimumab-containing regimens experienced improved (84%) or resolved (63%) 18-fluorodeoxyglucose uptake. Radiologic relapse occurred in 8 of 9 patients after immunosuppression cessation, 4 patients on methotrexate-containing regimens, and in no patients on adalimumab-containing regimens. Conclusions Corticosteroid-sparing regimens containing methotrexate with or without adalimumab is an effective maintenance therapy in patients after an initial response is confirmed. Disease recurrence in patients on and off immunosuppression support need for ongoing radiologic surveillance regardless of immunosuppression regimen

Isotopic ordering in atmospheric O2 as a tracer of ozone photochemistry and the tropical atmosphere

The distribution of isotopes within O2 molecules can be rapidly altered when they react with atomic oxygen. This mechanism is globally important: while other contributions to the global budget of O2 impart isotopic signatures, the O(3P) + O2 reaction resets all such signatures in the atmosphere on subdecadal timescales. Consequently, the isotopic distribution within O2 is determined by O3 photochemistry and the circulation patterns that control where that photochemistry occurs. The variability of isotopic ordering in O2 has not been established, however. We present new measurements of 18O18O in air (reported as Δ36 values) from the surface to 33 km altitude. They confirm the basic features of the clumped-isotope budget of O2: Stratospheric air has higher Δ36 values than tropospheric air (i.e., more 18O18O), reflecting colder temperatures and fast photochemical cycling of O3. Lower Δ36 values in the troposphere arise from photochemistry at warmer temperatures balanced by the influx of high-Δ36 air from the stratosphere. These observations agree with predictions derived from the GEOS-Chem chemical transport model, which provides additional insight. We find a link between tropical circulation patterns and regions where Δ36 values are reset in the troposphere. The dynamics of these regions influences lapse rates, vertical and horizontal patterns of O2 reordering, and thus the isotopic distribution toward which O2 is driven in the troposphere. Temporal variations in Δ36 values at the surface should therefore reflect changes in tropospheric temperatures, photochemistry, and circulation. Our results suggest that the tropospheric O3 burden has remained within a ±10% range since 1978

Data-driven neuropathological staging and subtyping of TDP-43 proteinopathies

TAR DNA-binding protein-43 (TDP-43) accumulation is the primary pathology underlying several neurodegenerative diseases. Charting the progression and heterogeneity of TDP-43 accumulation is necessary to better characterize TDP-43 proteinopathies, but current TDP-43 staging systems are heuristic and assume each syndrome is homogeneous. Here, we use data-driven disease progression modelling to derive a fine-grained empirical staging system for the classification and differentiation of frontotemporal lobar degeneration due to TDP-43 (FTLD-TDP, n = 126), amyotrophic lateral sclerosis (ALS, n = 141) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) with and without Alzheimer’s disease (n = 304). The data-driven staging of ALS and FTLD-TDP complement and extend previously described human-defined staging schema for ALS and behavioural variant frontotemporal dementia. In LATE-NC individuals, progression along data-driven stages was positively associated with age, but negatively associated with age in individuals with FTLD-TDP. Using only regional TDP-43 severity, our data driven model distinguished individuals diagnosed with ALS, FTLD-TDP or LATE-NC with a cross-validated accuracy of 85.9%, with misclassifications associated with mixed pathological diagnosis, age and genetic mutations. Adding age and SuStaIn stage to this model increased accuracy to 92.3%. Our model differentiates LATE-NC from FTLD-TDP, though some overlap was observed between late-stage LATE-NC and early-stage FTLD-TDP. We further tested for the presence of subtypes with distinct regional TDP-43 progression patterns within each diagnostic group, identifying two distinct cortical-predominant and brainstem-predominant subtypes within FTLD-TDP and a further two subcortical-predominant and corticolimbic-predominant subtypes within ALS. The FTLD-TDP subtypes exhibited differing proportions of TDP-43 type, while there was a trend for age differing between ALS subtypes. Interestingly, a negative relationship between age and SuStaIn stage was seen in the brainstem/subcortical-predominant subtype of each proteinopathy. No subtypes were observed for the LATE-NC group, despite aggregating individuals with and without Alzheimer’s disease and a larger sample size for this group. Overall, we provide an empirical pathological TDP-43 staging system for ALS, FTLD-TDP and LATE-NC, which yielded accurate classification. We further demonstrate that there is substantial heterogeneity amongst ALS and FTLD-TDP progression patterns that warrants further investigation in larger cross-cohort studies

Process Oscillations in Continuous Ethanol Fermentation with Saccharomyces cerevisiae

Based on ethanol fermentation kinetics and bioreactor engineering theory, a system composed of a continuously stirred tank reactor (CSTR) and three tubular bioreactors in series was established for continuous very high gravity (VHG) ethanol fermentation with Saccharomyces cerevisiae. Sustainable oscillations of residual glucose, ethanol, and biomass characterized by long oscillation periods and large oscillation amplitudes were observed when a VHG medium containing 280 g/L glucose was fed into the CSTR at a dilution rate of 0.027 h1. Mechanistic analysis indicated that the oscillations are due to ethanol inhibition and the lag response of yeast cells to ethanol inhibition. A high gravity (HG) medium containing 200 g/L glucose and a low gravity (LG) medium containing 120 g/L glucose were fed into the CSTR at the same dilution rate as that for the VHG medium, so that the impact of residual glucose and ethanol concentrations on the oscillations could be studied. The oscillations were not significantly affected when the HG medium was used, and residual glucose decreased significantly, but ethanol maintained at the same level, indicating that residual glucose was not the main factor triggering the oscillations. However, the oscillations disappeared after the LG medium was fed and ethanol concentration decreased to 58.2 g/L. Furthermore, when the LG medium was supplemented with 30 g/L ethanol to achieve the same level of ethanol in the fermentation system as that achieved under the HG condition, the steady state observed for the original LG medium was interrupted, and the oscillations observed under the HG condition occurred. The steady state was gradually restored after the original LG medium replaced the modified one. These experimental results confirmed that ethanol, whether produced by yeast cells during fermentation or externally added into a fermentation system, can trigger oscillations once its concentration approaches to a criterion. The impact of dilution rate on oscillations was also studied. It was found that oscillations occurred at certain dilution rate ranges for the two yeast strains. Since ethanol production is tightly coupled with yeast cell growth, it was speculated that the impact of the dilution rate on the oscillations is due to the synchronization of the mother and daughter cell growth rhythms. The difference in the oscillation profiles exhibited by the two yeast strains is due to their difference in ethanol tolerance. For more practical conditions, the behavior of continuous ethanol fermentation was studied using a self-flocculating industrial yeast strain and corn flour hydrolysate medium in a simulated tanks-in-series fermentation system. Amplified oscillations observed at the dilution rate of 0.12 h1 were postulated to be due to the synchronization of the two yeast cell populations generated by the continuous inoculation from the seed tank upstream of the fermentation system, which was partly validated by oscillation attenuation after the seed tank was removed from the fermentation system. The two populations consisted of the newly inoculated yeast cells and the yeast cells already adapted to the fermentation environment. Oscillations increased residual sugar at the end of the fermentation, and correspondingly, decreased the ethanol yield, indicating the need for attenuation strategies. When the tubular bioreactors were packed with ½” Intalox ceramic saddles, not only was their ethanol fermentation performance improved, but effective oscillation attenuation was also achieved. The oscillation attenuation was postulated to be due to the alleviation of backmixing in the packed tubular bioreactors as well as the yeast cell immobilization role of the packing. The residence time distribution analysis indicated that the mixing performance of the packed tubular bioreactors was close to a CSTR model for both residual glucose and ethanol, and the assumed backmixing alleviation could not be achieved. The impact of yeast cell immobilization was further studied using several different packing materials. Improvement in ethanol fermentation performance as well as oscillation attenuation was achieved for the wood chips, as well as the Intalox ceramic saddles, but not for the porous polyurethane particles, nor the steel Raschig rings. Analysis for the immobilized yeast cells indicated that high viability was the mechanistic reason for the improvement of the ethanol fermentation performance as well as the attenuation of the oscillations. A dynamic model was developed by incorporating the lag response of yeast cells to ethanol inhibition into the pseudo-steady state kinetic model, and dynamic simulation was performed, with good results. This not only provides a basis for developing process intervention strategies to minimize oscillations, but also theoretically support the mechanistic hypothesis for the oscillations

Using interpretative phenomenological analysis to inform physiotherapy practice: An introduction with reference to the lived experience of cerebellar ataxia

The attached file is a pre-published version of the full and final paper which can be found at the link below.This article has been made available through the Brunel Open Access Publishing Fund.Qualitative research methods that focus on the lived experience of people with health conditions are relatively underutilised in physiotherapy research. This article aims to introduce interpretative phenomenological analysis (IPA), a research methodology oriented toward exploring and understanding the experience of a particular phenomenon (e.g., living with spinal cord injury or chronic pain, or being the carer of someone with a particular health condition). Researchers using IPA try to find out how people make sense of their experiences and the meanings they attach to them. The findings from IPA research are highly nuanced and offer a fine grained understanding that can be used to contextualise existing quantitative research, to inform understanding of novel or underresearched topics or, in their own right, to provoke a reappraisal of what is considered known about a specified phenomenon. We advocate IPA as a useful and accessible approach to qualitative research that can be used in the clinical setting to inform physiotherapy practice and the development of services from the perspective of individuals with particular health conditions.This article is available through the Brunel Open Access Publishing Fund

The Absolute Magnitude of RRc Variables From Statistical Parallax

We present the first definitive measurement of the absolute magnitude of RR Lyrae c-type variable stars (RRc) determined purely from statistical parallax. We use a sample of 247 RRc selected from the All Sky Automated Survey (ASAS) for which high-quality light curves, photometry and proper motions are available. We obtain high-resolution echelle spectra for these objects to determine radial velocities and abundances as part of the Carnegie RR Lyrae Survey (CARRS). We find that M_(V,RRc) = 0.52 +/- 0.11 at a mean metallicity of [Fe/H] = -1.59. This is to be compared with previous estimates for RRab stars (M_(V,RRab) = 0.75 +/- 0.13 and the only direct measurement of an RRc absolute magnitude (RZ Cephei, M_(V, RRc) = 0.27 +/- 0.17). We find the bulk velocity of the halo to be (W_pi, W_theta, W_z) = (10.9,34.9,7.2) km/s in the radial, rotational and vertical directions with dispersions (sigma_(W_pi), sigma_(W_theta), sigma_(W_z)) = (154.7, 103.6, 93.8) km/s. For the disk, we find (W_pi, W_theta, W_z) = (8.5, 213.2, -22.1) km/s with dispersions (sigma_(W_pi), sigma_(W_theta), sigma_(W_z)) = (63.5, 49.6, 51.3) km/s. Finally, we suggest that UCAC2 proper motion errors may be overestimated by about 25%Comment: Submitted to ApJ. 11 pages including 6 figure