Physical Activity Characteristics across GOLD Quadrants Depend on the Questionnaire Used

BACKGROUND:The GOLD multidimensional classification of COPD severity combines the exacerbation risk with the symptom experience, for which 3 different questionnaires are permitted. This study investigated differences in physical activity (PA) in the different GOLD quadrants and patient's distribution in relation to the questionnaire used. METHODS:136 COPD patients (58±21% FEV1 predicted, 34F/102M) completed COPD assessment test (CAT), clinical COPD questionnaire (CCQ) and modified Medical Research Council (mMRC) questionnaire. Exacerbation history, spirometry and 6MWD were collected. PA was objectively measured for 2 periods of 1 week, 6 months apart, in 5 European centres; to minimise seasonal and clinical variation the average of these two periods was used for analysis. RESULTS:GOLD quadrants C+D had reduced PA compared with A+B (3824 [2976] vs. 5508 [4671] steps.d-1, p<0.0001). The choice of questionnaire yielded different patient distributions (agreement mMRC-CAT κ = 0.57; CCQ-mMRC κ = 0.71; CCQ-CAT κ = 0.72) with different clinical characteristics. PA was notably lower in patients with an mMRC score ≥2 (3430 [2537] vs. 5443 [3776] steps.d-1, p <0.001) in both the low and high risk quadrants. CONCLUSIONS:Using different questionnaires changes the patient distribution and results in different clinical characteristics. Therefore, standardization of the questionnaire used for classification is critical to allow comparison of different studies using this as an entry criterion. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov NCT01388218

Nanoscale glucan polymer network causes pathogen resistance.

Successful defence of plants against colonisation by fungal pathogens depends on the ability to prevent initial penetration of the plant cell wall. Here we report that the pathogen-induced (1,3)-β-glucan cell wall polymer callose, which is deposited at sites of attempted penetration, directly interacts with the most prominent cell wall polymer, the (1,4)-β-glucan cellulose, to form a three-dimensional network at sites of attempted fungal penetration. Localisation microscopy, a super-resolution microscopy technique based on the precise localisation of single fluorescent molecules, facilitated discrimination between single polymer fibrils in this network. Overexpression of the pathogen-induced callose synthase PMR4 in the model plant Arabidopsis thaliana not only enlarged focal callose deposition and polymer network formation but also resulted in the exposition of a callose layer on the surface of the pre-existing cellulosic cell wall facing the invading pathogen. The importance of this previously unknown polymeric defence network is to prevent cell wall hydrolysis and penetration by the fungus. We anticipate our study to promote nanoscale analysis of plant-microbe interactions with a special focus on polymer rearrangements in and at the cell wall. Moreover, the general applicability of localisation microscopy in visualising polymers beyond plant research will help elucidate their biological function in complex networks

Role of mitochondrial raft-like microdomains in the regulation of cell apoptosis

Lipid rafts are envisaged as lateral assemblies of specific lipids and proteins that dissociate and associate rapidly and form functional clusters in cell membranes. These structural platforms are not confined to the plasma membrane; indeed lipid microdomains are similarly formed at subcellular organelles, which include endoplasmic reticulum, Golgi and mitochondria, named raft-like microdomains. In addition, some components of raft-like microdomains are present within ER-mitochondria associated membranes. This review is focused on the role of mitochondrial raft-like microdomains in the regulation of cell apoptosis, since these microdomains may represent preferential sites where key reactions take place, regulating mitochondria hyperpolarization, fission-associated changes, megapore formation and release of apoptogenic factors. These structural platforms appear to modulate cytoplasmic pathways switching cell fate towards cell survival or death. Main insights on this issue derive from some pathological conditions in which alterations of microdomains structure or function can lead to severe alterations of cell activity and life span. In the light of the role played by raft-like microdomains to integrate apoptotic signals and in regulating mitochondrial dynamics, it is conceivable that these membrane structures may play a role in the mitochondrial alterations observed in some of the most common human neurodegenerative diseases, such as Amyotrophic lateral sclerosis, Huntington's chorea and prion-related diseases. These findings introduce an additional task for identifying new molecular target(s) of pharmacological agents in these pathologies

Towards High Capacity Li-ion Batteries Based on Silicon-Graphene Composite Anodes and Sub-micron V-doped LiFePO4 Cathodes

Lithium iron phosphate, LiFePO4 (LFP) has demonstrated promising performance as a cathode material in lithium ion batteries (LIBs), by overcoming the rate performance issues from limited electronic conductivity. Nano-sized vanadium-doped LFP (V-LFP) was synthesized using a continuous hydrothermal process using supercritical water as a reagent. The atomic % of dopant determined the particle shape. 5 at. % gave mixed plate and rod-like morphology, showing optimal electrochemical performance and good rate properties vs. Li. Specific capacities of >160 mAh g−1 were achieved. In order to increase the capacity of a full cell, V-LFP was cycled against an inexpensive micron-sized metallurgical grade Si-containing anode. This electrode was capable of reversible capacities of approximately 2000 mAh g−1 for over 150 cycles vs. Li, with improved performance resulting from the incorporation of few layer graphene (FLG) to enhance conductivity, tensile behaviour and thus, the composite stability. The cathode material synthesis and electrode formulation are scalable, inexpensive and are suitable for the fabrication of larger format cells suited to grid and transport applications

APEX and NOEMA observations of H<inf>2</inf>S in nearby luminous galaxies and the ULIRG Mrk 231: A possible relation between dense gas properties and molecular outflows

Context. In order to understand the evolution and feedback of active galactic nuclei (AGN) and star formation, it is important to use molecular lines as probes of physical conditions and chemistry. Aims. We use H2S to investigate the impact of starburst and AGN activity on the chemistry of the molecular interstellar medium in luminous infrared galaxies. Specifically, our aim is to search for evidence of shock enhancement of H2S related to galactic-scale mechanical feedback processes such as outflows. Methods. Using the APEX single-dish telescope, we have observed the 110 ~101 transition of ortho-H2S at 168 GHz towards the centres of 12 nearby luminous infrared galaxies. We have also observed the same line towards the ultra-luminous infrared galaxy Mrk 231 with the NOEMA interferometer. Results. We detected H2S towards NGC 253, NGC 1068, NGC 3256, NGC 4418, NGC 4826, NGC 4945, Circinus, M 83, and Mrk 231. Upper limits were obtained for NGC 1097, NGC 1377, and IC 860. We also detected line emission from HCN 2~1 in all galaxies in the APEX survey as well as HCO+, HNC, CH3CN, CH3OH, H2CS, HOC+, and SO in several of the sample galaxies. Mrk 231 has a rich 2 mm molecular spectrum and, in addition to H2S, we detect emission from HC3N, CH3OH, HC18O+, C2S, and CH3CCH. Four galaxies show elevated H2S emission relative to HCN: Circinus, NGC 3256, NGC 4826, and NGC 4418. We suggest that the high line ratios are caused by elevated H2S abundances in the dense gas. However, we do not find any clear connection between the H2S/HCN line intensity ratio and the presence (or speed) of molecular outflows in the sample galaxies. Therefore, H2S abundances do not seem to be globally affected by the large-scale outflows. In addition, the H2S/HCN line ratio is not enhanced in the line wings compared to the line core in Mrk 231. This suggests that H2S abundances do not increase in the dense gas in the outflow. However, we do find that the H2S and HCN luminosities (LH2S and LHCN) correlate well with the total molecular gas mass in the outflow, Moutflow(H2), in contrast to LCO and LHCO+. We also find that the line luminosity of H2S correlates with the total infrared luminosity in a similar way as that of H2O. Conclusions. We do not find any evidence of H2S abundance enhancements in the dense gas due to galactic-scale outflows in our sample galaxies, nor in the high-resolution study of Mrk 231. We discuss possible mechanisms behind the suggested H2S abundance enhancements in NGC 4418, Circinus, NGC 3256, and NGC 4826. These include radiative processes (for example X-rays or cosmic rays) or smaller-scale shocks. Further high-resolution and multi-transition studies are required to determine the cause behind the elevated H2S emission in these galaxies. We suggest that LH2S serves as a tracer of the dense gas content, similar to LHCN, and that the correlation between LH2S and Moutflow(H2) implies a relation between the dense gas reservoir and the properties and evolution of the molecular feedback. This potential link requires further study since it holds important keys to our understanding of how the properties of molecular outflows relate to those of their host galaxies. Finally, the similar infrared-correlation coefficients between H2S and H2O may indicate that they originate in the same regions in the galaxy: warm gas in shocks or irradiated by star formation or an AGN

Dynamic assembly of ribbon synapses and circuit maintenance in a vertebrate sensory system

Ribbon synapses transmit information in sensory systems, but their development is not well understood. To test the hypothesis that ribbon assembly stabilizes nascent synapses, we performed simultaneous time-lapse imaging of fluorescently-tagged ribbons in retinal cone bipolar cells (BCs) and postsynaptic densities (PSD95-FP) of retinal ganglion cells (RGCs). Ribbons and PSD95-FP clusters were more stable when these components colocalized at synapses. However, synapse density on ON-alpha RGCs was unchanged in mice lacking ribbons (ribeye knockout). Wildtype BCs make both ribbon-containing and ribbon-free synapses with these GCs even at maturity. Ribbon assembly and cone BC-RGC synapse maintenance are thus regulated independently. Despite the absence of synaptic ribbons, RGCs continued to respond robustly to light stimuli, although quantitative examination of the responses revealed reduced frequency and contrast sensitivity

Unfolding Simulations of Holomyoglobin from Four Mammals: Identification of Intermediates and β-Sheet Formation from Partially Unfolded States

Myoglobin (Mb) is a centrally important, widely studied mammalian protein. While much work has investigated multi-step unfolding of apoMb using acid or denaturant, holomyoglobin unfolding is poorly understood despite its biological relevance. We present here the first systematic unfolding simulations of holoMb and the first comparative study of unfolding of protein orthologs from different species (sperm whale, pig, horse, and harbor seal). We also provide new interpretations of experimental mean molecular ellipticities of myoglobin intermediates, notably correcting for random coil and number of helices in intermediates. The simulated holoproteins at 310 K displayed structures and dynamics in agreement with crystal structures (R g ~1.48-1.51 nm, helicity ~75%). At 400 K, heme was not lost, but some helix loss was observed in pig and horse, suggesting that these helices are less stable in terrestrial species. At 500 K, heme was lost within 1.0-3.7 ns. All four proteins displayed exponentially decaying helix structure within 20 ns. The C- and F-helices were lost quickly in all cases. Heme delayed helix loss, and sperm whale myoglobin exhibited highest retention of heme and D/E helices. Persistence of conformation (RMSD), secondary structure, and ellipticity between 2-11 ns was interpreted as intermediates of holoMb unfolding in all four species. The intermediates resemble those of apoMb notably in A and H helices, but differ substantially in the D-, E- and F-helices, which interact with heme. The identified mechanisms cast light on the role of metal/cofactor in poorly understood holoMb unfolding. We also observed β-sheet formation of several myoglobins at 500 K as seen experimentally, occurring after disruption of helices to a partially unfolded, globally disordered state; heme reduced this tendency and sperm-whale did not display any sheet propensity during the simulations

Design concepts for a next generation light source at LBNL

The NGLS collaboration is developing design concepts for a multi-beamline soft x-ray FEL array powered by a superconducting linear accelerator, operating with a high bunch repetition rate of approximately 1 MHz. The CW superconducting linear accelerator design is based on developments of TESLA and ILC technology, and is supplied by an injector based on a high-brightness, highrepetition- rate photocathode electron gun. Electron bunches from the linac are distributed by RF deflecting cavities to the array of independently configurable FEL beamlines with nominal bunch rates of ∼100 kHz in each FEL, with uniform pulse spacing, and some FELs capable of operating at the full linac bunch rate. Individual FELs may be configured for different modes of operation, including self-seeded and external-laser-seeded, and each may produce high peak and average brightness x-rays with a flexible pulse format, and with pulse durations ranging from femtoseconds and shorter, to hundreds of femtoseconds. In this paper we describe current design concepts, and progress in RandD activities. Copyright © 2013 CC-BY-3.0 and by the respective authors

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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