Identifying the roles played by individual heterotrophic bacteria in the degradation of high molecular weight (HMW) substrates is critical to understanding the constraints on carbon cycling in the ...ocean. At five sites in the Atlantic Ocean, we investigated the processing of organic matter by tracking changes in microbial community composition as HMW polysaccharides were enzymatically hydrolysed over time. During this investigation, we discovered that a considerable fraction of heterotrophic bacteria uses a newly-identified 'selfish' mode of substrate processing. We therefore additionally examined the balance of individual substrate utilisation mechanisms at different locations by linking individual microorganisms to distinct substrate utilisation mechanisms. Through FISH and uptake of fluorescently-labelled polysaccharides, 'selfish' organisms were identified as belonging to the Bacteroidetes, Planctomycetes and Gammaproteobacteria. 'Sharing' (extracellular enzyme producing) and 'scavenging' (non-enzyme producing) organisms predominantly belonged to the Alteromonadaceae and SAR11 clades, respectively. The extent to which individual mechanisms prevail depended on the initial population structure of the bacterial community at a given location and time, as well as the growth rate of specific bacteria. Furthermore, the same substrate was processed in different ways by different members of a pelagic microbial community, pointing to significant follow-on effects for carbon cycling.
Understanding drop size distribution (DSD) variability has important implications for remote sensing and numerical modeling applications. Twelve disdrometer datasets across three latitude bands are ...analyzed in this study, spanning a broad range of precipitation regimes: light rain, orographic, deep convective, organized midlatitude, and tropical oceanic. Principal component analysis (PCA) is used to reveal comprehensive modes of global DSD spatial and temporal variability. Although the locations contain different distributions of individual DSD parameters, all locations are found to have the same modes of variability. Based on PCA, six groups of points with unique DSD characteristics emerge. The physical processes that underpin these groups are revealed through supporting radar observations. Group 1 (group 2) is characterized by high (low) liquid water content (LWC), broad (narrow) distribution widths, and large (small) median drop diameters D
0
. Radar analysis identifies group 1 (group 2) as convective (stratiform) rainfall. Group 3 is characterized by weak, shallow radar echoes and large concentrations of small drops, indicative of warm rain showers. Group 4 identifies heavy stratiform precipitation. The low latitudes exhibit distinct bimodal distributions of the normalized intercept parameter N
w
, LWC, and D
0
and are found to have a clustering of points (group 5) with high rain rates, large N
w
, and moderate D
0
, a signature of robust warm rain processes. A distinct group associated with ice-based convection (group 6) emerges in the midlatitudes. Although all locations exhibit the same covariance of parameters associated with these groups, it is likely that the physical processes responsible for shaping the DSDs vary as a function of location.
Plasmalogens are a specific glycerophospholipid class containing a vinyl ether moiety at the sn-1-position of the glycerol backbone. The high susceptibility of this vinyl ether bond to oxidative ...damage and traces of acids may indicate the possible function of plasmalogens in biological systems: The regarded cell-internal antioxidative defense of membranes by protecting other phospholipids or lipoprotein particles against oxidative stress is controversial. Reactive oxygen species preferably affect the vinyl ether function as well as the olefinic acyl residues at the sn-2-position of plasmalogens. This review is dedicated to the role of plasmalogens in different cells and tissues as spermatozoal cells or brain tissue. The first chapter of this review will discuss the molecular structure and chemistry of plasmalogen molecules, their distributions in cells and tissues and the species-specificity. In the second chapter their functions as lipid mediators will be considered and the controversial antioxidative function will be discussed. The supposed function of plasmalogens as "scavengers" for reactive oxygen species (ROS) in biological membranes is challenged by the finding that plasmalogen oxidation products as alpha-hydroxyaldehydes and plasmalogen epoxides accumulate in all chronic diseases as atherosclerosis and myocardial infarction, upon aging as well as in Alzheimers disease and other neuropathological conditions. All these conditions, characterized by increased membrane instability and oxidative damage, will be reviewed in chapter three. Chronically proceeding processes can be described by permanently invading polymorphonuclear neutrophils into inflammatory loci. The degranulation of the azurophilic granula in polymorphonuclear leukocytes causes the release of highly reactive substances, for instance the myeloperoxidase-generated hypochlorous acid (HOCl) acting as effective oxidant. Therefore, special attention will be paid to neutrophil-derived HOCl. The last chapter deals with currently used methods of detecting plasmalogens and their degradation products. Although chromatographic methods will be also discussed, special attention will be given to (31)P NMR spectroscopy and soft ionization techniques of mass spectrometry as electrospray ionization or matrix-assisted laser desorption and ionization time-of-flight mass spectrometry.
Abstract
Plasmalogens are a unique class of glycerophospholipids (GPLs) containing a fatty alcohol linked by a vinyl-ether moiety at the sn-1 position of the glycerol backbone. There is normally a ...polyunsaturated fatty acyl residue at the sn-2 position. These two features provide interesting properties to the plasmalogen GPL. Their physiological roles have been challenging to elucidate, although plasmalogens represent up to 20% of the total membrane GPLs in humans. Recent studies have revealed plasmalogen deficiencies associated with several human disorders; therefore, plasmalogens are likely to be specific to different tissues, metabolic processes, and developmental stages.
The first chapter of this review will discuss the molecular structure and chemistry of plasmalogens, their biological roles, and their distributions in cells and tissues in different species. In the second chapter, currently used methods of analyzing plasmalogens and their degradation products are described. Although chromatographic methods will be also discussed, special attention will be given to (31P) nuclear magnetic resonance spectroscopy and soft ionization mass spectrometry (MS) techniques such as electrospray ionization and matrix-assisted laser desorption and ionization time-of-flight MS. Finally, in the third chapter of this review selected human diseases and disorders, which are presumably characterized by changes in plasmalogen contents and compositions, are described and the analytical methods used are discussed.
Background and Purpose
The cation channel transient receptor potential canonical (TRPC) 6 has been associated with several pathologies including focal segmental glomerulosclerosis, pulmonary ...hypertension and ischaemia reperfusion‐induced lung oedema. We set out to discover novel inhibitors of TRPC6 channels and investigate the therapeutic potential of these agents.
Experimental Approach
A library of potential TRPC channel inhibitors was designed and synthesized. Activity of the compounds was assessed by measuring intracellular Ca2+ levels. The lead compound SAR7334 was further characterized by whole‐cell patch‐clamp techniques. The effects of SAR7334 on acute hypoxic pulmonary vasoconstriction (HPV) and systemic BP were investigated.
Key Results
SAR7334 inhibited TRPC6, TRPC3 and TRPC7‐mediated Ca2+ influx into cells with IC50s of 9.5, 282 and 226 nM, whereas TRPC4 and TRPC5‐mediated Ca2+ entry was not affected. Patch‐clamp experiments confirmed that the compound blocked TRPC6 currents with an IC50 of 7.9 nM. Furthermore, SAR7334 suppressed TRPC6‐dependent acute HPV in isolated perfused lungs from mice. Pharmacokinetic studies of SAR7334 demonstrated that the compound was suitable for chronic oral administration. In an initial short‐term study, SAR7334 did not change mean arterial pressure in spontaneously hypertensive rats (SHR).
Conclusions and Implications
Our results confirm the role of TRPC6 channels in hypoxic pulmonary vasoregulation and indicate that these channels are unlikely to play a major role in BP regulation in SHR. SAR7334 is a novel, highly potent and bioavailable inhibitor of TRPC6 channels that opens new opportunities for the investigation of TRPC channel function in vivo.
An iterative procedure for the synthesis of sparse arrays radiating focused or shaped beampattern is presented. The algorithm consists in solving a sequence of weighted l 1 convex optimization ...problems. The method can thus be readily implemented and efficiently solved. In the optimization procedure, the objective is the minimization of the number of radiating elements and the constraints correspond to the pattern requirements. The method can be applied to synthesize either focused or shaped beampattern and there is no restriction regarding the array geometry and individual element patterns. Numerical comparisons with standard benchmark problems assess the efficiency of the proposed approach, whose computation time is several orders of magnitude below those of so-called global optimization algorithms.
Summary
Background
Several clinical and experimental studies have implicated IL‐33 and its receptor ST2 in the development of asthma. However, the effect of IL‐33/ST2 signalling on airway responses ...and inflammation in allergic asthma is not well established.
Objective
To investigate the role of IL‐33/ST2 signalling in promoting allergen‐induced airway hyperresponsiveness (AHR), airway inflammation, antigen‐specific IgE production and mast cell activity in a mouse model of asthma.
Methods
ST2‐deficient (ST2−/−) mice and control BALB/c mice were given house dust mite (HDM) extract over a 6‐week period. Forty‐eight hours after the final HDM administration, lung function and airway inflammation were evaluated. Airway responsiveness was determined in the central airways and peripheral lung. Cellular infiltration and mast cell protease mMCP‐1 levels were quantified in bronchoalveolar lavage fluid (BALF). Recruitment of inflammatory cells and inflammatory cytokine profiles were assessed in pulmonary tissue, and HDM‐specific IgE was measured in serum.
Results
ST2 deficiency diminished HDM‐induced AHR in the peripheral lung, while AHR in the central airways was unaffected. Inflammatory responses to HDM were also reduced in ST2−/− mice as reflected by the lower induction of HDM‐specific serum IgE, inhibition of HDM‐induced eosinophilia and reduced macrophage count in BALF, and a diminished influx of inflammatory cells and reduced goblet cell hyperplasia around the peripheral airways. Furthermore, the levels of the inflammatory cytokines IL‐1β, IL‐5, IL‐13, IL‐33, GM‐CSF, thymic stromal lymphopoietin and mast cell protease mMCP‐1 were reduced in HDM‐treated ST2−/− mice compared with wild‐type controls.
Conclusions
In addition to promoting Th2 inflammation, we now suggest a role for the IL‐33/ST2 pathway for the induction of peripheral inflammation and mucus production that causes AHR in the peripheral lung. This mechanism for inducing AHR at distal parts of the lung may be of specific importance as asthma is considered as a small airway disease.
Dogs with osteosarcoma provide an important model for the same disease in humans. In this report, the comparative nature of human and canine osteosarcoma including incidence and risk factors, ...clinical presentation and diagnosis, genetic abnormalities, biologic behaviour and prognostic factors, as well as treatment options are reviewed.
Enterococcus faecium has emerged as one of the most important pathogens in healthcare-associated infections worldwide due to its intrinsic and acquired resistance to many antibiotics, including ...vancomycin. Antimicrobial photodynamic therapy (aPDT) is an alternative therapeutic platform that is currently under investigation for the control and treatment of infections. PDT is based on the use of photoactive dye molecules, widely known as photosensitizer (PS). PS, upon irradiation with visible light, produces reactive oxygen species that can destroy lipids and proteins causing cell death. We employed Galleria mellonella (the greater wax moth) caterpillar fatally infected with E. faecium to develop an invertebrate host model system that can be used to study the antimicrobial PDT (alone or combined with antibiotics). In the establishment of infection by E. faecium in G. mellonella, we found that the G. mellonella death rate was dependent on the number of bacterial cells injected into the insect hemocoel and all E. faecium strains tested were capable of infecting and killing G. mellonella. Antibiotic treatment with ampicillin, gentamicin or the combination of ampicillin and gentamicin prolonged caterpillar survival infected by E. faecium (P = 0.0003, P = 0.0001 and P = 0.0001, respectively). In the study of antimicrobial PDT, we verified that methylene blue (MB) injected into the insect followed by whole body illumination prolonged the caterpillar survival (P = 0.0192). Interestingly, combination therapy of larvae infected with vancomycin-resistant E. faecium, with antimicrobial PDT followed by vancomycin, significantly prolonged the survival of the caterpillars when compared to either antimicrobial PDT (P = 0.0095) or vancomycin treatment alone (P = 0.0025), suggesting that the aPDT made the vancomycin resistant E. faecium strain more susceptible to vancomycin action. In summary, G. mellonella provides an invertebrate model host to study the antimicrobial PDT and to explore combinatorial aPDT-based treatments.
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