bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of platelet-activating factor synthesis in human monocytes by dipalmitoyl phosphatidylcholine
Authors: Tonks Amanda J , Tonks Alex , Morris Roger H K , Jones Kenneth P , Jackson Simon K 
Published: June 2003

Abstract
Platelet-activating factor (PAF) has a major role in inflammatory responses within the lung. This study investigates the effect of pulmonary surfactant on the synthesis of PAF in human monocytic cells. The pulmonary surfactant preparation Curosurf® significantly inhibited lipopolysaccharide (LPS)-stimulated PAF biosynthesis (P&lt;0.01) in a human monocytic cell line, Mono mac-6 (MM6), as determined by 3H PAF scintillation-proximity assay. The inhibitory properties of surfactant were determined to be associated, at least in part, with the 1,2-dipalmitoyl phosphatidylcholine (DPPC) component of surfactant. DPPC alone also inhibited LPS-stimulated PAF biosynthesis in human peripheral blood monocytes. DPPC treatment did not affect LPS-stimulated phospholipase A2 activity in MM6 cell lysates. However, DPPC significantly inhibited LPS-stimulated coenzyme A (CoA)-independent transacylase and acetyl CoA:lyso-PAF acetyltransferase activity. DPPC treatment of MM6 cells decreased plasma membrane fluidity as demonstrated by electron paramagnetic resonance spectroscopy coupled with spin labeling. Taken together, these findings indicate that pulmonary surfactant, particularly the DPPC component, can inhibit LPS-stimulated PAF production via perturbation of the cell membrane, which inhibits the activity of specific membrane-associated enzymes involved in PAF biosynthesis.
Neutrophil-activating potential of antineutrophil cytoplasm autoantibodies
Authors: Rarok Agnieszka A , Limburg Pieter C , Kallenberg Cees G M 
Published: June 2003

Abstract
Accumulating in vivo and in vitro evidence supports the hypothesis that antineutrophil cytoplasm autoantibodies (ANCA) with specificity for proteinase 3 (PR3) and myeloperoxidase (MPO) are involved in the pathophysiology of small-vessel vasculitis. The best-described effector function of these autoantibodies is stimulation of neutrophils to produce reactive oxygen species and to release proteolytic enzymes. Neutrophil activation requires interaction of monomeric ANCA with PR3/MPO and Fcγ receptors, but also other mechanisms—for instance, stimulation by ANCA-containing immune complexes—cannot be excluded. This review focuses on the mechanisms of neutrophil activation by ANCA. We discuss the molecules involved in ANCA binding to the neutrophil surface and in triggering the functional responses. We summarize current knowledge on the signal-transduction pathways initiated by ANCA and on the factors determining susceptibility of neutrophils to activation by these autoantibodies.
Mechanism of glucocorticoid-induced depletion of human CD14+CD16+ monocytes
Authors: Dayyani Farshid , Belge Kai-Uwe , Frankenberger Marion , Mack Matthias , Berki Timea , Ziegler-Heitbrock Loems 
Published: June 2003

Abstract
Healthy donors infused with high doses of glucocorticoids [GCs; methyl-prednisolone (MP); 500 mg/day for 3 days] suffer a selective depletion of the CD14+CD16+ monocytes such that these cells are reduced by 95% on day 5. In vitro studies revealed that at 11 h of culture in the presence of 10−5 M MP, no depletion was observed as yet, but a reduction by 80% was seen after 24 h. In dose-response analysis, MP still led to a 50% reduction of CD14+CD16+ monocytes at 10−7 M. Depletion could not be overcome by addition of the cytokines interleukin-1β or macrophage-colony stimulating factor, and it was independent of CD95. Depletion was, however, inhibited by the caspase 3,8 blocker z-Val-Ala-Asp, suggesting that cell death occurs in a caspase-dependent manner. Furthermore, blockade of depletion by RU-486 indicates that the intracellular GC receptor (GCR) is involved. Measurement of GCR by flow cytometry revealed a 50% higher level of expression in the CD14+CD16+ monocytes. Our studies show a selective depletion of CD14+CD16+ monocytes by GC treatment in vivo and in vitro, an effect to which the modestly increased level of GCR may contribute.
CD44v7 interferes with activation-induced cell death by up-regulation of anti-apoptotic gene expression
Authors: Marhaba Rachid , Bourouba Mehdi , Zöller Margot 
Published: June 2003

Abstract
Blockade of CD44v7 was described to cure trinitrobenzene sulfonic acid-induced colitis, a disease not developed by mice with targeted deletion of the CD44v7 exon. There was evidence for a reduction in activation-induced cell death on lamina propria lymphocytes of control as compared with CD44v7-deficient mice. To elucidate the mechanism underlying the relative apoptosis resistance of CD44v7-competent as compared with CD44v7-deficient lymphocytes, T cell activation and induction of apoptosis were analyzed on mesenteric lymph node cells and Peyer’s patch lymphocytes of CD44v7-deficient and CD44v4-v7-transgenic mice, which overexpress rat CD44v4-v7 on T lymphocytes. CD44v7 deficiency was characterized by an increase in the percentage of apoptotic cells after stimulation, increased numbers of CD95L- and CD152-positive cells, low levels of the anti-apoptotic proteins Bcl-2 and Bcl-Xl, and decreased phosphorylation of the pro-apoptotic protein BAD. Also, lymphocytes from CD44v4-v7-transgenic mice displayed reduced levels of CD95L, low numbers of apoptotic cells, and constitutively elevated levels of Bcl-Xl. When stimulating lymphocytes by CD3 cross-linking, CD44v7 was not recruited toward the immunological synapse and preferentially associated with the cytoskeletal-linker protein ezrin. Thus, as opposed to the CD44 standard isoform, CD44v7 does not function as an accessory molecule; instead, it supports survival of activated T cells by interfering with activation-induced cell death.
Radiation-induced versus endogenous DNA damage: possible effect of inducible protective responses in mitigating endogenous damage
Authors: Pollycove Myron , Feinendegen Ludwig E 
Published: June 2003

Ionizing radiation (IR) causes damage to DNA that is apparently proportional to absorbed dose. The incidence of radiation-induced cancer in humans unequivocally rises with the value of absorbed doses above about 300 mGy, in a seemingly linear fashion. Extrapolation of this linear correlation down to zero-dose constitutes the linear-no-threshold (LNT) hypothesis of radiation-induced cancer incidence. The corresponding dose-risk correlation, however, is questionable at doses lower than 300 mGy. Non-radiation induced DNA damage and, in consequence, oncogenic transformation in non-irradiated cells arises from a variety of sources, mainly from weak endogenous carcinogens such as reactive oxygen species (ROS) as well as from micronutrient deficiencies and environmental toxins. In order to relate the low probability of radiation-induced cancer to the relatively high incidence of non-radiation carcinogenesis, especially at low-dose irradiation, the quantitative and qualitative differences between the DNA damages from non-radiation and radiation sources need to be addressed and put into context of physiological mechanisms of cellular protection. This paper summarizes a co-operative approach by the authors to answer the questions on the quantitative and qualitative DNA damages from non-radiation sources, largely endogenous ROS, and following exposure to low doses of IR. The analysis relies on published data and justified assumptions and considers the physiological capacity of mammalian cells to protect themselves constantly by preventing and repairing DNA damage. Furthermore, damaged cells are susceptible to removal by apoptosis or the immune system. The results suggest that the various forms of non-radiation DNA damage in tissues far outweigh corresponding DNA damage from low-dose radiation exposure at the level of, and well above, background radiation. These data are examined within the context of low-dose radiation induction of cellular signaling that may stimulate cellular protection systems over hours to weeks against accumulation of DNA damage. The particular focus is the hypothesis that these enhanced and persisting protective responses reduce the steady state level of nonradiation DNA damage, thereby reducing deleterious outcomes such as cancer and aging. The emerging model urgently needs rigorous experimental testing, since it suggests, importantly, that the LNT hypothesis is invalid for complex adaptive systems such as mammalian organisms.
Disruption of a Receptor-Mediated Mechanism for Intracellular Sorting of Proinsulin in Familial Hyperproinsulinemia
Authors: Dhanvantari Savita , Shen Fu-Sheng , Adams Tiffany , Snell Christopher R. , Zhang ChunFa , Mackin Robert B. , Morris Stephen J. , Loh Y. Peng 
Published: July 2003

AbstractIn familial hyperproinsulinemia, specific mutations in the proinsulin gene are linked with a profound increase in circulating plasma proinsulin levels. However, the molecular and cellular basis for this disease remains uncharacterized. Here we investigated how these mutations may disrupt the sorting signal required to target proinsulin to the secretory granules of the regulated secretory pathway, resulting in the unregulated release of proinsulin. Using a combination of molecular modeling and site-directed mutagenesis, we have identified structural molecular motifs in proinsulin that are necessary for correct sorting into secretory granules of endocrine cells. We show that membrane carboxypeptidase E (CPE), previously identified as a prohormone-sorting receptor, is essential for proinsulin sorting. This was demonstrated through short interfering RNA-mediated depletion of CPE and transfection with a dominant negative mutant of CPE in a β-cell line. Mutant proinsulins found in familial hyperproinsulinemia failed to bind to CPE and were not sorted efficiently. These findings provide evidence that the elevation of plasma proinsulin levels found in patients with familial hyperproinsulinemia is caused by the disruption of CPE-mediated sorting of mutant proinsulins to the regulated secretory pathway.
Dynamic behavior of Nuf2-Hec1 complex that localizes to the centrosome and centromere and is essential for mitotic progression in vertebrate cells
Authors: Hori Tetsuya , Haraguchi Tokuko , Hiraoka Yasushi , Kimura Hiroshi , Fukagawa Tatsuo 
Published: July 2003

Nuf2 and Hec1 are evolutionarily conserved centromere proteins. To clarify the functions of these proteins in vertebrate cells, we characterized them in chicken DT40 cells. We generated GFP fusion constructs of Nuf2 and Hec1 to examine in detail the localization of these proteins during the cell cycle. We found that Nuf2 is associated with Hec1 throughout the cell cycle and that this complex is localized to the centrosomes during G1 and S phases and then moves through the nuclear membrane to the centromere in G2 phase. During mitosis, this complex is localized to the centromere.We also created conditional loss-of-function mutants of Nuf2 and Hec1. In both mutants, the cell cycle arrested at prometaphase, suggesting that the Nuf2-Hec1 complex is essential for mitotic progression. The inner centromere proteins CENP-A, -C, and -H and checkpoint protein BubR1 were localized to chromosomes in the mutant cells arrested at prometaphase, but Mad2 localization was abolished. Furthermore, photobleaching experiments revealed that the Nuf2-Hec1 complex is stably associated with the centromere and that interaction of this complex with the centrosome is dynamic.
The further development of the active urine collection device: A novel continence management system
Authors: Tinnion E , Jowitt F , Clarke-O'Neill S , Cottenden A M , Fader M , Sutherland I 
Published: July 2003

Continence difficulties affect the lives of a substantial minority of the population. Women are far more likely than men to be affected by urinary incontinence but the range of management options for them is limited. There has been considerable interest in developing an external urine collection system for women but without success to date. This paper describes the development and preliminary clinical testing of an active urine collection device (AUCD), which could provide a solution for sufferers. The device uses stored vacuum, protected by a high bubble point filter, to remove urine as quickly as it is produced. This allows a small battery-operated pump to provide the required vacuum, enabling the device to be portable. Two different types of non-invasive patient/device interface were developed, and tested by volunteers: urinal and small pad. The slimline urinal was popular with users although liquid noise was a problem. The pad interface was successful on occasions but further work is necessary to produce a reliable pad. This study has successfully demonstrated that a prototype AUCD liquid handling system can remove urine at clinically relevant flowrates. While further development is required, volunteer tests have shown that the AUCD could be a useful advance in continence management.
A One-pot Synthesis of Cyclic Pyrido[1,2-a]quinoxaline Phosphate, a New Molecule of Biological Importance from a Quinoxaline Derivative of Sugar
Authors: Goswami Shyamaprosad , Adak Avijit Kumar 
Published: July 2003

Abstract
A five membered cyclic pyrido[1,2-a]quinoxaline phosphate has been first synthesized in one step in a good yield by phosphorylation of the quinoxaline derivative of sugar 1a with (PhO)P(O)Cl2. Phosphorylation of the tetrols (1a and 1b) and the diol acetals with other phosphorylating agents, however, affords a dehydration product 2-(2-furyl)quinoxaline.
Affinity Capillary Electrophoresis in a Poly(dimethylsiloxane)-glass Hybrid Microchip
Authors: Ito Toshiyuki , Inoue Akira , Sato Kae , Hosokawa Kazuo , Maeda Mizuo 
Published: July 2003

Abstract
Affinity capillary electrophoresis of DNA was conducted in a poly(dimethylsiloxane)-glass hybrid microchip with a 100 μm (width) × 130 μm (height) microchannel containing poly(N,N-dimethylacrylamide)-DNA conjugate. By this method, sample 12-mer oligonucleotide composed of c-K-ras codon 10-13 was separated from its single-base substituted mutant within 2 min.
The sensitivity of tropical squall lines to surface fluxes: Three‐dimensional cloud‐resolving model simulations
Authors: Wang Yansen , Tao Wei‐Kuo , Simpson Joanne , Lang Stephen 
Published: July 2003

AbstractTwo tropical oceanic squall lines, from the Tropical Ocean–Global Atmosphere Coupled Ocean–Atmosphere Response Experiment (TOGA COARE) and the Global Atmospheric Research Program Atlantic Tropical Experiment (GATE), that developed over the west Pacific and east Atlantic, respectively, are simulated using a three‐dimensional cloud‐resolving model to examine the impact of surface fluxes on tropical squall line development and associated precipitation processes. The important question of how convective available potential energy (CAPE) is maintained in clear and cloudy areas in the tropics is investigated. The boundary‐layer structure and evolution in the clear inflow area are also discussed. Although the cloud structure and precipitation intensity are different between the TOGA COARE and GATE squall line cases, the effects of the surface fluxes on the amount of rainfall and on the cloud development processes are quite similar. The area where surface fluxes originated was categorized into clear and cloudy regions according to whether there was cloud in the vertical column. The model results indicated that the surface fluxes from the large clear‐air environment are the dominant moisture source for tropical squall line development, even though the surface fluxes in the cloud region display a large peak. The high‐energy air from the boundary layer in the clear area is what feeds the convection, while the CAPE is removed by the convection. Trajectory and water budget analyses also indicate that most of the moisture (90%) is from the boundary layer of the clear‐air environment. Copyright © 2003 Royal Meteorological Society
Terrain influences on the dynamics of heat lows
Authors: Reichmann Zsuzsanna , Smith Roger K. 
Published: June 2003

AbstractThe hydrostatic primitive‐equation numerical model we used earlier to study the basic dynamics of heat lows in an idealized flow configuration is extended to investigate the effects of orography. Calculations are carried out over a heated land mass with an elevated plateau for the case with no surrounding sea, as well as with the sea present. We investigate the effect of the shape of the terrain on the mature heat low. In the presence of orography the mixed layer over land becomes deeper than without orography and the induced flow is stronger also. The width of the plateau influences, among other things, the relative‐vorticity distribution and the nocturnal jet development. The flow behaviour in the presence of orography provides an explanation for the different vertical profiles of vertical velocity in heat lows discussed in the literature. Copyright © 2003 Royal Meteorological Society
Validation and intercomparison of three mesoscale models on three FASTEX cloud systems: comparison with coarse‐resolution simulations
Authors: Lopez Philippe , Finkele Klara , Clark Peter , Mascart Patrick 
Published: June 2003

AbstractTaking advantage of the observations collected during the Fronts and Atlantic Storm‐Track EXperiment (FASTEX), three FASTEX midlatitude cloud systems are simulated with three state‐of‐the‐art, mesoscale, limited‐area models (the Met Office's Unified Model (UM), Met Éireann's High Resolution Limited Area Model (HIRLAM), and the French Laboratoire d'Aérologie research modèle de Méso‐échelle Non‐Hydrostatique (Méso‐NH)), at an 11 km horizontal resolution and with about 50 vertical levels. The dynamical, thermodynamic, cloud and precipitation fields obtained from these numerical integrations are then intercompared and validated against various observational sources, including radio‐ and dropsondes, satellite radiometer, and rain‐gauges. The similarities and the deficiencies of the three models are summarized in the paper. After this validation work, the mesoscale fields are degraded in resolution, so that they can be directly compared with the outputs of 300 km resolution simulations, run with Météo‐France's atmospheric general‐circulation model (AGCM) Action de Recherche Petite Echelle et Grande Echelle (ARPEGE). The deviations between the upscaled mesoscale models and the coarse AGCM turn out to be significant and highly dependent on the location relative to the storm, with, in particular, a large contrast between the trailing cold region and the warm sector with thick layer clouds, suggesting the existence of some deficiencies in the AGCM. Copyright © Royal Meteorological Society, 2003. Peter Clark's contribution is Crown copyright.
A modelling study of ice‐spectrum modes in deep frontal clouds
Authors: Cardwell J. , Field P. R. , Choularton T. W. 
Published: June 2003

AbstractResults from a one‐dimensional mixed‐layer model with explicit microphysics and a discrete ice‐spectrum were compared to in situ data provided by the Met Office C‐130 aircraft. Bimodal ice‐spectra were observed. The first mode was found at diameters near the lower limit of the instrumentation resolution (25 µm) at a roughly constant concentration. The second mode was found initially at diameters exceeding 200 µm but it shifted to larger sizes and smaller peak concentrations as depths below the cloud top increased.The objectives of the paper are threefold: validation of the model with real cloud data; an analysis of parameters controlling the rate of aggregation, and to show that a secondary ice‐production process is needed to maintain the first mode and produce a second mode which is sensible.A reasonable first mode could only be maintained by producing a constant supply of small ice particles at a rate of at least 10 m−3s−1. Primary nucleation was unable to supply this rate of ice‐particle production at temperatures above −20°C. In the model, it was achieved by invoking a secondary ice‐particle production process, such as the break‐up of evaporating ice crystals. The rate of production required is in broad agreement with laboratory investigations of secondary ice‐particle production during evaporation.The relative importance of the processes of aggregation, deposition and sedimentation to the production of the bimodal spectra is also studied. While it is possible to grow ice particles to large sizes by deposition alone, the number concentration observed in these clouds produces so much competition for water vapour that deposition growth is very limited. The aggregation process is the strongest mechanism for the production of the larger ice‐particles, which then precipitate. Consequently, its strength controls the rate of small ice‐particle production needed, and so is mainly responsible for the second mode. Copyright © Royal Meteorological Society, 2003. P. R. Field's contribution is Crown copyright.
Developments of a targeted ensemble prediction system
Authors: Hersbach H. , Mureau R. , Opsteegh J. D. , Barkmeijer J. 
Published: June 2003

AbstractBased on results presented in a previous paper, an Ensemble Prediction System, especially designed for the short‐range to early‐medium range for the European domain (TEPS), was further developed. Between 1 January 1999 and 27 February 2000 this system was run for two cases per week. Results were compared to the ensemble prediction system (EPS) that was operational at the European Centre for Medium‐Range Weather Forecasts at the time. The focus was on weather parameters. Several configurations were tested. Besides perturbations that optimize total error growth for the European domain at 48 h, perturbations relevant for shorter forecast times were included as well. Firstly, in accordance with EPS, evolved northern hemispheric singular vectors (ETEPS) and secondly, targeted singular vectors with an optimization time of 12 h (STEPS) were added. Compared to EPS, ensemble spread was increased in the short range, having a beneficial effect on statistical properties such as reliability and the frequency of outliers. Spread–skill correlations improved as well. Best performance was found for the STEPS configuration. The impact on Brier scores, relative operating characteristic curves and cost‐loss analyses was less clear. From the singular vector point of view, the positive impact of using targeted perturbations is evident. However, after integration (STEPS or ETEPS), it was difficult to find synoptic cases in which this clear impact is still present. Copyright © 2003 Royal Meteorological Society
Sensitivity of extratropical cyclone mesoscale structure to the parametrization of ice microphysical processes
Authors: Forbes Richard M. , Clark Peter A. 
Published: July 2003

AbstractThe ability of numerical weather prediction models to represent and forecast mesoscale structure accurately in extratropical cyclones depends on the resolution and dynamical formulation of the model and the way in which the subgrid‐scale processes are parametrized. This study investigates the sensitivity of extratropical cyclone forecasts to aspects of the microphysical parametrization in a mesoscale version of the Met Office Unified Model. Case‐studies of rapidly developing cyclones over the North Atlantic Ocean from the Fronts and Atlantic Storm‐Track Experiment period are used to study the forecast sensitivity to the ice sublimation and deposition rate, and the ice terminal fall speed. Modifying these parameters not only changes the balance between ice content, liquid‐water content and water vapour in the model but also affects the mesoscale dynamics of the frontal rain bands associated with the cyclone. In particular, the cooling due to sublimating ice beneath slantwise ascending frontal updraughts has a significant effect on the dynamics of the front and on the development of further post‐frontal rain bands. The study highlights the need for a microphysical parametrization that produces an appropriate cooling profile from sublimating ice particles for the forecasting of mesoscale structure in extratropical cyclones. © Crown copyright, 2003. Royal Meteorological Society