bluuebunny/crossref_metadata_2025 huggingface dataset:
Endothelial-specific CYP4A2 overexpression leads to renal injury and hypertension via increased production of 20-HETE
Authors: Inoue Kazuyoshi , Sodhi Komal , Puri Nitin , Gotlinger Katherine H. , Cao Jiang , Rezzani Rita , Falck John R. , Abraham Nader G. , Laniado-Schwartzman Michal
Published: August 2009

We have previously reported that adenoviral-mediated delivery of cytochrome P-450 (CYP) 4A2, which catalyzes the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE), results in endothelial dysfunction and hypertension in Sprague-Dawley (SD) rats (Wang JS, Singh H, Zhang F, Ishizuka T, Deng H, Kemp R, Wolin MS, Hintze TH, Abraham NG, Nasjletti A, Laniado-Schwartzman M. Circ Res 98: 962–969, 2006). In this study, we targeted the vascular endothelium by using a lentivirus construct expressing CYP4A2 under the control of the endothelium-specific promoter VE-cadherin (VECAD-4A2) and examined the effect of long-term CYP4A2 overexpression on blood pressure and kidney function in SD rats. A bolus injection of VECAD-4A2 increased blood pressure ( P < 0.001) by 26, 36, and 30 mmHg 10, 20, and 30 days postinjection, respectively. Arteries from VECAD-4A2-transduced rats produced increased levels of 20-HETE ( P < 0.01), expressed lower levels of endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (p-eNOS) ( P < 0.05), generated higher levels of superoxide anion, and displayed decreased relaxing responsiveness to acetylcholine ( P < 0.05). Proteinuria increased by twofold in VECAD-4A2-transduced rats compared with controls. Treatment of VECAD-4A2-transduced rats with HET0016, an inhibitor of 20-HETE biosynthesis, not only attenuated the increase in blood pressure ( P < 0.05) but also improved vascular function (acetylcholine-induced relaxations) and reduced plasma creatinine and proteinuria. HET0016 treatment decreased oxidative stress and increased the phosphorylated state of key proteins that regulate endothelial function, including eNOS, AKT, and AMPK. Collectively, these findings demonstrate that augmentation of vascular endothelial 20-HETE levels results in hypertension, endothelial dysfunction, and renal injury, which is offset by HET0016 through a reduction in vascular 20-HETE coupled with a lessening of oxidative stress and the amplification of pAKT, pAMPK, and p-eNOS levels leading to normalization of endothelial responses.
Influence of central command and muscle afferent activation on anterior cerebral artery blood velocity responses to calf exercise in humans
Authors: Vianna Lauro C. , Araújo Claudio Gil S. , Fisher James P.
Published: August 2009

The purpose of the present study was to determine the relative importance of peripheral feedback from mechanically (mechanoreflex) and metabolically (metaboreflex) sensitive muscle afferents and central signals arising from higher centers (central command) to the exercise-induced increases in regional cerebral perfusion. To accomplish this, anterior cerebral artery (ACA) mean blood velocity ( Vmean) responses were assessed during sustained and rhythmic passive calf muscle stretch (mechanoreflex), volitional calf exercise (mechanoreflex, metaboreflex, and central command), and electrically stimulated calf exercise (mechanoreflex and metaboreflex but no central command) at 35% of maximum voluntary contraction ( n = 16). In addition, a period of postexercise muscle ischemia (PEMI) was used to isolate the metaboreflex. Blood pressure, cardiac output, and the end-tidal partial pressure of carbon dioxide (PetCO2) were also measured. ACA Vmean was unchanged from rest during either sustained or rhythmic calf muscle stretch ( P > 0.05). However, ACA Vmean was increased from rest during both isometric (+15 ± 1%) and rhythmic (+15 ± 2%, voluntary exercise P < 0.05) but remained unchanged during stimulated exercise ( P > 0.05). Isometric and rhythmic exercise-induced increases in blood pressure and cardiac output were similar during voluntary and stimulated exercise ( P > 0.05 between conditions). Blood pressure remained elevated during PEMI after all exercise conditions ( P < 0.05 vs. rest), whereas cardiac output and ACA Vmean were not different from rest ( P > 0.05). PetCO2 was unchanged from rest throughout. These data suggest that selective activation of skeletal muscle afferents (i.e., stretch, PEMI, or stimulated exercise) does not increase ACA Vmean and that increases in ACA Vmean during volitional contractions of an exercising calf muscle are dependent on the presence of central command.
Pressed for time: the circadian clock and hypertension
Authors: Rudic R. Daniel , Fulton David J.
Published: August 2009

Hypertension is a major risk factor for cardiovascular disease and death. The “silent” rise of blood pressure that occurs over time is largely asymptomatic. However, its impact is deafening—causing and exacerbating cardiovascular disease, end-organ damage, and death. The present article addresses recent observations from human and animal studies that provide new insights into how the circadian clock regulates blood pressure, contributes to hypertension, and ultimately evolves vascular disease. Further, the molecular components of the circadian clock and their relationship with locomotor activity, metabolic control, fluid balance, and vascular resistance are discussed with an emphasis on how these novel, circadian clock-controlled mechanisms contribute to hypertension.
SK Channels Gate Information Processing In Vivo by Regulating an Intrinsic Bursting Mechanism Seen In Vitro
Authors: Toporikova Natalia , Chacron Maurice J.
Published: August 2009

Understanding the mechanistic substrates of neural computations that lead to behavior remains a fundamental problem in neuroscience. In particular, the contributions of intrinsic neural properties such as burst firing and dendritic morphology to the processing of behaviorally relevant sensory input have received much interest recently. Pyramidal cells within the electrosensory lateral line lobe of weakly electric fish display an intrinsic bursting mechanism that relies on somato-dendritic interactions when recorded in vitro: backpropagating somatic action potentials trigger dendritic action potentials that lead to a depolarizing afterpotential (DAP) at the soma. We recorded intracellularly from these neurons in vivo and found firing patterns that were quite different from those seen in vitro: we found no evidence for DAPs as each somatic action potential was followed by a pronounced afterhyperpolarization (AHP). Calcium chelators injected in vivo reduced the AHP, thereby unmasking the DAP and inducing in vitro-like bursting in pyramidal cells. These bursting dynamics significantly reduced the cell's ability to encode the detailed time course of sensory input. We performed additional in vivo pharmacological manipulations and mathematical modeling to show that calcium influx through N-methyl-d-aspartate (NMDA) receptors activate dendritic small conductance (SK) calcium-activated potassium channels, which causes an AHP that counteracts the DAP and leads to early termination of the burst. Our results show that ion channels located in dendrites can have a profound influence on the processing of sensory input by neurons in vivo through the modulation of an intrinsic bursting mechanism.
Enhanced Calcium Buffering in F344 Rat Cholinergic Basal Forebrain Neurons Is Associated With Age-Related Cognitive Impairment
Authors: Murchison David , McDermott Angelika N. , LaSarge Candi L. , Peebles Kathryn A. , Bizon Jennifer L. , Griffith William H.
Published: August 2009

Alterations in neuronal Ca2+homeostasis are important determinants of age-related cognitive impairment. We examined the Ca2+influx, buffering, and electrophysiology of basal forebrain neurons in adult, middle-aged, and aged male F344 behaviorally assessed rats. Middle-aged and aged rats were characterized as cognitively impaired or unimpaired by water maze performance relative to young cohorts. Patch-clamp experiments were conducted on neurons acutely dissociated from medial septum/nucleus of the diagonal band with post hoc identification of phenotypic marker mRNA using single-cell RT-PCR. We measured whole cell calcium and barium currents and dissected these currents using pharmacological agents. We combined Ca2+current recording with Ca2+-sensitive ratiometric microfluorimetry to measure Ca2+buffering. Additionally, we sought changes in neuronal firing properties using current-clamp recording. There were no age- or cognition-related changes in the amplitudes or fractional compositions of the whole cell Ca2+channel currents. However, Ca2+buffering was significantly enhanced in cholinergic neurons from aged cognitively impaired rats. Moreover, increased Ca2+buffering was present in middle-aged rats that were not cognitively impaired. Firing properties were largely unchanged with age or cognitive status, except for an increase in the slow afterhyperpolarization in aged cholinergic neurons, independent of cognitive status. Furthermore, acutely dissociated basal forebrain neurons in which choline acetyltransferase mRNA was detected had the electrophysiological profiles of identified cholinergic neurons. We conclude that enhanced Ca2+buffering by cholinergic basal forebrain neurons may be important during aging.
X-ray diffraction study of anisotropic state of residual stress after down-cut and up-cut face grinding
Authors: Pala Zdenek , Ganev Nikolaj , Drahokoupil Jan
Published: August 2009

Differences between up-cut and down-cut grinding are usually not considered since both modes are alternating during conventional face grinding. Nevertheless, there is a pronounced distinction in the fashion of material removal which could lead to unequal states of surface residual stress. By means of X-ray diffraction analysis, ground plates made from three types of steel were investigated in order to compute and compare both macroscopic and microscopic residual stress and domains of coherent scattering. With respect to the main sources of residual stress generation, i.e., plastic and thermal deformation, machining process was carried out in two types of cooling environment. The results indicate significant influence of heat removal since differences between the two grinding modes are virtually nonexistent for liquid cooling, whereas dry grinding results in higher compressive normal residual stresses for down-cut mode in comparison to the up cut.
Grain growth in nanocrystalline copper thin films investigated by non-ambient X-ray diffraction measurements
Authors: Kuru Y. , Wohlschlögel M. , Welzel U. , Mittemeijer E.J.
Published: August 2009

The microstructure evolution (crystallite size and microstrain) as well as the residual stress of Cu thin films of various thicknesses (250 nm, 500 nm, and 1 μm) on passivated Si substrates during isochronal annealing was investigated by in situ X-ray diffraction measurements in the temperature range between 25 °C and 250 °C. Before annealing, the thermoelastic behavior was investigated excluding the occurrence of thermally activated relaxation processes occurring above ambient temperature by in situ stress measurements below ambient temperature. On this basis, above ambient temperature, effects of stress relaxation and emerging secondary stresses (due to grain growth and annihilation of crystal defects, giving rise to a considerable tensile stress contribution development) could be identified for all three layers in the temperature regime between ambient temperature and 250 °C. Grain growth in the nanocrystalline thin films started at much lower temperatures as compared to coarse-grained materials. The results were discussed in terms of the effects of different driving forces and grain-boundary mobilities acting in nanocrystalline materials.
X-ray diffraction characterization of MOVPE ZnSe films deposited on (100) GaAs using conventional and high-resolution diffractometers
Authors: Blanton T. N. , Barnes C. L. , Holland M. , Kahen K. B. , Gupta S. K. , Bai F.
Published: August 2009

ZnSe-based heterostructures grown on GaAs substrates have been investigated for use in pin-diode LED applications. In this study, a conventional Bragg-Brentano diffractometer (BBD) has been used to screen samples for phase identification, crystallite size, presence of polycrystalline ZnSe, and initial rocking curve (RC) analysis. A limitation of the conventional diffractometer is that the smallest RC full width at half maximum (FWHM) that can be achieved is 500 to 600 arc sec. As deposition parameters are optimized and the RC limit of the conventional diffractometer is reached, analysis is moved to a four-bounce high-resolution diffractometer (HRD). Although more time for analysis is required, using the HRD has a RC resolution advantage, where RCs of <20 arc sec are obtained for neat GaAs wafers. Combining the BBD and HRD instruments for analysis of ZnSe films grown on GaAs substrates allows for an efficient means of high sample throughput combined with an accurate measurement of film alignment.
An innovative EDXRD verification probe
Authors: Dozier Charles M. , Anibou Noureddine
Published: August 2009

Verification of materials is an increasingly important need in pharmaceutical distribution. XStream Systems, Inc. has developed an energy dispersive X-ray diffraction (EDXRD) system which can quickly verify crystalline pharmaceuticals in the distribution cycle. Materials may be in solid or powder form and the technique is nondestructive. Unlike angular X-ray diffraction (AXRD), a “white” X-ray beam between 20 and 80 keV is used. This energetic beam can penetrate through relatively thick materials, diffracting from crystallites within the samples. Materials can be observed even when they are located within opaque, sealed containers. That is, for most cases the drugs can be examined in their sealed, packaged vials without any sample preparation. The tabletop unit uses a confocal geometry to maximize the X-ray intensity from a relatively low-powered, air-cooled X-ray source. The beam is collimated by a circular slit assembly before the sample. A similar slit assembly after the sample collimates the diffracted beam. A single, state-of-the-art, CdTe solid-state detector with a multichannel analyzer is used to process the diffracted signal. This collimation system interrogates a doughnut-shaped volume within the sample under test. One of the design goals was to develop a unit that is capable of performing quick verification or detection of complex materials and mixtures at a number of points along the distribution paths yet can be operated by personnel with minimal scientific knowledge. Rapid identification of unknowns is possible using neural network search algorithms or pattern matching techniques. The Material Recognition Software Engine (MRSE) utilizes a localized SQL database to store and process the raw spectra data. The MRSE takes the sample data and determines if it matches any known patterns within its database. This engine has demonstrated that it can verify a number of drugs within 30 s with better than 97% accuracy.
Influence of the sample morphology on total reflection X-ray fluorescence analysis
Authors: Horntrich C. , Meirer F. , Streli C. , Kregsamer P. , Pepponi G. , Zoeger N. , Wobrauschek P.
Published: August 2009

Total reflection X-ray fluorescence analysis (TXRF) is a method for qualitative and quantitative analysis of trace elements. In general TXRF is known to allow for linear calibration typically using an internal standard for quantification. For small sample amounts (low ng region) the thin film approximation is valid neglecting absorption effects of the exciting and the detected radiation. However, for higher total amounts of samples deviations from the linear relation between fluorescence intensity and sample amount have been observed. The topic of the presented work is an investigation of the parameters influencing the absorption phenomenon. Samples with different total amounts of arsenic have been prepared to determine the upper limit of sample mass where the linear relation between fluorescence intensity and sample amount is no longer guaranteed. It was found that the relation between fluorescence intensity and sample amount is linear up to ∼100 ng arsenic. A simulation model was developed to calculate the influence of the absorption effects. Even though the results of the simulations are not satisfying yet it could be shown that one of the key parameters for the absorption effect is the density of the investigated element in the dried residues.
Natural nanoparticle structure, properties and reactivity from X-ray studies
Authors: Waychunas G. A.
Published: August 2009

Synthetic analogs of naturally occurring nanoparticles have been studied by a range of X-ray techniques to determine their structure and chemistry, and relate these to their novel chemical properties and physical behavior. ZnS nanoparticles, formed in large concentrations naturally bymicrobial action, have an interesting core-shell structure with a highly distorted and strained outer layer. The strain propagates through the particles and produces unusual stiffness but can be relieved by changing the nature of the surface ligand binding. Weaker bound ligands allow high surface distortion, but strongly bound ligands relax this structure and reduce the overall strain. Only small amounts of ligand exchange causes transformations from the strained to the relaxed state. Most remarkably, minor point contacts between strained nanoparticles also relax the strain. Fe oxyhydroxide nanoparticles appear to go through structural transformations dependent on their size and formation conditions, and display a crystallographically oriented form of aggregation at the nanoscale that alters growth kinetics. At least one Fe oxyhydroxide mineral may only be stable on the nanoscale, and nonstoichiometry observed on the hematite surface suggests that for this phase and possibly other natural metal oxides, chemistry may be size dependent. Numerous questions exist on nanominerals formed in acid mine drainage sites and by reactions at interfaces.
Preconcentration of environmental waters by agar for XRF analysis
Authors: Nakano Kazuhiko , Okubo Kenta , Tsuji Kouichi
Published: August 2009

We have developed a convenient and effective XRF analysis procedure for trace amount of K, Ca, V, Mn, Fe, Ni, Cu, Zn, Cd, and Pb in environmental waters by using a preconcentration using the natural polymer (agar). The thin agar film was prepared by drying a homogeneous agar gel after mixing the aqueous sample solution with the agar powder. XRF analysis of the preconcentrated thin agar films containing trace metals showed a good repeatability because agar films were homogeneous enough. SB (signal to noise) ratios of the XRF intensity of the analytes were improved drastically. The linear calibration curves of K, Ca, V, Mn, Fe, Ni, Cu, Zn, Cd, and Pb showed a good linearity within the calibration ranges. The lower limits of detection (LLD) were 1.4 μg/mL for K, 0.26 μg/mL for Ca, 0.088 μg/mL for V, 0.029 μg/mL for Mn, 0.11 μg/mL for Fe, 0.016 μg/mL for Ni, 0.030 μg/mL for Cu, 0.017 μg/mL for Zn, 0.20 μg/mL for Cd, and 0.066 μg/mL for Pb, respectively. The proposed preconcentration method was applied to several environmental water samples.
Evidence and analysis of thermal static strain aging in the deformed surface zone of finish-machined hardened steel
Authors: Gegner Jürgen , Schlier Lorenz , Nierlich Wolfgang
Published: August 2009

After heat treating, finish machining of the hardened steel represents the last manufacturing step of machine elements. The practically most important operation of grinding is applied to achieve edge zone compressive residual stresses, best surface quality, and dimensional accuracy. Metal removal involves high plastic deformation work. Glide and intersection processes raise the density and produce lower energy substructures of dislocations. The temperature and time behavior of postmachining thermal treatment is analyzed on ground and honed martensitic SAE 52100 rolling bearing steel. Microstructure stabilization is reflected in a large XRD peak width decrease in the surface. The kinetics are modeled by rate-controlling carbide dissolution as the carbon source for Cottrell-type segregation at dislocations. This thermal static strain aging is verified by the formation of a slight white etching surface layer. The model is also extended to consider superimposed thermal dislocation recovery. Both effects are separable. In rolling contact fatigue tests under mixed friction conditions, air reheating below the tempering temperature, which avoids hardness loss, leads to a significant lifetime increase. The effect also occurs after cold working.
Preliminary study of a Georgia O'Keeffe pastel drawing using XRF and μXRD
Authors: Brostoff Lynn B. , Maynor Catherine I. , Speakman Robert J.
Published: August 2009

X-ray fluorescence spectrometry (XRF) and micro-X-ray diffraction (μXRD) were used to analyze the composition of pigments on a pastel drawing, Special No. 32, by Georgia O’Keeffe. XRF analyses showed that, among other pigments present in the drawing, the red, orange, and yellow pigments may possibly be identified with lead- and chromium-based pigments: lead chromates, red and yellow lead oxides, and/or lead carbonates, plus calcium-based pastel fillers, such as whiting or gypsum. XRD examination of a sample removed from a dark mottled area of coral red pastel confirmed that this pigment layer, which is associated with a darkened appearance and high Pb:Cr ratios, matches the red lead oxide, minium (2PbO⋅PbO2).
Measuring residual stresses in stainless steel—recent experiences within a VAMAS exercise
Authors: Fry A. T. , Lord J. D.
Published: August 2009

Residual stresses impact on a wide variety of industrial sectors including the automotive, power generation, industrial plant, construction, aerospace, railway and transport industries, and a range of materials manufacturers and processing companies. The X-ray diffraction (XRD) technique is one of the most popular methods for measuring residual stress (Kandil et al., 2001) used routinely in quality control and materials characterization for validating models and design. The VAMAS TWA20 Project 3 activity on the “Measurement of Residual Stresses by X-ray Diffraction” was initiated by NPL in 2005 to examine various aspects of the XRD test procedure in support of work aimed at developing an international standard in this area. The purpose of this project was to examine and reduce some of the sources of scatter and uncertainty in the measurement of residual stress by X-ray diffraction on metallic materials, through an international intercomparison and validation exercise. One of the major issues the intercomparison highlighted was the problem associated with measuring residual stresses in austenitic stainless steel. The following paper describes this intercomparison, reviews the results of the exercise and details additional work looking at developing best practice for measuring residual stresses in austenitic stainless steel, for which X-ray measurements are somewhat unreliable and problematic.
Application of energy-dispersive diffraction to the analysis of highly inhomogeneous residual stress fields in thin film structures
Authors: Klaus M. , Reimers W. , Genzel Ch.
Published: August 2009

For residual stress evaluation in complex substrate-coating systems, energy-dispersive (ED) diffraction with energies up to 100 keV can be applied to analyze the near interface residual stress state in the substrate, because the high energy white beam penetrates the coating completely. By the example of an Al2O3/TiCN on WC coating system we have studied the feasibility for using the coating reflections being stored in the ED diffraction patterns together with the substrate diffraction lines to analyze the residual stress state in individual sublayers of which the coating system consists. The results indicate that the ED method is suitable to detect even steep intralayer stress gradients, if the diffraction conditions are adapted to the coating geometry.
Microstrain accumulation in multiphase superalloys
Authors: Repper J. , Hofmann M. , Krempaszky C. , Wimpory R. C. , Petry W. , Werner E.
Published: August 2009

Four matrix-phase crystallographic directions of IN718 are investigated by in situ tensile tests using neutron diffraction. The elastic diffraction constants for all directions measured are compared to theoretical values calculated by the Kröner model. The differences between the microscopic and the macroscopic material response are given. The accumulation of microstrains in the different crystallographic directions is discussed. A comparison between the results of a single phase material (ingot IN718) and two differently thermal treated multiphase materials is presented.
Neutron diffraction studies on strain evaluation of rebar in reinforced concrete
Authors: Suzuki Hiroshi , Kanematsu Manabu , Kusunoki Koichi
Published: August 2009

The neutron diffraction technique was applied to measure strain distributions in a rebar in a reinforced concrete. At first, absorption coefficients of several kinds of concrete with different compounding ratios of water, cement, and aggregate were measured, and it was confirmed that the absorption coefficient of concrete was affected by the amounts of water and aggregate. In addition, it was also clarified by measuring strain change of the rebar under tensile loading that accuracy of the strain measurement in the rebar in the reinforced concrete was not affected by the neutron absorption by the concrete. Second, the size of the anchorage zone was evaluated by measuring strain distributions in the rebar under pull-out loading. The length of the anchorage zone measured by neutron diffraction was shorter than that measured by strain gauges. Moreover, detailed strain distributions in the rebar around cracks in the concrete were measured under tensile loading, and it was confirmed that the bond condition between rebar and concrete around cracks could be evaluated using the neutron diffraction technique.
Residual stresses in novel metal/ceramic composites exhibiting a lamellar microstructure
Authors: Roy Siddhartha , Gibmeier Jens , Wanner Alexander
Published: August 2009

The aim of this study is to analyze the mechanics of a new class of metal/ceramic composites on a mesoscopic length scale. These composites are produced by melt infiltration of porous ceramic preforms produced by freeze casting and subsequent sintering. This production route has a high application potential since it offers a cost-effective way to obtain composites with ceramic content in the 30 to 70 vol.%range. The as-produced material exhibits a hierarchical domain structure with each domain composed of alternating layers of metallic and ceramic lamellae. Residual stresses present in all phases of the composite produced by infiltrating alumina preforms with a eutectic aluminum-silicon alloy have been measured. Integral as well as spatially resolved measurements were carried out on single-domain samples at the high-energy, energy-dispersive diffraction (EDDI) beamline at the synchrotron radiation source BESSY (Berlin, Germany). Results show that strongly fluctuating residual stresses are introduced by the production process, which can be rationalized by taking into account the thermal expansion mismatch of alloy and preform.
Determination of residual stresses around blisters in Zr-2.5%Nb pressure tubes
Authors: Santisteban Javier R. , Steuwer Axel , Domizzi Gladys , Peel Matthew J.
Published: August 2009

We have used synchrotron X-ray diffraction experiments to measure the strain field introduced by a hydride blister grown on a section of a pressure tube from a CANDU nuclear reactor. After charging the tube section with a homogeneous hydrogen concentration of 300 wt ppm, the blister was produced by creating a small cold spot on its surface (∼200 °C), while the bulk was kept at a temperature of 338 °C over a period of 1008 h. The blister studied here is ellipsoidal in shape, with its long axis along the tube axial direction. The experiments were performed on the wiggler beam line ID15 at the European Synchrotron Radiation Facility (ESRF) using a polychromatic beam of high-energy X-rays (60 to 300 keV). Unlike conventional X-ray diffraction, in this mode the scattering angle is fixed and the diffracted beam is discriminated on the basis of the photon energy. The results show that the blister is composed by two crystallographic phases (δ-ZrH and α-Zr), with volume fractions varying with position. The maximum stresses appear at the blister-matrix interfaces. Near the tube outer surface, we found large compressive stresses of (−450±90) MPa along the blister long axis, and tensile stresses (+320±90) MPa along the tube hoop direction. The main uncertainty in these stresses results from the uncertainty in the elastic constants of the hydride phase. Large strains and broad peaks were observed for this phase, which were explained by a rather low Young’s modulus (35 GPa) for the hydride. The results are compared with finite element simulations found in the literature.
The extent of relaxation of weld residual stresses on cutting out cross-weld test-pieces
Authors: Altenkirch J. , Steuwer A. , Peel M. J. , Withers P. J.
Published: August 2009

Weld residual stress (RS) measurements are often undertaken on test-pieces which have been cut out from large components, yet it remains unclear to what extent the RSs in test-pieces are representative of those present in the original component. Similarly weld mechanical performance tests are frequently undertaken on cross-weld test-pieces without a proper understanding of the level or influence of retained RS. We present a systematic study of the relaxation of longitudinal RS in thin-plate butt welds produced using different materials and welding methods (FSW, laser-MIG, and pulsed-MIG). In each case the RSs were measured repeatedly in the same location as the welds were progressively and symmetrically cut down. Although cutting inevitably leads to stress redistribution, significant relaxation of the longitudinal RS was only observed when the weld length or width was reduced to below a certain value. This critical value appears to correlate with the lateral width of the tensile zone local to the weld-line and may be considered to be the characteristic length as defined in St. Venant’s principle. Further, it was found that the level of stress relaxation as a function of weld length for all the welds studied could be collapsed onto a single empirical curve using a simple approach based on the characteristic length scales of the weld. Given the range of materials and welding methods used, this relation appears to be of general use for thin-plate welds although further work is required to test the limits of its applicability.
Fracture Toughness of Vapor Grown Carbon Nanofiber‐Reinforced Polyethylene Composites
Authors: Adhikari A. R. , Partida E. , Petty T. W. , Jones R. , Lozano K. , Guerrero C.
Published: August 2009

The impact fracture behavior of a vapor grown carbon nanofiber (VGCNF) reinforced high‐density polyethylene (PE) composite was evaluated. The samples consisting of pure PE and composites with 10 wt% and 20 wt% of VGCNFs were prepared by a combination of hot‐pressing and extrusion methods. Extrusion was used to produce samples with substantially different shear histories. The fracture behavior of these samples was analyzed using the essential work of fracture (EWF) approach. The results showed an increase of 292% in the essential work of fracture for the loading of 10 wt%. Further increasing fiber loading to 20 wt% caused the essential work of fracture to increase only 193% with respect to the unmodified material. Evaluation of the fracture surface morphology indicated that the fibril frequency and microvoid size within the various fiber loadings depended strongly on processing conditions.
Inhibitory Effect of Flavonoids on the Efflux ofN‐Acetyl 5‐Aminosalicylic Acid Intracellularly Formed in Caco‐2 Cells
Authors: Shin Yoshimura , Kentaro Kawano , Ryusuke Matsumura , Narumi Sugihara , Koji Furuno
Published: August 2009

N‐acetyl 5‐aminosalicylic acid (5‐AcASA) that was intracellularly formed from 5‐aminosalicylic acid (5‐ASA) at 200 μM was discharged 5.3, 7.1, and 8.1‐fold higher into the apical site than into the basolateral site during 1, 2, and 4‐hour incubations, respectively, in Caco‐2 cells grown in Transwells. The addition of flavonols (100 μM) such as fisetin and quercetin with 5‐ASA remarkably decreased the apically directed efflux of 5‐AcASA. When 5‐ASA (200 μM) was added to Caco‐2 cells grown in tissue culture dishes, the formation of 5‐AcASA decreased, and, in addition, the formed 5‐AcASA was found to be accumulated within the cells in the presence of such flavonols. Thus, the decrease in 5‐AcASA efflux by such flavonols was attributed not only to the inhibition ofN‐acetyl‐conjugation of 5‐ASA but to the predominant cellular accumulation of 5‐AcASA. Various flavonoids also had both of the effects with potencies that depend on their specific structures. The essential structure of flavonoids was an absence of a hydroxyl substitution at the C5 position on the A‐ring of flavone structure for the inhibitory effect on theN‐acetyl‐conjugation of 5‐ASA, and a presence of hydroxyl substitutions at the C3′or C4′position on the B‐ring of flavone structure for the promoting effect on the cellular accumulation of 5‐AcASA. Both the decrease in 5‐AcASA apical efflux and the increase in 5‐AcASA cellular accumulation were also caused by MK571 and indomethacin, inhibitors of MRPs, but not by quinidine, cyclosporin A, P‐glycoprotein inhibitors, and mitoxantrone, a BCRP substrate. These results suggest that certain flavonoids suppress the apical efflux of 5‐AcASA possibly by inhibiting MRPs pumps located on apical membranes in Caco‐2 cells.
Memory with Memory in Genetic Programming
Authors: Poli Riccardo , McPhee Nicholas Freitag , Citi Luca , Crane Ellery
Published: August 2009

We introduce Memory with Memory Genetic Programming (MwM-GP), where
we use soft assignments and soft return operations. Instead of
having the new value completely overwrite the old value of registers
or memory, soft assignments combine such values. Similarly, in soft
return operations the value of a function node is a blend between
the result of a calculation and previously returned results.
In extensive empirical tests, MwM-GP almost always does as well as
traditional GP, while significantly outperforming it in several
cases. MwM-GP also tends to be far more consistent than traditional
GP. The data suggest that MwM-GP works by successively refining an
approximate solution to the target problem and that it is much less
likely to have truly ineffective code. MwM-GP can continue to
improve over time, but it is less likely to get the sort of
exact solution that one might find with traditional GP.
Underdominance, Multiscale Interactions, and Self-Organizing Barriers to Gene Flow
Authors: Eppstein Margaret J. , Payne Joshua L. , Goodnight Charles J.
Published: August 2009

Understanding mechanisms for the evolution of barriers to gene flow within interbreeding populations continues to be a topic of great interest among evolutionary theorists. In this work, simulated evolving diploid populations illustrate how mild underdominance (heterozygote disadvantage) can be easily introduced at multiple loci in interbreeding populations through simultaneous or sequential mutational events at individual loci, by means of directional selection and simple forms of epistasis (non-linear gene-gene interactions). It is then shown how multiscale interactions (within-locus, between-locus, and between-individual) can cause interbreeding populations with multiple underdominant loci to self-organize into clusters of compatible genotypes, in some circumstances resulting in the emergence of reproductively isolated species. If external barriers to gene flow are also present, these can have a stabilizing effect on cluster boundaries and help to maintain underdominant polymorphisms, even when homozygotes have differential fitness. It is concluded that multiscale interactions can potentially help to maintain underdominant polymorphisms and may contribute to speciation events.
Cell Type–Specific Targeted Mutations of Kras and Pten Document Proliferation Arrest in Granulosa Cells versus Oncogenic Insult to Ovarian Surface Epithelial Cells
Authors: Fan Heng-Yu , Liu Zhilin , Paquet Marilene , Wang Jinrong , Lydon John P. , DeMayo Francesco J. , Richards JoAnne S.
Published: August 2009

The small G-protein KRAS is crucial for mediating gonadotropin-induced events associated with ovulation. However, constitutive expression of KrasG12D in granulosa cells disrupted normal follicle development leading to the persistence of abnormal follicle-like structures containing nonmitotic cells. To determine what factors mediate this potent effect of KrasG12D, gene profiling analyses were done. We also analyzed KrasG12D;Cyp19-Cre and KrasG12;Pgr-Cre mutant mouse models that express Cre prior to or after the initiation of granulosa cell differentiation, respectively. KrasG12D induced cell cycle arrest in granulosa cells of the KrasG12D;Cyp19-Cre mice but not in the KrasG12D;Pgr-Cre mice, documenting the cell context–specific effect of KrasG12D. Expression of KrasG12D silenced the Kras gene, reduced cell cycle activator genes, and impaired the expression of granulosa cell and oocyte-specific genes. Conversely, levels of PTEN and phosphorylated p38 mitogen-activated protein kinase (MAPK) increased markedly in the mutant granulosa cells. Because disrupting Pten in granulosa cells leads to increased proliferation and survival, Pten was disrupted in the KrasG12D mutant mice. The Pten/Kras mutant mice were infertile but lacked granulosa cell tumors. By contrast, the Ptenfl/fl;KrasG12D;Amhr2-Cre mice developed aggressive ovarian surface epithelial cell tumors that did not occur in the Ptenfl/fl;KrasG12D;Cyp19-Cre or Ptenfl/fl;KrasG12D;Pgr-Cre mouse strains. These data document unequivocally that Amhr2-Cre is expressed in and mediates allelic recombination of oncogenic genes in ovarian surface epithelial cells. That KrasG12D/Pten mutant granulosa cells do not transform but rather undergo cell cycle arrest indicates that they resist the oncogenic insults of Kras/Pten by robust self-protecting mechanisms that silence the Kras gene and elevate PTEN and phosphorylated p38 MAPK. [Cancer Res 2009;69(16):6463–72]
The Dendritic Cell–like Functions of IFN-Producing Killer Dendritic Cells Reside in the CD11b+ Subset and Are Licensed by Tumor Cells
Authors: Terme Magali , Mignot Grégoire , Ullrich Evelyn , Bonmort Mathieu , Minard-Colin Véronique , Jacquet Alexandra , Schultze Joachim L. , Kroemer Guido , Leclerc Claude , Chaput Nathalie , Zitvogel Laurence
Published: August 2009

IFN producing killer dendritic cells (IKDC) were originally defined as CD11cint B220+NK1.1+ (or CD49b+) cells that exert a potent tumoricidal activity in animals lacking B, T, and conventional natural killer effectors. MHC class II expression on tumor infiltrating IKDC prompted us to investigate their putative antigen presenting function. Here, we show that tumor cells license IKDC to acquire the properties of antigen presenting cells, i.e., expression of MHC class II and costimulatory CD86 molecules. We show that the CD11b+ subset of IKDC are able to prime naïve CD4+ T cells and cross-prime naïve CD8+ T lymphocytes. Licensing of IKDC by tumor cells was mandatory for the full differentiation of T cells into polarized effectors. IKDC could engulf and process soluble Ova protein in a CD206-dependent manner. Finally, we show that CD11b+IKDC is selectively endowed with CTLA4Ig-inhibitable antigen presenting capacities and that targeting this subset with the detoxified adenylate cyclase toxin of Bordetella pertussis fused to antigen resulted in efficient cross-presentation of antigen by IKDC to specific TCR transgenic CD8+T cells in vivo. Collectively, our data indicate that upon exposure to tumor cells, IKDC subserve DC-like functions. [Cancer Res 2009;69(16):6590–7]
Premenopausal Mammographic Density in Relation to Cyclic Variations in Endogenous Sex Hormone Levels, Prolactin, and Insulin-like Growth Factors
Authors: Walker Kate , Fletcher Olivia , Johnson Nichola , Coupland Ben , McCormack Valerie A. , Folkerd Elizabeth , Gibson Lorna , Hillier Stephen G. , Holly Jeff M. , Moss Sue , Dowsett Mitchell , Peto Julian , dos Santos Silva Isabel
Published: August 2009

Mammographic density is strongly associated with breast cancer risk, and endogenous hormones, which are risk factors for breast cancer, may be involved in the mechanism. This cross-sectional study of 494 premenopausal women is the first to account for cyclic variations in estrogen levels, by measuring urinary estrone glucuronide (E1G) in the periovulatory and luteal phases of the menstrual cycle, and to assess the role of androgens. Computer-assisted density readings were obtained from digitized mammograms. Mean ovulatory E1G level and daily E1G load were both positively associated with percent density before adjustment for body mass index (BMI), with women in the top fourth having 10.2% (95% CI: 2.9%, 18.1%) and 8.9% (1.7%, 16.7%), respectively, higher density than those in the bottom fourth (Ptrend before/after BMI adjustment = 0.006/0.11 and 0.01/0.13, respectively). Neither the peak nor luteal E1G levels were predictive of density after adjustment for E1G levels at other points in the cycle. The plasma androgens testosterone, androstenedione, and dehydroepiandrosterone sulfate were negatively associated with density. In mutually adjusted analyses, density was positively associated with insulin-like growth factor (IGF)-I and negatively with IGF-II (Ptrend = 0.006 for both) but not with IGF binding protein-3. There was also weak evidence of a positive association of prolactin with density. The study supports the hypothesis that endogenous hormones affect density in premenopausal women; in particular, it shows a positive association between estrogen levels and density and suggests that the mean level throughout the cycle is the most biologically relevant measure. Most of these hormone-density associations were attenuated with further adjustment for BMI. [Cancer Res 2009;69(16):6490–99]
Overexpression of Protease-Activated Receptor-1 Contributes to Melanoma Metastasis via Regulation of Connexin 43
Authors: Villares Gabriel J. , Dobroff Andrey S. , Wang Hua , Zigler Maya , Melnikova Vladislava O. , Huang Li , Bar-Eli Menashe
Published: August 2009

Protease-activated receptor-1 (PAR-1) is a key player in melanoma metastasis with higher expression seen in metastatic melanoma cell lines and tissue specimens. cDNA microarray and Western blot analyses reveal that the gap junctional intracellular communication molecule connexin 43 (Cx-43), known to be involved in tumor cell diapedesis and attachment to endothelial cells, is significantly decreased after PAR-1 silencing in metastatic melanoma cell lines. Furthermore, Cx-43 promoter activity was significantly inhibited in PAR-1–silenced cells, suggesting that PAR-1 regulates Cx-43 at the transcriptional level. Chromatin immunoprecipitation studies showed a reduction in the binding of SP-1 and AP-1 transcription factors to the promoter of Cx-43. Both transcription factors have been shown previously to be required for maximal Cx-43 promoter activity. These results were corroborated by mutating the AP-1 and SP-1 binding sites resulting in decreased Cx-43 promoter activity in PAR-1–positive cells. Moreover, as Cx-43 has been shown to facilitate arrest of circulating tumor cells at the vascular endothelium, melanoma cell attachment to endothelial cells was significantly decreased in PAR-1–silenced cells, with this effect being abrogated after PAR-1 rescue. Herein, we report that up-regulation of PAR-1 expression, seen in melanoma progression, mediates high levels of Cx-43 expression. As both SP-1 and AP-1 transcription factors act as positive regulators of Cx-43, our data provide a novel mechanism for the regulation of Cx-43 expression by PAR-1. Indeed, Cx-43 expression was restored following PAR-1 rescue in PAR-1–silenced cells. Taken together, our data support the tumor promoting function of Cx-43 in melanoma. [Cancer Res 2009;69(16):6730–7]
The Decline in U.S. Cancer Mortality in People Born since 1925
Authors: Kort Eric J. , Paneth Nigel , Vande Woude George F.
Published: August 2009

The conventional practice of analyzing overall age-adjusted cancer mortality rates heavily emphasizes the experience of older, higher mortality age groups. This may conceal shifts in lifetime cancer mortality experience emerging first in younger age groups. We examined age-specific cancer mortality rates and birth cohort–specific cancer mortality rates in U.S. mortality data recorded since 1955 to assess the effects of age, period, and cohort in secular mortality trends. Cancer mortality and population data were obtained from WHO Statistical Information System. Age-specific cancer mortality rates have been steadily declining in the United States since the early 1950s, beginning with children and young adults and now including all age groups. During the second half of the 20th century, each successive decade of births from 1925 to 1995 experienced a lower risk of cancer death than its predecessor at virtually every age for which such a comparison can be made. A major decline in cancer mortality has been occurring in the United States for the past 50 years, affecting birth cohorts born as long as 80 years ago. Excepting lung cancer, much of this decline has occurred despite relatively stable cancer incidence. These findings suggest that improvements in cancer detection, treatment, and/or prevention have reduced the risk of cancer death across the life span for individuals born in the last three quarters of the 20th century. [Cancer Res 2009;69(16):6500–5]
IFN-Producing Killer Dendritic Cells Are Antigen-Presenting Cells Endowed with T-Cell Cross-Priming Capacity
Authors: Pletneva Maria , Fan Hongni , Park Jang-June , Radojcic Vedran , Jie Chunfa , Yu Yanxing , Chan Camie , Redwood Alec , Pardoll Drew , Housseau Franck
Published: August 2009

IFN-producing killer dendritic cells (IKDC) represent a recently discovered cell type in the immune system that possesses a number of functions contributing to innate and adaptive immunity, including production of type 1 and 2 IFNs, interleukin (IL)-12, natural killing, and ultimately antigen presentation to naïve T cells. Here, we compared in vitro and in vivo responses of mouse IKDC, conventional dendritic cells (DC), and natural killer (NK) cells to murine cytomegalovirus infection and found distinct functions among these cell subsets. Upon recognition of infected fibroblasts, IKDC, as well as NK, produced high level of IFN-γ, but unlike NK, IKDC simultaneously produced IL-12p40 and up-regulated MHC class II (MHC-II) and costimulatory molecules. Using MHC-II molecule expression as a phenotypic marker to distinguish activated IKDC from activated NK, we further showed that highly purified MHC-II+ IKDC but not NK cross-present MHC class I–restricted antigens derived from MCMV-infected targets to CD8+ T cells in vitro and in vivo. Our findings emphasize the unique nature of IKDC as a killer antigen-presenting cell directly linking innate and adaptive immunity. [Cancer Res 2009;69(16):6607–14]