bluuebunny/crossref_metadata_2025 huggingface dataset:
Cyclopentenone prostaglandin-induced unfolding and aggregation of the Parkinson disease-associated UCH-L1
Authors: Koharudin Leonardus M. I. , Liu Hao , Di Maio Roberto , Kodali Ravindra B. , Graham Steven H. , Gronenborn Angela M.
Published: March 2010

Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) has been implicated in Parkinson’s disease (PD) and is present in neurofibrillary tangles or Lewy bodies. However, the molecular basis for UCH-L1s involvement in proteinacious fibril formation is still elusive, especially in regard to the pathogenicity of the I93M mutation. Here we show that modification of UCH-L1 by cyclopentenone prostaglandins causes unfolding and aggregation. A single thiol group on Cys152 reacts with the α,β-unsaturated carbonyl center in the cyclopentenone ring of prostaglandins, resulting in a covalent adduct. We also show that the PD-associated I93M mutant of UCH-L1 is well-folded, structurally similar to the wild-type protein, and aggregates upon conjugation by cyclopentenone prostaglandins. Our findings suggest a possible mechanistic link between UCH-L1 modification by cyclopentenone prostaglandins and the etiology of neurodegeneration.
Joubert syndrome Arl13b functions at ciliary membranes and stabilizes protein transport in Caenorhabditis elegans
Authors: Cevik Sebiha , Hori Yuji , Kaplan Oktay I. , Kida Katarzyna , Toivenon Tiina , Foley-Fisher Christian , Cottell David , Katada Toshiaki , Kontani Kenji , Blacque Oliver E.
Published: March 2010

The small ciliary G protein Arl13b is required for cilium biogenesis and sonic hedgehog signaling and is mutated in patients with Joubert syndrome (JS). In this study, using Caenorhabditis elegans and mammalian cell culture systems, we investigated the poorly understood ciliary and molecular basis of Arl13b function. First, we show that Arl13b/ARL-13 localization is frequently restricted to a proximal ciliary compartment, where it associates with ciliary membranes via palmitoylation modification motifs. Next, we find that loss-of-function C. elegans arl-13 mutants possess defects in cilium morphology and ultrastructure, as well as defects in ciliary protein localization and transport; ciliary transmembrane proteins abnormally accumulate, PKD-2 ciliary abundance is elevated, and anterograde intraflagellar transport (IFT) is destabilized. Finally, we show that arl-13 interacts genetically with other ciliogenic and ciliary transport–associated genes in maintaining cilium structure/morphology and anterograde IFT stability. Together, these data implicate a role for JS-associated Arl13b at ciliary membranes, where it regulates ciliary transmembrane protein localizations and anterograde IFT assembly stability.
Loss of Aip1 reveals a role in maintaining the actin monomer pool and an in vivo oligomer assembly pathway
Authors: Okreglak Voytek , Drubin David G.
Published: March 2010

Although actin filaments can form by oligomer annealing in vitro, they are assumed to assemble exclusively from actin monomers in vivo. In this study, we show that a pool of actin resistant to the monomer-sequestering drug latrunculin A (lat A) contributes to filament assembly in vivo. Furthermore, we show that the cofilin accessory protein Aip1 is important for establishment of normal actin monomer concentration in cells and efficiently converts cofilin-generated actin filament disassembly products into monomers and short oligomers in vitro. Additionally, in aip1Δ mutant cells, lat A–insensitive actin assembly is significantly enhanced. We conclude that actin oligomer annealing is a physiologically relevant actin filament assembly pathway in vivo and identify Aip1 as a crucial factor for shifting the distribution of short actin oligomers toward monomers during disassembly.
Regulated targeting of protein phosphatase 1 to the outer kinetochore by KNL1 opposes Aurora B kinase
Authors: Liu Dan , Vleugel Mathijs , Backer Chelsea B. , Hori Tetsuya , Fukagawa Tatsuo , Cheeseman Iain M. , Lampson Michael A.
Published: March 2010

Regulated interactions between kinetochores and spindle microtubules are essential to maintain genomic stability during chromosome segregation. The Aurora B kinase phosphorylates kinetochore substrates to destabilize kinetochore–microtubule interactions and eliminate incorrect attachments. These substrates must be dephosphorylated to stabilize correct attachments, but how opposing kinase and phosphatase activities are coordinated at the kinetochore is unknown. Here, we demonstrate that a conserved motif in the kinetochore protein KNL1 directly interacts with and targets protein phosphatase 1 (PP1) to the outer kinetochore. PP1 recruitment by KNL1 is required to dephosphorylate Aurora B substrates at kinetochores and stabilize microtubule attachments. PP1 levels at kinetochores are regulated and inversely proportional to local Aurora B activity. Indeed, we demonstrate that phosphorylation of KNL1 by Aurora B disrupts the KNL1–PP1 interaction. In total, our results support a positive feedback mechanism by which Aurora B activity at kinetochores not only targets substrates directly, but also prevents localization of the opposing phosphatase.
Arginine methylation of the B cell antigen receptor promotes differentiation
Authors: Infantino Simona , Benz Beate , Waldmann Tanja , Jung Manfred , Schneider Robert , Reth Michael
Published: March 2010

Signals processed through the B cell antigen receptor (BCR) control both the proliferation and differentiation of B lymphocytes. How these different signaling modes are established at the BCR is poorly understood. We show that a conserved arginine in the tail sequence of the Igα subunit of the BCR is methylated by the protein arginine methyltransferase 1. This modification negatively regulates the calcium and PI-3 kinase pathways of the BCR while promoting signals leading to B cell differentiation. Thus, Igα arginine methylation can play an important role in specifying the outcome of BCR signaling.
Survival effect of PDGF-CC rescues neurons from apoptosis in both brain and retina by regulating GSK3β phosphorylation
Authors: Tang Zhongshu , Arjunan Pachiappan , Lee Chunsik , Li Yang , Kumar Anil , Hou Xu , Wang Bin , Wardega Piotr , Zhang Fan , Dong Lijin , Zhang Yongqing , Zhang Shi-Zhuang , Ding Hao , Fariss Robert N. , Becker Kevin G. , Lennartsson Johan , Nagai Nobuo , Cao Yihai , Li Xuri
Published: March 2010

Platelet-derived growth factor CC (PDGF-CC) is the third member of the PDGF family discovered after more than two decades of studies on the original members of the family, PDGF-AA and PDGF-BB. The biological function of PDGF-CC remains largely to be explored. We report a novel finding that PDGF-CC is a potent neuroprotective factor that acts by modulating glycogen synthase kinase 3β (GSK3β) activity. In several different animal models of neuronal injury, such as axotomy-induced neuronal death, neurotoxin-induced neuronal injury, 6-hydroxydopamine–induced Parkinson’s dopaminergic neuronal death, and ischemia-induced stroke, PDGF-CC protein or gene delivery protected different types of neurons from apoptosis in both the retina and brain. On the other hand, loss-of-function assays using PDGF-C null mice, neutralizing antibody, or short hairpin RNA showed that PDGF-CC deficiency/inhibition exacerbated neuronal death in different neuronal tissues in vivo. Mechanistically, we revealed that the neuroprotective effect of PDGF-CC was achieved by regulating GSK3β phosphorylation and expression. Our data demonstrate that PDGF-CC is critically required for neuronal survival and may potentially be used to treat neurodegenerative diseases. Inhibition of the PDGF-CC–PDGF receptor pathway for different clinical purposes should be conducted with caution to preserve normal neuronal functions.
Glycolytic oscillations in single ischemic cardiomyocytes at near anoxia
Authors: Ganitkevich Vladimir , Mattea Violeta , Benndorf Klaus
Published: March 2010

Previous studies have shown that oscillations of the metabolism can occur in cardiomyocytes under conditions simulating ischemia/reperfusion. It is not known whether they can also occur during real ischemia with near-anoxic oxygen tension. Here, using oxygen clamp in on-chip picochambers, we exposed single resting cardiomyocytes to near anoxia (pO2 < 0.1 mm Hg). We show that at near anoxia, the mitochondrial membrane potential (ΔΨ) was kept by the F1F0-ATPase reversal, using glycolytic adenosine triphosphate (ATP). In many cells, activation of current through sarcolemmal KATP channels (IKATP) started after a delay with one or several oscillations (frequency of 0.044 ± 0.002 Hz). These oscillations were time correlated with oscillations of ΔΨ. Metabolic oscillations at near anoxia are driven by glycolysis because (a) they were inhibited when glycolysis was blocked, (b) they persisted in cells treated with cytoplasmic reactive oxygen species scavengers, and (c) the highest rate of ATP synthesis during an oscillation cycle was associated with the generation of reducing equivalents. Glycolytic oscillations could be initiated upon rapid, but not slow, transition to near anoxia, indicating that the speed of ATP/ADP ratio drop is a determinant of their occurrence. At enhanced oxidative stress, the rate of ATP consumption was increased as indicated by rapid IKATP activation with large-scale oscillations. These results show that metabolic oscillations occur in cardiomyocytes at near anoxia and are driven by glycolysis and modulated by mitochondria through the rate of ATP hydrolysis, which, in turn, can be accelerated by oxidative stress.
P2X4 receptors in activated C8-B4 cells of cerebellar microglial origin
Authors: Toulme Estelle , Garcia Angie , Samways Damien , Egan Terrance M. , Carson Monica J. , Khakh Baljit S.
Published: March 2010

We investigated the properties and regulation of P2X receptors in immortalized C8-B4 cells of cerebellar microglial origin. Resting C8-B4 cells expressed virtually no functional P2X receptors, but largely increased functional expression of P2X4 receptors within 2–6 h of entering the activated state. Using real-time polymerase chain reaction, we found that P2X4 transcripts were increased during the activated state by 2.4-fold, but this increase was not reflected by a parallel increase in total P2X4 proteins. In resting C8-B4 cells, P2X4 subunits were mainly localized within intracellular compartments, including lysosomes. We found that cell surface P2X4 receptor levels increased by ∼3.5-fold during the activated state. This change was accompanied by a decrease in the lysosomal pool of P2X4 proteins. We next exploited our findings with C8-B4 cells to investigate the mechanism by which antidepressants reduce P2X4 responses. We found little evidence to suggest that several antidepressants were antagonists of P2X4 receptors in C8-B4 cells. However, we found that moderate concentrations of the same antidepressants reduced P2X4 responses in activated microglia by affecting lysosomal function, which indirectly reduced cell surface P2X4 levels. In summary, our data suggest that activated C8-B4 cells express P2X4 receptors when the membrane insertion of these proteins by lysosomal secretion exceeds their removal, and that antidepressants indirectly reduce P2X4 responses by interfering with lysosomal trafficking.
Universal prediction of intramolecular hydrogen bonds in organic crystals
Authors: Galek Peter T. A. , Fábián László , Allen Frank H.
Published: March 2010

A complete exploration of intramolecular hydrogen bonds (IHBs) has been undertaken using a combination of statistical analyses of the Cambridge Structural Database and computation ofab initiointeraction energies for prototypical hydrogen-bonded fragments. Notable correlations have been revealed between computed energies, hydrogen-bond geometries, donor and acceptor chemistry, and frequencies of occurrence. Significantly, we find that 95% of all observed IHBs correspond to the five-, six- or seven-membered rings. Our method to predict a propensity for hydrogen-bond occurrence in a crystal has been adapted for such IHBs, applying topological and chemical descriptors derived from our findings. In contrast to intermolecular hydrogen bonding, it is found that IHBs can be predicted across the complete chemical landscape from a single optimized probability model, which is presented. Predictivity of 85% has been obtained for generic organic structures, which can exceed 90% for discrete classes of IHB.
L-2-Aminobutyric acid: two fully ordered polymorphs withZ′ = 4
Authors: Görbitz Carl Henrik
Published: March 2010

The crystal structure of L-2-aminobutyric acid, an L-alanine analogue with an ethyl rather than a methyl side chain, has proved elusive owing to problems growing diffraction quality crystals. Good diffraction data have now been obtained for two polymorphs, in space groupsP21andI2, revealing surprisingly complex, yet fully ordered crystalline arrangements withZ′ = 4. The closely related structures are divided into hydrophilic and hydrophobic layers, the latter being the thinnest ever found for an amino acid (other than α-glycine). The hydrophobic layers furthermore contain conspicuous pseudo-centers-of-symmetry, leading to overall centrosymmetric intensity statistics. Uniquely, the four molecules in the asymmetric unit can be divided into two pairs that each forms an independent hydrogen-bond network.
More examples of the 15-crown-5...H2O—M—OH2...15-crown-5 motif, M = Al3+, Cr3+ and Pd2+
Authors: Siegler Maxime A. , Prewitt Jacob H. , Kelley Steven P. , Parkin Sean , Selegue John P. , Brock Carolyn Pratt
Published: March 2010

Five structures of co-crystals grown from aqueous solutions equimolar in 15-crown-5 (or 15C5) and [M(H2O)6](NO3)
n
, M = Al3+, Cr3+ and Pd2+, are reported. The hydrogen-bonding patterns in all are similar: metal complexes including the fragment trans-H2O—M—OH2 alternate with 15C5 molecules, to which they are hydrogen bonded, to form stacks. A literature survey shows that this hydrogen-bonding pattern is very common. In each of the two polymorphs of the compound [Al(H2O)6](NO3)3·15C5·4H2O there are two independent cations; one forms hydrogen bonds directly to the 15C5 molecules adjacent in the stack, while the other cation is hydrogen-bonded to two water molecules that act as spacers in the stack. These stacks are then crosslinked by hydrogen bonds formed by the three nitrate counterions and the three lattice water molecules. The hydrogen-bonded stacks in [Cr(H2O)5(NO3)](NO3)2·1.5(15C5)·H2O are discrete rather than infinite; each unit contains two Cr3+ complex cations and three 15C5 molecules. These units are again crosslinked by the uncoordinated nitrate ions and a lattice water molecule. In [Pd(H2O)2(NO3)2]·15C5 the infinite stacks are electrically neutral and are not crosslinked. In [Pd(H2O)2(NO3)2]·2(15C5)·2H2O·2HNO3 a discrete, uncharged unit containing one Pd complex and two 15C5 molecules is `capped off' at either end by a lattice water molecule and an included nitric acid molecule. In all five structures the infinite stacks or discrete units form an array that is at least approximately hexagonal.
Effect of Polymer Crystallinity on Morphology in Ceramic Injection Molding
Authors: Krug Steffen , Evans Julian R. G. , Ter Maat Johan H. H.
Published: March 2010

Many ceramic injection molding vehicles include semicrystalline polymers which characteristically adopt a spherulitic growth morphology. Usually the spherulites are rendered invisible by the opacity of the ceramic powder but in this study they are clearly visible. Polyoxymethylene (POM), has been used as the vehicle. The growth of the spherulites is shown to be dependent on cooling rate and hence on position in the molding. Furthermore, migration of low molecular weight additives by syneresis is shown to occur and to influence the crack path in the as‐molded state. An unusual composite fractograph is shown in which fracture faces made after molding, after binder removal, and after sintering are contiguous. Only after molding does the crack path follow the spherulite boundaries; behavior that is also widely reported for unfilled POM.
Cosintering Simulation and Experimentation: Case Study of Nanocrystalline Zirconia
Authors: Kanters Johannes , Eisele Ulrich , Rödel Jürgen
Published: March 2010

Laminates consisting of two different nanocrystalline zirconia materials (undoped and 3Y‐TZP doped) were sintered, and their densification and curvature were quantified using optical dilatometry. The experimental results agreed well with a continuum‐mechanical description for the cosintering of laminates with diffusion coefficients and activation energies determined using densification of the free‐sintering materials. The comparison covered various relative layer thicknesses and heating rates, but was developed only for the intermediate and late stages of sintering. Sintering stresses and compatibility stresses also were determined from the model.
Alumina/NiCu Laminate under Thermal Shock up to 1000°C: II, Prediction of the Laminate Behavior
Authors: Sherman Dov
Published: March 2010

In this investigation, a multilayered, multimaterial system with strong interface subjected to thermal shock loading was analyzed. The analysis was based on a one‐dimensional spatio‐temporal finite difference scheme of the temperature field, and the thermal residual stresses and zero misfit stress temperature were considered. Using a failure criterion based on crack initiation, the number of broken layers due to thermal shock and residual mechanical strength at room temperature could be predicted. Furthermore, the room temperature residual strength of the laminate as a function of thermal shock temperature was constructed, demonstrating steplike behavior. Using this model, the mechanical behavior of the alumina/NiCu laminate system subjected to thermal shock loading of up to 1000°C was predicted. The model revealed the superiority of this material system over monolithic ceramics under thermal shock conditions.
Growth of Tetragonal Zirconia Coatings by Reactive Sputter Deposition
Authors: Ji Zhiqiang , Rigsbee J. M.
Published: March 2010

Zirconia coatings were produced by reactive dc magnetron sputter deposition, using a system with multiple sputter sources and a biased substrate stage. Tetragonal zirconia with either a random orientation or a highly (111) preferred orientation was formed by applying a substrate bias. Coating grown with no substrate bias had the equilibrium monoclinic structure. X‐ray diffraction and transmission electron microscopy analyses revealed that bias sputtering could effectively decrease crystalline size in the as‐deposited coating, which resulted in room‐temperature stabilization of the tetragonal phase. The fraction of tetragonal phase, the desired phase for transformation‐toughening behavior, was strongly dependent on the substrate bias and post‐deposition annealing temperature.
Translucent Polycrystalline Alumina with Improved Resistance to Sodium Attack
Authors: Wei George C. , Hecker Arlene , Goodman David A.
Published: March 2010

Reaction of sodium with polycrystalline alumina (PCA) arc tubes in high‐pressure sodium lamps can limit lamp performance. The rate of degradation depends on the grain‐boundary diffusion of a reaction product, aluminum, through the PCA wall. The effects of sintering aids and other dopants on the sodium resistance of PCA are investigated via accelerated lamp tests and microstructural analyses. Key material parameters for sodium resistance are the spinel (MgAl2O4) second phase and the grain‐boundary MgO level. Eliminating spinel in the sintered body, doping with tetravalent cations to charge‐compensate the Mg2+ solutes, and creating a second phase to absorb MgO in situ, significantly improve the resistance of PCA to sodium attack.
Processing and Properties of Strontium Bismuth Vanadate Niobate Ferroelectric Ceramics
Authors: Wu Yun , Nguyen Chau , Seraji Seana , Forbess Mike J. , Limmer Steven J. , Chou Tammy , Cao Guozhong
Published: March 2010

The processing conditions, microstructure, and dielectric properties of strontium bismuth niobate vanadate ceramics, SrBi2(VxNb1−x)2O9(SBVN, with 0 ≤x≤ 0.3), were systematically studied. A relative density of >90% was obtained for all the samples using a two‐step sintering process. XRD showed that a single phase with the layered perovskite structure of SrBi2Nb2O9(SBN) was formed with a vanadium content of up to 30 at.%. SEM revealed that the average grain size decreased gradually with an increase in vanadium content. The Curie point was found to gradually increase from ∼418°C for SBN to ∼459°C for SBVN with 30 at.% vanadium. Dielectric constants at room temperature and their respective Curie points were found to peak at a composition with 10–15 at.%; vanadium. Moreover, a high concentration of vanadium (>5 at.%) resulted in a significant increase in tangent loss at low frequencies (<1000 Hz). The relationships between chemical composition, processing condition, microstructure, and dielectric properties of SBVN ferroelectric ceramics are discussed.
Conductivity Measurement Using Four Linear Electrodes Embedded Inside a Rectangular Sample
Authors: Riess Ilan , Rutman Jeremy , Rosenstock Zvi
Published: March 2010

Using solid materials prepared by melting or sintering allows inert metal electrodes to be embedded inside the solid. The I–V relations for four linear electrodes embedded inside a rectangular sample are evaluated. Two cases are considered: (a) a sample with uniform electronic (electron/hole) conductivity and (b) the electron/hole partial current in a sample that is a mixed ionic‐electronic conductor with a nonuniform electron/hole distribution. Equations are derived which allow the determination of the conductivity from four‐electrode measurements if a pure electronic conductor is considered or if a mixed ionic‐electronic conductor is considered with the ionic current being blocked.
Effect of the Magnetostrictive Layer on Magnetoelectric Properties in Lead Zirconate Titanate/Terfenol‐D Laminate Composites
Authors: Ryu Jungho , Priya Shashank , Carazo Alfredo Vázquez , Uchino Kenji , Kim Hyoun‐Ee
Published: March 2010

Magnetoelectric laminate composites of piezoelectric/magnetostrictive materials were prepared by stacking and bonding together a PZT disk and two layers of Terfenol‐D disks with different directions of magnetostriction. These composites were studied to investigate (i) dependence on the magnetostriction direction of the Terfenol‐D disk and (ii) dependence on the direction of the applied ac magnetic field. Three different types of assemblies were prepared by using two types of disks: one with magnetostriction along the radial direction, the other with magnetostriction along the thickness direction. The maximum magnetoelectric voltage coefficient (dE/dH) of 5.90 V/cm·Oe was obtained for a design where the composite was made by two Terfenol‐D layers with a radial magnetostriction direction.
Cyclic Fatigue‐Crack Growth and Fracture Properties in Ti3SiC2 Ceramics at Elevated Temperatures
Authors: Chen Da , Shirato Kiroshi , Barsoum Michel W. , El‐Raghy Tamer , Ritchie Robert O.
Published: March 2010

The cyclic fatigue and fracture toughness behavior of reactive hot‐pressed Ti3SiC2 ceramics was examined at temperatures from ambient to 1200°C with the objective of characterizing the high‐temperature mechanisms controlling crack growth. Comparisons were made of two monolithic Ti3SiC2 materials with fine‐ (3–10 μm) and coarse‐grained (70–300 μm) microstructures. Results indicate that fracture toughness values, derived from rising resistance‐curve behavior, were significantly higher in the coarser‐grained microstructure at both low and high temperatures; comparative behavior was seen under cyclic fatigue loading. In each microstructure, ΔKth fatigue thresholds were found to be essentially unchanged between 25° and 1100°C; however, there was a sharp decrease in ΔKth at 1200°C (above the plastic‐to‐brittle transition temperature), where significant high‐temperature deformation and damage are first apparent. The substantially higher cyclic‐crack growth resistance of the coarse‐grained Ti3SiC2 microstructure was associated with extensive crack bridging behind the crack tip and a consequent tortuous crack path. The crack‐tip shielding was found to result from both the bridging of entire grains and from deformation kinking and bridging of microlamellae within grains, the latter forming by delamination along the basal planes.
Distributed Porosity as a Control Parameter for Oxide Thermal Barriers Made by Physical Vapor Deposition
Authors: Lu Tian Jian , Levi Carlos G. , Wadley Haydn N. G. , Evans Anthony G.
Published: March 2010

Thermal barrier coatings (TBCs) made by electron‐beam physical vapor deposition (EB‐PVD) exhibit a thermal conductivity strongly affected by a hierarchy of pores introduced during the deposition process. These pores are in the form of narrow gaps, aligned spheroids, and random spheres at specific sites within the coatings. Models for the effects on thermal conductivity of pores having these shapes and spatial arrangements are taken from the literature and combined with new results to provide descriptors of overall relationships between the relative density and pore morphology of a coating and its thermal conductivity. Correlations between conductivity and elastic modulus are also explored as a means for determining the viability of modulus measurements as a simple‐to‐use conductivity probe. For the types of pore commonly found in EB‐PVD TBCs, there appears to be a tight correlation at typical porosity levels.
Residual Stresses in Alumina/Zirconia Composites: Effect of Cooling Rate and Grain Size
Authors: Merlani Enrico , Schmid Chiara , Sergo Valter
Published: March 2010

Alumina/zirconia composites with various compositions at the zirconia‐rich part of the phase diagram have been prepared with various grain sizes of the starting alumina powders. After firing under identical conditions, the pellets have been cooled systematically, changing the cooling rates from 0.5 to 8000 K/min. Subsequently, the residual stresses in alumina have been determined by monitoring the frequency shifts of the R2 luminescence line of alumina (14 430 cm−1). The data indicate that the stress in alumina is compressive in all cases, with increasing absolute values of the stress with decreasing alumina content. Within the same composition, the residual stress as a function of the cooling rate presents a minimum for values between 10 and 100 K/min, with no clear dependence on the alumina or zirconia grain size. An interpretation of the experimental data in terms of a Coble‐type diffusional relaxation applies for intermediate cooling rates (from 10 to 800 K/min), but it fails to account for the large stresses at low cooling rates. The width of the stress distribution is narrow (∼150 MPa) and constant for all compositions and grain sizes at low cooling rates, but it increases for cooling rates >10 K/min, depending on the grain size but not on the composition. For fast cooling rates, a correlation is found when reporting the average width of the stress distribution as function of the average sintered grain‐size distribution of alumina. Overall, zirconia grain size seems to influence the average stress, whereas alumina grain size determines the stress distribution.
Apatite‐Forming Ability of Sodium‐Containing Titania Gels in a Simulated Body Fluid
Authors: Uchida Masaki , Kim Hyun‐Min , Kokubo Tadashi , Nakamura Takashi
Published: March 2010

An essential condition for an artificial material to bond to living bone is the formation of bonelike apatite on its surface in the living body. The bonelike apatite can be reproduced on the bone‐bonding material even in an acellular simulated body fluid (SBF) with ion concentrations almost equal to those of human blood plasma. In the present study, the dependence of the apatite‐forming abilities of sodium‐containing titania gels in a SBF on composition and structure is examined. The sodium‐containing titania gels are model substances produced on the surface layer of bioactive titanium metal prepared by sodium hydroxide solution and heat treatments. When sodium‐containing titania gels are immersed in the SBF, Na+ ions incorporated in the gels are exchanged with the H3O+ ions in the SBF. This ion exchange causes an accompanying increase in the pH of the SBF and increases its ionic activity product, thus providing favorable conditions for apatite nucleation on the surfaces of the gels. Nevertheless, sodium‐containing titania gels that do not contain anatase do not form apatite on their surfaces. Independent of the composition, the gels form apatite on their surfaces in the SBF, specifically when they contain anatase. These results imply that the Ti‐OH groups on titania, which have been proposed to be responsible for the apatite formation, are effective for apatite nucleation when they are arranged in a specific structural unit based on the anatase structure.
Synthesis of Nanocrystalline Titanium Nitride Powders by Direct Nitridation of Titanium Oxide
Authors: Li Jingguo , Gao Lian , Sun Jing , Zhang Qinghong , Guo Jingkun , Yan Dongsheng
Published: March 2010

Nanocrystalline TiN powder has been synthesized by the direct nitridation of nanocrystalline TiO2 powder. Powder XRD patterns indicated that the TiN nanocrystalline powder could be obtained by nitridation at 800°C for 5 h. TEM micrographs showed that the synthesized TiN powders consisted of uniform spherical particles with an average diameter of ∼20 nm. The effect of the nitridation temperature and holding time on the powder properties is discussed.
Preparation of Dense Lead Magnesium Niobate–Lead Titanate (Pb(Mg1/3Nb2/3)O3–PbTiO3) Ceramics by Spark Plasma Sintering
Authors: Park Jong‐Keuk , Chung Ui‐Jin , Hwang Nong M. , Kim Doh‐Yeon
Published: March 2010

The effect of spark plasma sintering (SPS) on the densification behavior of Pb(Mg1/3Nb2/3)O3–PbTiO3 ceramics has been investigated. Specimens with a density of >99% of the theoretical density (TD) were obtained using SPS treatment at 900°C. Through normal sintering at 1200°C, however, the density of the specimen was only ∼92% of TD.
Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus
Authors: Cairo Mitchell S. , Coiffier Bertrand , Reiter Alfred , Younes Anas ,   on behalf of the TLS Expert Panel
Published: March 2010

Tumour lysis syndrome (TLS) is a life‐threatening oncological emergency characterized by metabolic abnormalities including hyperuricaemia, hyperphosphataemia, hyperkalaemia and hypocalcaemia. These metabolic complications predispose the cancer patient to clinical toxicities including renal insufficiency, cardiac arrhythmias, seizures, neurological complications and potentially sudden death. With the increased availability of newer therapeutic targeted agents, such as rasburicase (recombinant urate oxidase), there are no published guidelines on the risk classification of TLS for individual patients at risk of developing this syndrome. We convened an international TLS expert consensus panel to develop guidelines for a medical decision tree to assign low, intermediate and high risk to patients with cancer at risk for TLS. Risk factors included biological evidence of laboratory TLS (LTLS), proliferation, bulk and stage of malignant tumour and renal impairment and/or involvement at the time of TLS diagnosis. An international TLS consensus expert panel of paediatric and adult oncologists, experts in TLS pathophysiology and experts in TLS prophylaxis and management, developed a final model of low, intermediate and high risk TLS classification and associated TLS prophylaxis recommendations.
Systematic review of the addition of vincristine plus steroid pulses in maintenance treatment for childhood acute lymphoblastic leukaemia – an individual patient data meta‐analysis involving 5659 children
Authors:   Childhood Acute Lymphoblastic Leukaemia Collaborative Group (CALLCG)
Published: March 2010

Vincristine plus steroid pulses have long been a part of maintenance treatment in many protocols for childhood acute lymphoblastic leukaemia (ALL). A collaborative individual patient data meta‐analysis of all randomised trials of the addition of vincristine plus prednisone/prednisolone (VP) pulses in childhood ALL was updated and extended to include trials comparing vincristine plus dexamethasone (VD) pulses to maintenance without pulses. VP pulses improved event‐free survival (EFS) (70·1% vs. 62·0% at 5 years; odds ratio (OR) = 0·71; 95% confidence interval (CI) = 0·61–0·84; P = 0·00004); VD pulses did not have a significant effect (80·9% vs. 79·9% 5 year EFS; OR = 0·94; 95% CI = 0·80–1·11; P = 0·5). Heterogeneity between groups (VP or VD) was significant (P = 0·02). Neither treatment clearly affected overall survival. The difference between the VP and VD results is probably due to the greater early intensity of the backbone of the VD trial protocols and improved outcome seen in the VD trials, which were more recent. Pulses may still be useful in cases where less intensive early therapy is used and the balance between these treatments in terms of both effectiveness and toxicity needs to be considered.
Modelling of landscape variables at multiple extents to predict fine sediments and suitable habitat for Tubifex tubifex in a stream system
Authors: ANLAUF KARA J. , MOFFITT CHRISTINE M.
Published: March 2010

1. Aggregations of fine sediments are a suitable proxy for the presence and abundance of Tubifex tubifex, one of the obligate hosts in the parasitic life cycle that causes salmonid whirling disease (Myxobolus cerebralis).

2. To determine and evaluate practical approaches to predict fine sediments (<2 mm diameter) that could support Tubifex spp. aggregations, we measured habitat features in a catchment with field measures and metrics derived from digital data sets and geospatial tools at three different spatial extents (m2) within a hierarchical structure.

3. We used linear mixed models to test plausible candidate models that best explained the presence of fine sediments measured in stream surveys with metrics from several spatial extents.

4. The percent slow water habitat measured at the finest extent provided the best model to predict the likely presence of fine sediments. The most influential models to predict fine sediments using landscape metrics measured at broader extents included variables that measure the percentage land cover in conifer or agriculture, specifically, decreases in conifer cover and increases in agriculture.

5. The overall best‐fitting model of the presence of fine sediments in a stream reach combined variables measured and operating at different spatial extents.

6. Landscape features modelled within a hierarchical framework may be useful tools to evaluate and prioritise areas with fine sediments that may be at risk of infection by Myxobolus cerebralis.
Role of N‐end rule ubiquitin ligases UBR1 and UBR2 in regulating the leucine‐mTOR signaling pathway
Authors: Kume Kanako , Iizumi Yosuke , Shimada Masashi , Ito Yuki , Kishi Tsutomu , Yamaguchi Yuki , Handa Hiroshi
Published: March 2010

Of 20 natural amino acids, leucine is particularly important for promoting cellular protein synthesis. The effect of leucine involves mammalian target of rapamycin (mTOR), a key protein kinase controlling cell growth. Leucine enhances mTOR‐mediated phosphorylation of S6K1 and 4E‐BP, thereby promoting protein synthesis. However, how the presence of leucine is sensed and transmitted to mTOR is poorly understood. Here, we show evidence that UBR1 and UBR2 might be cellular targets of leucine. UBR1 and UBR2 are E3 ubiquitin ligases that recognize the identity of N‐terminal residues and contribute to selective destabilization of target proteins according to the N‐end rule. Using leucine‐immobilized affinity beads, we identified UBR1 and UBR2 as leucine‐binding proteins from leucine‐responsive rat hepatoma H4IIE cells. Over‐expression of UBR1 or UBR2 resulted in a reduction in mTOR‐dependent S6K1 phosphorylation, whereas knockdown of UBR1 or UBR2 increased S6K1 phosphorylation in amino acid‐starved human 293T cells. We also found that leucine binds to the substrate‐recognition domain of UBR2 and inhibits degradation of N‐end rule substrates in vitro. These findings suggest that UBR1 and UBR2 are negative regulators of the leucine‐mTOR signaling pathway. Leucine might activate this pathway in part through inhibition of their ubiquitin ligase activity.
Balance dysfunction in adults with haemophilia
Authors: FEARN M. , HILL K. , WILLIAMS S. , MUDGE L. , WALSH C. , McCARTHY P. , WALSH M. , STREET A.
Published: March 2010

Summary.  The main focus of lower limb physical performance assessment in people with haemophilia (PWH) has usually been on function, muscle strength and joint flexibility. The impact of haemophilic arthropathy on balance and falls risk is relatively under‐explored. The aim of this study was to evaluate balance and related performance in PWH compared with age and gender matched healthy controls. It involved a comprehensive suite of clinical and laboratory measures of static and dynamic balance, mobility, strength, physical activity and falls efficacy completed in 20 PWH (mean age 39.4, 100% male) and 20 controls. Fifty percent of PWH reported falls in the past 12 months. Moderate impairment of balance and related measures were identified in PWH compared with the controls, with an average 35% difference between groups. Significant differences were evident between groups on both clinical and laboratory measures, including measures of dynamic bilateral stance balance [limits of stability measures on the laboratory test, functional reach; (P < 0.001); dynamic single leg balance (Step Test, P < 0.001)], gait and mobility (gait speed, step width and turning measures on the laboratory test, timed up and go test; P < 0.001); muscle strength (timed sit to stand, P = 0.002; quadriceps strength, P < 0.001); and activity level and falls efficacy, (P < 0.004). The dynamic clinical and laboratory measures testing similar domains of balance, gait and mobility had moderate correlations (0.310 < r < 0.531, P < 0.01). Moderate impairments in balance, mobility and related measures were identified in PWH, compared with the control group. Clinicians should include assessments of balance and related measures when reviewing adults with haemophilia.
Increased expression of HMGA1 correlates with tumour invasiveness and proliferation in human pituitary adenomas
Authors: Wang Elaine Lu , Qian Zhi Rong , Rahman Md Mustafizur , Yoshimoto Katsuhiko , Yamada Shozo , Kudo Eiji , Sano Toshiaki
Published: March 2010

Wang E L, Qian Z R, Rahman M M, Yoshimoto K, Yamada S, Kudo E & Sano T  (2010) Histopathology56, 501–509

Increased expression of HMGA1 correlates with tumour invasiveness and proliferation in human pituitary adenomas

Aims:  High‐mobility group A1 (HMGA1) is highly expressed in various benign and malignant tumours. The development of pituitary adenoma in Hmga1 transgenic mice has been reported. However, no studies have investigated HMGA1 expression and its clinical significance in human pituitary adenomas.

Methods and results:  Immunohistochemical expression of HMGA1 was analysed with respect to various clinicopathological factors in 95 pituitary adenomas. Nuclear expression of HMGA1 was observed in 62% of pituitary adenomas, whereas normal adenohypophysial tissues were negative. Although HMGA1 expression was frequently detected in clinically non‐functioning adenomas – 90% of silent adrenocorticotropic hormone (ACTH), 76.2% of follicle‐stimulating hormone/luteinizing hormone and 100% of null cell adenomas – it was also detected in 48.1% of growth hormone (GH), 60% of mixed GH/prolactin (PRL), 62.5% of PRL, 66.6% of thyroid‐stimulating hormone and 37.5% of ACTH adenomas. HMGA1 expression was significantly higher in invasive adenomas or macroadenomas than in non‐invasive adenomas or microadenomas (invasive versus non‐invasive, P < 0.05; macroadenoma versus microadenoma, P < 0.05). In addition, HMGA1 showed the highest level in grade IV, more aggressive pituitary adenomas, than in grades I, II and III (IV versus I, P = 0.01; IV versus II, P = 0.01; IV versus III, P = 0.07). Furthermore, a significant correlation between HMGA1 expression and MIB‐1 labelling index was observed (R = 0.368, P < 0.0002).

Conclusions:  These findings suggest that HMGA1 up‐regulation has an important oncogenic role in pituitary tumorigenesis, as well as being a novel molecular marker of tumour proliferation and invasiveness.
Expression of L1CAM, COX‐2, EGFR, c‐KIT and Her2/neu in anaplastic pancreatic cancer: putative therapeutic targets?
Authors: Bergmann Frank , Moldenhauer Gerhard , Herpel Esther , Gaida Matthias M , Strobel Oliver , Werner Jens , Esposito Irene , Müerköster Susanne Sebens , Schirmacher Peter , Kern Michael A
Published: March 2010

Bergmann F, Moldenhauer G, Herpel E, Gaida M M, Strobel O, Werner J, Esposito I, Sebens Müerköster S, Schirmacher P & Kern M A (2010) Histopathology56, 440–448 Expression of L1CAM, COX‐2, EGFR, c‐KIT and Her2/neu in anaplastic pancreatic cancer: putative therapeutic targets?

Aims:  Undifferentiated (anaplastic) pancreatic cancer and undifferentiated pancreatic carcinoma with osteoclast‐like giant cells (giant cell tumour) are rare variants of pancreatic ductal adenocarcinoma. Representing biologically highly aggressive neoplasms, they are frequently diagnosed at an advanced stage. The response to established chemo‐ or radiochemotherapeutic treatment regimens is poor, and undifferentiated pancreatic cancer generally has a dismal prognosis. As additional therapeutic options have not yet been investigated in undifferentiated pancreatic cancer, the aim was to analyse the expression of putative therapeutic targets that have shown promising results in various other neoplasms.

Methods and results:  Fifteen cases of undifferentiated pancreatic cancer (seven containing osteoclast‐like giant cells) were investigated clinicopathologically and immunohistochemically for putative therapeutic targets. Whereas L1CAM, cyclooxygenase (COX)‐2 and epidermal growth factor receptor (EGFR) were found to be significantly expressed in 80%, 93% and 87% of the investigated tumours, respectively, there was no substantial expression of c‐kit (CD117) and there was no detectable expression of Her2/neu.

Conclusions:  The expression of L1CAM, COX‐2 and EGFR in the majority of undifferentiated pancreatic carcinomas suggests that they might represent targets for adjuvant therapy in anaplastic pancreatic cancer. On the other hand, c‐kit and Her2/neu seem to have no relevance for the therapy of these tumours.
Physiological hepatic nuclear vacuolation—how long does it persist?
Authors: Levene Adam P , Goldin Robert D
Published: March 2010

Levene A P & Goldin R D (2010) Histopathology56, 426–429 Physiological hepatic nuclear vacuolation—how long does it persist?

Aims:  Nuclear vacuolation\glycogenation is a characteristic histological feature of non‐alcoholic fatty liver disease (NAFLD) that can help distinguish it from alcohol‐induced liver disease. There are, however, other associations of nuclear vacuolation of which the commonest is as a normal feature of childhood. The aim of this study was to identify how long this physiological nuclear vacuolation persists.

Methods and results:  Liver biopsy specimens from 872 patients with chronic hepatitis B virus infection (a condition known not to be associated with nuclear vacuolation) were studied to assess the frequency of nuclear vacuolation at different ages. All the patients studied had a body mass index of <25 kg/m2 and an alcohol intake of <15 units/week, as well as no other risk factors for liver disease. It was found that the frequency of nuclear vacuolation, in the absence of NAFLD, fell from 13% at age 20–24 years to 4% in the early 30s and to 0% at age 60–64 years.

Conclusions:  Physiological hepatic nuclear vacuolation is common in the 20s and persists into the 30s. This knowledge can help in the assessment of liver biopsy specimens in which nuclear vacuolation is a feature.
Determination of HER2 amplification in primary breast cancer using dual‐colour chromogenic in situ hybridization is comparable to fluorescence in situ hybridization: a European multicentre study involving 168 specimens
Authors: García‐Caballero Tomás , Grabau Dorthe , Green Andrew R , Gregory John , Schad Arno , Kohlwes Elke , Ellis Ian O , Watts Sarah , Mollerup Jens
Published: March 2010

García‐Caballero T, Grabau D, Green A R, Gregory J, Schad A, Kohlwes E, Ellis I O, Watts S & Mollerup J (2010) Histopathology56, 472–480 Determination of HER2 amplification in primary breast cancer using dual‐colour chromogenic in situ hybridization is comparable to fluorescence in situ hybridization: a European multicentre study involving 168 specimens

Aims:  Fluorescence in situ hybridization (FISH) can be used to reveal several genomic imbalances relevant to proper cancer diagnosis and to the correct treatment regime. However, FISH requires expensive and advanced fluorescence microscopes in addition to expertise in fluorescence microscopy. To determine whether a newly developed dual‐colour chromogenic in situ hybridization (CISH) method is a suitable alternative to FISH, we analysed the human epidermal growth factor receptor 2 gene (HER2) amplification level of 168 breast cancer specimens using dual‐colour CISH and FISH and compared the results.

Methods and results:  We found 100% agreement between HER2 status determined by FISH and dual‐colour CISH. Furthermore, we observed that the time used to score slides was significantly reduced by 28% in dual‐colour CISH compared with the FISH protocol. Concordance between HER2 protein status and dual‐colour CISH or FISH was equally good with an overall agreement of 96.8%. Correlation between the HER2/centromere 17 gene ratios obtained with dual‐colour CISH and FISH was highly significant with an overall correlation coefficient (ρ) of 0.96.

Conclusions:  We conclude that dual‐colour CISH and bright field microscopy are excellent alternatives to FISH when analysing the HER2 status of primary breast cancer.
Microvascular irregularities are associated with composition of squamous epithelial lesions and correlate with subepithelial invasion of superficial‐type pharyngeal squamous cell carcinoma
Authors: Fujii Satoshi , Yamazaki Manabu , Muto Manabu , Ochiai Atsushi
Published: March 2010

Fujii S, Yamazaki M, Muto M & Ochiai A (2010) Histopathology56, 510–522

Microvascular irregularities are associated with composition of squamous epithelial lesions and correlate with subepithelial invasion of superficial‐type pharyngeal squamous cell carcinoma

Aims:  Superficial squamous epithelial lesions of the pharynx are increasingly recognized by architectural changes in the intraepithelial papillary capillary loop (IPCL) assessed by narrow‐band imaging (NBI). The aim was to explore the histology of squamous epithelial precursor lesions and superficial‐type pharyngeal squamous cell carcinoma (STPSCC), including squamous cell carcinoma (SCC) in situ and early invasive SCC, by focusing on microvascular irregularities to investigate the composition of those lesions and to explore the pathological characteristics of STPSCCs.

Methods and results:  Several pathological factors including thickness of intraepithelial squamous cell carcinoma (IESCC) and tumour thickness and microvascular density (MVD) were examined in 104 STPSCCs from 69 patients. The results show that architectural change of IPCL was recognized in precursor lesions in parallel with architectural disturbance and cytological atypia for criteria of diagnosing dysplasia. In 104 STPSCCs, the MVD of IESCC was correlated with the thickness of IESCC (P = 0.0115). Moreover, invasive SCC showed significantly higher MVD of IESCC (P = 0.0078) and there was significant correlation between the thickness of IESCC and subepithelial invasion (P < 0.0001).

Conclusions:  Microvascular irregularities are an important pathological factor in carcinogenesis and early invasiveness of SCC of the pharynx.