bluuebunny/crossref_metadata_2025 huggingface dataset:
Isopeptide bonds in bacterial pili and their characterization by X‐ray crystallography and mass spectrometry
Authors: Kang Hae Joo , Middleditch Martin , Proft Thomas , Baker Edward N.
Published: February 2009

Pili are long, filamentous protein assemblies which extend from the surfaces of many bacteria, and mediate their adhesion to host cells and other matrices. For pathogenic bacteria they are critical to colonization and infection. Whereas the pili of gram‐negative bacteria are formed by noncovalent association of their pilin subunits, those of gram‐positive bacteria are assembled with the aid of sortase enzymes that mediate the formation of covalent isopeptide bonds between successive pilin subunits. Sequence comparisons, mutagenesis and crystallography have implicated specific lysine residues in the formation of these intermolecular bonds and mass spectral analyses of native and modified pili have now provided definitive proof of these linkages. Crystallographic studies of pilin subunits have also led to the unexpected discovery of internal isopeptide crosslinks formed between lysine and asparagine residues. These, too, have been confirmed by mass spectrometry. © 2009 Wiley Periodicals, Inc. Biopolymers 91: 1126–1134, 2009.

This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com
Biochemical correlation of Raman spectra of normal, benign and malignant breast tissues: A spectral deconvolution study
Authors: Chowdary M. V. P. , Kalyan Kumar K. , Mathew Stanley , Rao Lakshmi , Krishna C. Murali , Kurien Jacob
Published: February 2009

The aim of this study was to understand and correlate spectral features and biochemical changes in normal, fibroadenoma and infiltrating ductal carcinoma of breast tissues using Raman spectra that were part of the spectroscopic models developed and evaluated by us earlier. Spectra were subjected to curve fitting and intensities plots of resultant curve resolved bands were computed. This study has revealed that fat (1301 and 1440 cm−1), collagen (1246, 1271, and 1671 cm−1) and DNA (1340 and 1480 cm−1) bands have strong presence in normal, benign and malignant breast tissues, respectively. Intensity plots of various combinations of curved resolved bands were also explored to classify tissue types. Combinations of fat (1301 cm−1) and collagen (1246, 1271, and 1671 cm−1)/amide I; DNA (1340 cm−1) and fat (1301 cm−1); collagen (1271 cm−1) and DNA (1480 cm−1) are found to be good discriminating parameters. These results are in tune with findings of earlier studies carried out on western population as well as our molecular biological understanding of normal tissues and neoplastic processes. Thus the finding of this study further demonstrates the efficacy Raman spectroscopic approaches in diagnostic applications as well as in understanding molecular phenomenon in breast cancers. © 2009 Wiley Periodicals, Inc. Biopolymers 91: 539–546, 2009.

This article was originally published online as an accepted preprint. The “Published Online”date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com
Impact of estradiol on insulin signaling in the rat heart
Authors: Koricanac Goran , Milosavljevic Tijana , Stojiljkovic Mojca , Zakula Zorica , Tepavcevic Snezana , Ribarac‐Stepic Nevena , Isenovic Esma R.
Published: February 2009

It is well known that variation in the concentration of estrogens affects insulin action. In this study we examine the impact of estradiol (E2) on insulin signaling in the rat heart. Ovariectomized female rats were treated with E2 6 h prior to analysis of basal protein and mRNA content of insulin signaling molecules, and additionally with insulin 30 min before the experiment to delineate E2 effects on phosphorylations and molecular associations relevant for insulin signaling. The results show that E2 decreased insulin receptor (IR) tyrosine phosphorylation, while it did not alter IR protein and mRNA content. E2 administration did not change IR substrate 1 (IRS‐1) protein content and tyrosine phosphorylation, while decreased mRNA content and increased its association with the p85 subunit of phosphatidylinositol 3‐kinase (PI3K). E2 decreased protein and mRNA content of IR substrate 2 (IRS‐2), while did not change IRS‐2 tyrosine phosphorylation and IRS‐2 association with p85. The increase of IRS‐1/p85 is accompanied by increase of p85 protein and mRNA levels, and by stimulation of protein kinase B (Akt) Ser473 phosphorylation. In contrast, Akt protein and mRNA content were not changed. In summary, although in some aspects cardiac insulin signaling is obviously improved by E2 treatment (increase of p85 mRNA and protein levels, enhancement of IRS‐1/p85 association and Ser473Akt phosphorylation), the observed decrease of IR tyrosine phosphorylation, IRS‐2 protein content, and IRSs mRNA contents, suggest very complex interplay of beneficial and suppressive effects of E2, both genomic and non‐genomic, in regulation of heart insulin signaling. Copyright © 2009 John Wiley & Sons, Ltd.
Identification of Cytochrome P450s Required for Fumitremorgin Biosynthesis in Aspergillus fumigatus
Authors: Kato Naoki , Suzuki Hirokazu , Takagi Hiroshi , Asami Yukihiro , Kakeya Hideaki , Uramoto Masakazu , Usui Takeo , Takahashi Shunji , Sugimoto Yoshikazu , Osada Hiroyuki
Published: February 2009

Missing links in the fumitremorgin biosynthetic pathway have been elucidated as 1) hydroxylation of the tryprostatin B indole ring at C‐6 by FtmC, 2) CN bond formation by FtmE to produce fumitremorgin C, and 3) the subsequent dihydroxylation of fumitremorgin C by FtmG to afford fumitremorgin B. These are also crucial processes for the inhibitory activity of fumitremorgin C against breast cancer resistance protein (BCRP).

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Fumitremorgin C, a diketopiperazine mycotoxin produced by Aspergillus fumigatus, is a potent and specific inhibitor of breast cancer resistance protein (BCRP). Elucidation of the fumitremorgin C biosynthetic pathway provides a strategy for new drug design. A structure–activity relationship study based on metabolites related to the ftm gene cluster revealed that the process most crucial for inhibitory activity against BCRP was cyclization to form fumitremorgin C. To determine the gene involved in the cyclization reaction, targeted gene inactivation was performed with candidate genes in the ftm cluster. Analysis of the gene disruptants allowed us to identify ftmE, one of the cytochrome P450 genes in the cluster, as the gene responsible for the key step in fumitremorgin biosynthesis. Additionally, we demonstrated that the other two cytochrome P450 genes, ftmC and ftmG, were involved in hydroxylation of the indole ring and successive hydroxylation of fumitremorgin C, respectively.
Synthesis and Conformational Analysis of Cyclotetrapeptide Mimetic β‐Turn Templates and Validation as 3D Scaffolds
Authors: Gentilucci Luca , Cardillo Giuliana , Tolomelli Alessandra , De Marco Rossella , Garelli Andrea , Spampinato Santi , Spartà Antonino , Juaristi Eusebio
Published: February 2009

The conformations of all stereoisomers of PMRI cyclotetrapeptide mimetics 1–8 are essentially determined by the predisposition of the diamine to stabilize β‐turns. The peptide mimetics can be regarded as 3D scaffolds for designing molecules with a predictable display of the pharmacophores. We used the models for testing novel RGD analogues as αvβ3‐integrin receptor antagonists.

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Dynamic gene and protein expression patterns of the autism‐associated met receptor tyrosine kinase in the developing mouse forebrain
Authors: Judson Matthew C. , Bergman Mica Y. , Campbell Daniel B. , Eagleson Kathie L. , Levitt Pat
Published: February 2009

The establishment of appropriate neural circuitry depends on the coordination of multiple developmental events across space and time. These events include proliferation, migration, differentiation, and survival—all of which can be mediated by hepatocyte growth factor (HGF) signaling through the Met receptor tyrosine kinase. We previously found a functional promoter variant of theMETgene to be associated with autism spectrum disorder, suggesting that forebrain circuits governing social and emotional function may be especially vulnerable to developmental disruptions in HGF/Met signaling. However, little is known about the spatiotemporal distribution of Met expression in the forebrain during the development of such circuits. To advance our understanding of the neurodevelopmental influences of Met activation, we employed complementary Western blotting, in situ hybridization, and immunohistochemistry to comprehensively map Met transcript and protein expression throughout perinatal and postnatal development of the mouse forebrain. Our studies reveal complex and dynamic spatiotemporal patterns of expression during this period. Spatially,Mettranscript is localized primarily to specific populations of projection neurons within the neocortex and in structures of the limbic system, including the amygdala, hippocampus, and septum. Met protein appears to be principally located in axon tracts. Temporally, peak expression of transcript and protein occurs during the second postnatal week. This period is characterized by extensive neurite outgrowth and synaptogenesis, supporting a role for the receptor in these processes. Collectively, these data suggest that Met signaling may be necessary for the appropriate wiring of forebrain circuits, with particular relevance to the social and emotional dimensions of behavior. J. Comp. Neurol. 513:511–531, 2009. © 2009 Wiley‐Liss, Inc.
Macromolecular connections of active zone material to docked synaptic vesicles and presynaptic membrane at neuromuscular junctions of mouse
Authors: Nagwaney Sharuna , Harlow Mark Lee , Jung Jae Hoon , Szule Joseph A. , Ress David , Xu Jing , Marshall Robert M. , McMahan Uel Jackson
Published: February 2009

Electron tomography was used to view macromolecules composing active zone material (AZM) in axon terminals at mouse neuromuscular junctions. Connections of the macromolecules to each other, to calcium channels in the presynaptic membrane, and to synaptic vesicles docked on the membrane prior to fusing with it during synaptic transmission were similar to those of AZM macromolecules at frog neuromuscular junctions previously examined by electron tomography and support the hypothesis that AZM regulates vesicle docking and fusion. A species difference in the arrangement of AZM relative to docked vesicles may help account for a greater vesicle‐presynaptic membrane contact area during docking and a greater probability of fusion during synaptic transmission in mouse. Certain AZM macromolecules in mouse were connected to synaptic vesicles contacting the presynaptic membrane at sites where fusion does not occur. These secondary docked vesicles had a different relationship to the membrane and AZM macromolecules than primary docked vesicles, consistent with their having a different AZM‐regulated behavior. J. Comp. Neurol. 513:457–468, 2009. © 2009 Wiley‐Liss, Inc.
Close homologue of adhesion molecule L1 promotes survival of Purkinje and granule cells and granule cell migration during murine cerebellar development
Authors: Jakovcevski Igor , Siering Janina , Hargus Gunnar , Karl Nicole , Hoelters Laura , Djogo Nevena , Yin Shengming , Zecevic Nada , Schachner Melitta , Irintchev Andrey
Published: February 2009

Several L1‐related adhesion molecules, expressed in a well‐coordinated temporospatial pattern during development, are important for fine tuning of specific cerebellar circuitries. We tested the hypothesis that CHL1, the close homologue of L1, abundantly expressed in the developing and adult cerebellum, is also required for normal cerebellar histogenesis. We found that constitutive ablation of CHL1 in mice caused significant loss (20–23%) of Purkinje and granule cells in the mature 2‐month‐old cerebellum. The ratio of stellate/basket interneurons to Purkinje cells was abnormally high (+38%) in CHL1‐deficient (CHL1−/−) mice compared with wild‐type (CHL1+/+) littermates, but the γ‐aminobutyric acid (GABA)ergic synaptic inputs to Purkinje cell bodies and dendrites were normal, as were numbers of Golgi interneurons, microglia, astrocytes, and Bergmann glia. Purkinje cell loss occurred before the first postnatal week and was associated with enhanced apoptosis, presumably as a consequence of CHL1 deficiency in afferent axons. In contrast, generation of granule cells, as indicated by in vivo analyses of cell proliferation and death, was unaffected in 1‐week‐old CHL1−/− mice, but numbers of migrating granule cells in the molecular layer were increased. This increase was likely related to retarded cell migration because CHL1−/− granule cells migrated more slowly than CHL1+/+ cells in vitro, and Bergmann glial processes guiding migration in vivo expressed CHL1 in wild‐type mice. Granule cell deficiency in adult CHL1−/− mice appeared to result from decreased precursor cell proliferation after the first postnatal week. Our results indicate that CHL1 promotes Purkinje and granule cell survival and granule cell migration during cerebellar development. J. Comp. Neurol. 513:496–510, 2009. © 2009 Wiley‐Liss, Inc.
Color processing in the medulla of the bumblebee (Apidae: Bombus impatiens)
Authors: Paulk Angelique C. , Dacks Andrew M. , Gronenberg Wulfila
Published: February 2009

The mechanisms of processing a visual scene involve segregating features (such as color) into separate information channels at different stages within the brain, processing these features, and then integrating this information at higher levels in the brain. To examine how this process takes place in the insect brain, we focused on the medulla, an area within the optic lobe through which all of the visual information from the retina must pass before it proceeds to central brain areas. We used histological and immunocytochemical techniques to examine the bumblebee medulla and found that the medulla is divided into eight layers. We then recorded and morphologically identified 27 neurons with processes in the medulla. During our recordings we presented color cues to determine whether response types correlated with locations of the neural branching patterns of the filled neurons among the medulla layers. Neurons in the outer medulla layers had less complex color responses compared to neurons in the inner medulla layers and there were differences in the temporal dynamics of the responses among the layers. Progressing from the outer to the inner medulla, neurons in the different layers appear to process increasingly complex aspects of the natural visual scene. J. Comp. Neurol. 513:441–456, 2009. © 2009 Wiley‐Liss, Inc.
Preparation of Buckypaper–Copper Composites and Investigation of their Conductivity and Mechanical Properties
Authors: Byrne Michele T. , Hernandez Yenny R. , Conaty Thomas , Blighe Fiona M. , Coleman Johnathan N. , Gun'ko Yurii K.
Published: February 2009

Buckypaper‐metal composites are prepared by substrate‐enhanced electroless deposition of copper onto strips of buckypaper (see picture). Electrical conductivity and mechanical properties of these buckypaper‐copper composites at different copper content are investigated. The conductivity is shown to increases by up to 350 %, and the Young's modulus and the ultimate tensile strength of the composites by 282 % and 290 % respectively over pristine buckypaper.

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Preservation of the Morphology of a Self‐Encapsulated Thin Titania Film in a Functional Multilayer Stack: An X‐Ray Scattering Study
Authors: Perlich Jan , Memesa Mine , Diethert Alexander , Metwalli Ezzeldin , Wang Weinan , Roth Stephan V. , Timmann Andreas , Gutmann Jochen S. , Müller‐Buschbaum Peter
Published: February 2009

Looks matter: Generally, the morphology of titania thin films is crucial for their performance, hence much effort is spent to tailor the desired morphology. X‐ray scattering enables the monitoring of the crystalline titania layer morphology during build‐up of the functional multilayer stack (see Figure). Herein evidence is provided that the morphology is preserved throughout the fabrication process.

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Tailoring of the titania morphology is achieved by the combination of a triblock copolymer, acting as structure‐directing agent, and a sol–gel chemistry enabling the incorporation of the provided inorganic material (titania) into the selected phase of the triblock copolymer. Spin‐coating of the solution on FTO‐coated glass, followed by plasma etching and calcination of the thin film results in the formation of self‐encapsulated crystalline titania nanostructures. The fabricated nanostructures are coated stepwise with dye, conductive polymers and gold forming a functional multilayer stack. An advanced small‐angle scattering technique probing the sample with X‐ray synchrotron radiation under grazing incidence (GISAXS) is employed for the characterization of the preparation route, as scattering allows accessing the structure inside the multilayers. The tailored titania morphology is preserved during the preparation route towards the functional multilayer stack of a photovoltaic demonstration cell. Two clearly distinguishable structures originate from the substrate and the titania templated by the triblock copolymer; hence the other layers induce no additional structures. Therefore, this investigation provides the evidence that the effort spent to tailor the morphology is justified by the preservation of the self‐encapsulated titania morphology that is created by the structure‐directing agent throughout the functional multilayer stack build‐up.
Preparation and characterization of Nd doped gadolinium gallium garnet nanopowders and crystals
Authors: Lipińska L. , Ryba‐Romanowski W. , Rzepka A. , Ganschow S. , Lisiecki R. , Diduszko R. , Pajączkowska A.
Published: February 2009

The structural and optical features of gallium gadolinium garnet (GGG) nanopowders doped with neodymium were investigated. Nanopowders of GGG:Nd were prepared by modified sol‐gel method using acetic acid as complexing agent. This way permitted to incorporate large amounts of dopant (up to 10 %) without destroying garnet structure. Small single crystals of Nd:GGG were grown by a μ‐pulling down method and spectroscopic features of nanopowders and their single crystal counterparts were compared. It has concluded that the Nd3+ ions are located preferentially in the same type of sites in crystal lattices of GGG:Nd nanopowders and their single crystal counterparts. In addition, it follows from the perfect agreement of emission wavelengths and line width recorded for nanopowders and single crystal samples that the crystal lattice of GGG in nanopowders is not distorted. (© 2009 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Flux growth and characterization of Ti‐ and Ni‐doped forsterite single crystals
Authors: Bloise A. , Barrese E. , Apollaro C. , Miriello D.
Published: February 2009

Forsterite monocrystals doped with Ti and Ni were grown by the flux growth technique. A suitable mixture of flux (MoO3, V2O5, Li2CO3) and nutrient was slowly cooled down to 750 °C from 1250 °C or 1350 °C. The crystals were then characterized by powder and single‐crystal X‐ray diffraction, scanning electron microscopy and differential scanning calorimetry (DSC). Variations observed in crystal size were attributed by both the varying experimental conditions in which they had been obtained, and to the amount of Ni substituted for Mg in the structure. High abundances of doped forsterite required a cooling rate of 1.8 K h‐1. These synthetic, well‐characterized Ti and Ni doped forsterite crystals may have potential for exploitation in industrial fields. (© 2009 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Thermoelectric properties of Tl‐doped Bi2Se3 single crystals
Authors: Janíček P. , Drašar Č. , Beneš L. , Lošťák P.
Published: February 2009

The single crystals of the ternary system based on Bi2‐xTlxSe3 (nominaly x = 0.0‐0.1) were prepared using the Bridgman technique. Samples with varying content of Tl were characterized by the measurement of lattice parameters, electrical conductivity σ⊥c , Hall coefficient RH (B∥c), and Seebeck coefficient S (ΔT ⊥c). The measurements indicate that by incorporating Tl in Bi2Se3 one lowers the concentration of free electrons and enhances their mobility. This effect is explained in terms of the point defects in the crystal lattice – formation of substitutional defects thallium on the site of bismuth TlBi and the decrease of concentration of selenium vacancies VSe+2. We also discuss the temperature dependence of the power factor σS2 of the samples. Upon the thallium doping we observe a significant increase of the power factor compare to the parental Bi2Se3. (© 2009 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Two Cyano‐Functionalized, Cadmium‐Containing Ionic Liquids
Authors: Tang Sifu , Mudring Anja‐Verena
Published: February 2009

The new ionic liquids 3‐cyanomethyl‐1‐methylimidazolium tetrachlorocadmate (1) and 3‐(4‐cyanobutyl)‐1‐methylimidazolium tetrachlorocadmate (2) were obtained from the reaction of the respective alkylimidazolium chlorides with cadmium chloride in 2:1 molar ratios. Structural characterization of 1 by single‐crystal X‐ray diffraction reveals the existence of [CdCl4]2– tetrahedra and substantial C–H···Cl hydrogen bonding. Although compound 1 melts congruently at 105 °C, once molten it can be retained as a liquid at room temperature. Compound 2 just forms a glass upon solidification at approximately –42 °C.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
N‐Heterocyclic Carbene Rhodium Complexes and Their Reactions with H2 and with CO
Authors: Yu Xiao‐Yan , Sun Hongsui , Patrick Brian O. , James Brian R.
Published: February 2009

The NHC‐RhI complexes [RhCl(COE)(NHC)]2 1 and 2 [COE = cyclooctene, NHC in 1 = N,N‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene (IPr) and, in 2, N,N‐bis(2,4,6‐trimethylphenyl)imidazol‐2‐ylidene (IMes)] react with H2 in hexane to give the dimeric, mono‐carbene dihydrido species [Rh(H)2Cl(NHC)]2 (NHC = IPr (3), IMes (4)). In the presence offurther NHC, the bis‐carbene dihydrido species Rh(H)2Cl(NHC)2 are formed; a crystal structure of the IPr complex 5 is analogous to that of the known IMes analogue. The dihydride‐mixed‐carbene species Rh(H)2Cl(IPr)(IMes) (5a) was also observed but not isolated. A benzene solution of 5 under D2 slowly generates the corresponding dideuteride. Reactions of the mono‐carbenes (1/3, or 2/4) with CO in hexane afford the respective dicarbonyl complexes RhCl(CO)2(NHC) [NHC = IPr (6), IMes (7)], while CO reactions with the bis‐carbene dihydrides give, respectively, the mono‐carbonyl complex RhCl(CO)(IPr)2 (8) and the known IMes analogue. All the complexes are characterized by elemental analysis, 1H and 13C{1H} NMR and IR spectroscopies and, in the case of 5, by X‐ray crystallography. The catalytic activities of 5 and the previously reported Rh(H)2Cl(IMes)2 for hydrogenation of COE and 1‐octene (and isomerization of the latter) are shown to be poor.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Multi‐Tier Dendrimers with an Aromatic Core
Authors: Haridas V. , Sharma Yogesh K. , Naik Sarala
Published: February 2009

We report various multi‐tier designer dendritic molecules that incorporate an aromatic core and heterocyclic and peptide units. The 5‐(azidomethyl)benzene‐1,3‐dicarbonyl unit was chosen as the scaffold as this unit allows two identical units and a reactive end to be incorporated, thus generating a dendron suitable for dendrimer synthesis. The design and synthesis of dendrimers with multi‐tier architectures will be useful for generating dendritic structures with various functions.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Synthesis of Three C‐Glycoside Analogues of UDP‐Galactopyranose as Conformational Probes for the Mutase‐Catalyzed Furanose/Pyranose Interconversion
Authors: Caravano Audrey , Vincent Stéphane P.
Published: February 2009

UDP‐galactopyranose mutase (UGM) catalyzes the isomerization of UDP‐galactopyranose (UDP‐Galp) into UDP‐galactofuranose (UDP‐Galf), an essential step of the mycobacterial cell wall biosynthesis. In order to probe the UGM binding pocket, we synthesized the α‐ and β‐C‐glycosidic analogues of UDP‐galacopyranose along with the corresponding UDP‐exo‐galactal. Preliminary inhibition evaluation indicated that UDP‐exo‐galactal inhibits UGM with a binding affinity similar to that of UDP‐α‐C‐galactopyranose.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Carbonylative Suzuki–Miyaura Coupling of Arylboronic Acids with Aryl Iodides Catalyzed by the MCM‐41‐Supported Bidentate Phosphane Palladium(II) Complex
Authors: Cai Mingzhong , Zheng Guomin , Zha Lingfang , Peng Jian
Published: February 2009

The first heterogeneous carbonylative Suzuki–Miyaura cross‐coupling reaction of arylboronic acids with aryl iodides under an atmospheric pressure of carbon monoxide has been achieved in anisole at 80 °C in the presence of a catalytic amount of an MCM‐41‐supported bidentate phosphane palladium(II) complex (MCM‐41‐2P‐PdII), yielding unsymmetrical biaryl ketones in good‐to‐high yields. This polymeric palladium catalyst exhibited higher activity and selectivity than [PdCl2(PPh3)2] and can be reused at least 10 times without any decrease in activity. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Stereoselective Synthesis of 2,6‐Disubstituted‐4‐Aryltetrahydropyrans Using Sakurai–Hosomi–Prins–Friedel–Crafts Reaction
Authors: Reddy Udagandla C. , Bondalapati Somasekhar , Saikia Anil K.
Published: February 2009

The reaction of aldehydes with allyltrimethylsilane in arene solvents gives symmetrical 2,6‐disubstituted‐4‐aryltetrahydropyrans in good yields. The reaction is highly stereoselective. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Novel technique to improve the fault detection sensitivity in transformer maintenance test
Authors: Al‐Ammar E. A. , Karady G. G. , Sim H. J.
Published: February 2009

Early detection of incipient faults in transformer windings is important, so that required corrective measures can be taken to help prevent interruption during operation. Low voltage impulse (LVI) and sweep frequency response analysis (SFRA) tests have been widely adopted within the industry to determine a transformer winding's deformation. However, these tests have drawbacks, including limited frequency ranges for the LVI test and time‐consuming measurements for the SFRA test. To obtain better signature analysis in the transformer maintenance test, especially detection of minor faults, this paper suggests a new input signal using a pulse sequence (PS) in the transfer function (TF) analysis. The results of the PS test are compared against the LVI and SFRA tests to complete the assessments, which are derived from experimental works on the 25 kVA distribution transformer. It is concluded that the PS method improves fault detection sensitivity significantly. Copyright © 2009 John Wiley & Sons, Ltd.
Distinct patterns of DNA copy number alterations associate with BRAF mutations in melanomas and melanoma‐derived cell lines
Authors: Greshock J. , Nathanson K. , Medina A. , Ward M. R. , Herlyn M. , Weber B. L. , Zaks T. Z.
Published: February 2009

A majority of malignant melanomas harbor an oncogenic mutation in either BRAF or NRAS. If BRAF and NRAS transform melanoma cells by a similar mechanism, then additional genetic aberrations would be similar (or random). Alternatively, distinct mutation‐associated changes would suggest the existence of unique cooperating requirements for each mutation group. We first analyzed a panel of 52 melanoma cell lines (n = 35, 11, 6 for BRAF*, NRAS*, and BRAF/NRASwt/wt, respectively) by array‐based comparative genomic hybridization for unique alterations that associate with each mutation subgroup. Subsequently, those DNA copy number changes that correlated with a mutation subgroup were used to predict the mutation status of an independent panel of 43 tumors (n = 17, 13, 13 for BRAF*, NRAS*, and BRAF/NRASwt/wt, respectively). BRAF mutant tumors were classified with a high rate of success (74.4%, P = 0.002), whereas NRAS mutants were not significantly distinguished from wild types (26/43, P = 0.12). Copy number gains of 7q32.1‐36.3, 5p15.31, 8q21.11, and 8q24.11 were most strongly associated with BRAF* tumors and cell lines, as were losses of 11q24.2‐24.3. BRAF* melanomas appear to be associated with a specific profile of DNA copy number aberrations that is distinct from those found in NRAS* and BRAF/NRASwt/wt tumors. These findings suggest that although both BRAF and NRAS appear to function along the same signal transduction pathway, each may have different requirements for cooperating oncogenic events. The genetic loci that make up this profile may harbor therapeutic targets specific for tumors with BRAF mutations. © 2009 Wiley‐Liss, Inc.
Screening for mild cognitive impairment: a systematic review
Authors: Lonie Jane A. , Tierney Kevin M. , Ebmeier Klaus P.
Published: February 2009

Objective

Patients with mild cognitive impairment account for a significant number of referrals to old age psychiatry services and specialist memory clinics. The cognitive evaluation of such patients is commonly restricted to brief dementia screens, with no consideration to their suitability for assessing MCI. Here, we review the utility of such cognitive screens for MCI and provide an overview of validated instruments.

Methods

We identified papers published after Petersen and colleagues 1999 MCI criteria (Petersen et al., 1999) and examining face‐to‐face cognitive screening for MCI from publication databases using combinations of the search terms ‘mild cognitive impairment’ and ‘cognitive screening’. We also combined the former search with the names of 39 screening tests recently identified in a relevant review (Cullen et al., 2007).

Results

Fifteen cognitive screening instruments were identified, 11 cover a restricted range of cognitive domains. High sensitivity and specificity for MCI relative to healthy controls were reported for two comprehensive and two noncomprehensive screening instruments, adequate test‐retest and inter‐rater reliability for only one of these. With the exception of three studies, sample sizes were universally small (i.e. n ≤ 100), and prognostic values were reported for only two of the identified 15 screening measures. Sensitivities of the full domain measures were universally high, but information about their specificity against psychiatric and non‐progressive neurological conditions and predictive validity is lacking.

Conclusion

Several cognitive screening instruments afford the clinician the ability to detect MCI, early AD, and in some cases non‐AD dementia, but they cannot currently be used to make reliable inferences about the course and eventual outcome of MCI. Copyright © 2009 John Wiley & Sons, Ltd.
Vigorous activation of monocytes in juvenile autoimmune liver disease escapes the control of regulatory T-cells #
Authors: Longhi Maria Serena , Mitry Ragai R. , Samyn Marianne , Scalori Astrid , Hussain Munther J. , Quaglia Alberto , Mieli-Vergani Giorgina , Ma Yun , Vergani Diego
Published: February 2009

Interface hepatitis, the histological lesion typical of autoimmune hepatitis (AIH), is composed of CD4 and CD8 T lymphocytes and of innate immunity cells, particularly monocytes. Studies in AIH have focused on autoreactive CD4 and CD8 T cells and impairment of CD4+CD25+ regulatory T cells (T-regs), whereas little is known about the role of monocytes and their relationship with T-regs. We have investigated 51 patients with autoimmune liver disease (AILD) and 27 healthy subjects, finding that monocytes were higher in number (P = 0.044), had a more vigorous spontaneous migration (P < 0.0005 in patients with inactive disease [ID], and P < 0.001 in those with active disease [AD]), displayed a higher tumor necrosis factor alpha (TNF-α) over interleukin (IL)-10 production (P = 0.07 in ID and P = 0.0005 in AD), and expressed higher levels of Toll-like receptor (TLR) 4 (P = 0.048 in ID and P = 0.03 in AD). Addition of conventional T-regs (cT-regs) in AILD enhanced monocyte migration (P = 0.05 in ID and P = 0.08 in AD), magnified TNF-α over IL-10 production (P = 0.0005 in ID and P = 0.006 in AD), and markedly increased TLR4 expression levels (P = 0.01 in ID and P = 0.004 in AD), whereas in normal subjects it either restrained or left unchanged monocyte function. Because a CD127-negative subpopulation within CD4+CD25+ T cells exerts the strongest regulatory activity, we performed additional experiments using purified CD4+CD25+CD127− T cells (true T-regs [tT-regs]). Addition of tT-regs to monocytes decreased monocyte migration (P = 0.03) and promoted IL-10 production (P = 0.009), leaving unchanged TLR4 expression in healthy subjects, whereas in patients with AILD it induced only a marginal increase in IL-10 production (P = 0.045 in ID and P = 0.13 in AD). Conclusion: Monocyte overactivation and inability of cT-regs and tT-regs to restrain it may contribute to the loss of immune tolerance and perpetuation of the autoimmune attack in AILD. (Hepatology 2009.)
Statins potentiate the in vitro anti-hepatitis C virus activity of selective hepatitis C virus inhibitors and delay or prevent resistance development #
Authors: Delang Leen , Paeshuyse Jan , Vliegen Inge , Leyssen Pieter , Obeid Susan , Durantel David , Zoulim Fabien , Op de Beeck Anne , Neyts Johan
Published: February 2009

Statins are 3-hydroxyl-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors used for the treatment of hypercholesterolemia. It was recently reported that statins inhibit in vitro hepatitis C virus (HCV) RNA replication. We here report that, of five statins studied, mevastatin and simvastatin exhibit the strongest in vitro anti-HCV activity, lovastatin and fluvastatin have moderate inhibitory effects, and pravastatin is devoid of an antiviral effect. A combination of statins with interferon-alpha (IFN-α) or HCV nonstructural (NS)5B polymerase or NS3 protease inhibitors results in an additive antiviral activity in short-term (3 days) antiviral assays. Neither statins, at a concentration of five-fold their median effective concentration (EC50) value, nor polymerase, protease inhibitors, or IFN-α, at concentrations 10- or 20-fold their EC50 value, were able to clear cells from their replicon following four or six consecutive passages of antiviral pressure. However, the combination of HCV polymerase or protease inhibitors with mevastatin or simvastatin resulted in an efficient clearance of the cultures from their replicon. In colony formation experiments, mevastatin reduced the frequency or prevented the selection of HCV replicons resistant to the nonnucleoside inhibitor HCV-796. Conclusion: A combination of specific HCV inhibitors with statins may result in a more profound antiviral effect and may delay or prevent the development of resistance to such inhibitors. (Hepatology 2009.)
L-ornithine phenylacetate attenuates increased arterial and extracellular brain ammonia and prevents intracranial hypertension in pigs with acute liver failure # †
Authors: Ytrebφ Lars Marius , Kristiansen Rune Gangsφy , Mæhre Hanne , Fuskevåg Ole Martin , Kalstad Trine , Revhaug Arthur , Cobos María Jover , Jalan Rajiv , Rose Christopher F.
Published: February 2009

Hyperammonemia is a feature of acute liver failure (ALF), which is associated with increased intracranial pressure (ICP) and brain herniation. We hypothesized that a combination of L-ornithine and phenylacetate (OP) would synergistically reduce toxic levels of ammonia by (1) L-ornithine increasing glutamine production (ammonia removal) through muscle glutamine synthetase and (2) phenylacetate conjugating with the ornithine-derived glutamine to form phenylacetylglutamine, which is excreted into the urine. The aims of this study were to determine the effect of OP on arterial and extracellular brain ammonia concentrations as well as ICP in pigs with ALF (induced by liver devascularization). ALF pigs were treated with OP (L-ornithine 0.07 g/kg/hour intravenously; phenylbutyrate, prodrug for phenylacetate; 0.05 g/kg/hour intraduodenally) for 8 hours following ALF induction. ICP was monitored throughout, and arterial and extracellular brain ammonia were measured along with phenylacetylglutamine in the urine. Compared with ALF + saline pigs, treatment with OP significantly attenuated concentrations of arterial ammonia (589.6 ± 56.7 versus 365.2 ± 60.4 μmol/L [mean ± SEM], P= 0.002) and extracellular brain ammonia (P= 0.01). The ALF-induced increase in ICP was prevented in ALF + OP-treated pigs (18.3 ± 1.3 mmHg in ALF + saline versus 10.3 ± 1.1 mmHg in ALF + OP-treated pigs; P= 0.001). The value of ICP significantly correlated with the concentration of extracellular brain ammonia (r
2 = 0.36, P< 0.001). Urine phenylacetylglutamine levels increased to 4.9 ± 0.6 μmol/L in ALF + OP-treated pigs versus 0.5 ± 0.04 μmol/L in ALF + saline-treated pigs (P< 0.001). Conclusion: L-Ornithine and phenylacetate act synergistically to successfully attenuate increases in arterial ammonia, which is accompanied by a significant decrease in extracellular brain ammonia and prevention of intracranial hypertension in pigs with ALF. (Hepatology 2009;50:165–174.)
MicroRNA-195 suppresses tumorigenicity and regulates G1/S transition of human hepatocellular carcinoma cells #
Authors: Xu Teng , Zhu Ying , Xiong Yujuan , Ge Yi-Yuan , Yun Jing-Ping , Zhuang Shi-Mei
Published: February 2009

Growing evidence indicates that deregulation of microRNAs (miRNAs) contributes to tumorigenesis. Down-regulation of miR-195 has been observed in various types of cancers. However, the biological function of miR-195 is still largely unknown. In this study we aimed to elucidate the pathophysiologic role of miR-195. Our results showed that miR-195 expression was significantly reduced in as high as 85.7% of hepatocellular carcinoma (HCC) tissues and in all of the five HCC cell lines examined. Moreover, introduction of miR-195 dramatically suppressed the ability of HCC and colorectal carcinoma cells to form colonies in vitro and to develop tumors in nude mice. Furthermore, ectopic expression of miR-195 blocked G1/S transition, whereas inhibition of miR-195 promoted cell cycle progression. Subsequent investigation characterized multiple G1/S transition-related molecules, including cyclin D1, CDK6, and E2F3, as direct targets of miR-195. Silencing of cyclin D1, CDK6, or E2F3 phenocopied the effect of miR-195, whereas overexpression of these proteins attenuated miR-195-induced G1 arrest. In addition, miR-195 significantly repressed the phosphorylation of Rb as well as the transactivation of downstream target genes of E2F. These results imply that miR-195 may block the G1/S transition by repressing Rb-E2F signaling through targeting multiple molecules, including cyclin D1, CDK6, and E2F3. Conclusion: Our data highlight an important role of miR-195 in cell cycle control and in the molecular etiology of HCC, and implicate the potential application of miR-195 in cancer therapy. (Hepatology 2009.)
Regulation of Apoptotic Signaling Pathways in Hepatocytes In Vivo
Authors: Jaeschke Hartmut , Bajt Mary Lynn
Published: February 2009

The mitochondrial pathway is critical for the efficient execution of death receptor–initiated apoptosis in certain cell types. Questions remain as to why the mitochondria are required in that scenario. We investigated the molecular events that determined the need for the mitochondria by using an in vivo model of anti–Fas–induced hepatocyte apoptosis. In wild–type mice, Fas stimulation resulted in normal activation of caspase–3, with the generation of the active p19–p12 complex. In bid–deficient mice, caspase–3 activation was arrested after the initial cleavage at Asp175. This allowed the generation of the p12 small subunit, but the p20 large subunit could not be further processed to the p19 subunit. The p20–p12 complex generated by Fas stimulation in bid–deficient hepatocytes was inactive, arresting the death program. Failure of p20/p12 caspase–3 to mature and to exhibit activity was because of the inhibition by the inhibitor–of–apoptosis proteins (IAPs), such as XIAP, and also to a low caspase–8 activity. This block could be overcome in wild–type mice by two mechanisms. Smac was released from mitochondria early following Fas activation and was competitively bound to the IAPs to reverse their effects. XIAP could also be cleaved, and this occurred later and was likely mediated by enhanced caspase activities. Both mechanisms were dependent on Bid and thus were not operative in bid–deficient hepatocytes. In conclusion, mitochondrial activation by Bid is required for reversing the IAP inhibition through Smac release. It is also required for the alternative activation of caspases through cytochrome c release, as demonstrated previously. Together, these events ensure a successful progression of the death program initiated by the death receptor activation in the hepatocyte.
Neurocognitive effects of switching from methylphenidate‐IR to OROS‐methylphenidate in children with ADHD
Authors: Kim Yeni , Shin Min‐Sup , Kim Jae‐Won , Yoo Hee‐Jung , Cho Soo‐Churl , Kim Boong‐Nyun
Published: February 2009

Objectives

This study evaluated neurocognitive changes after switching from immediate release forms of methylphenidate (MPH‐IR) to osmotic release oral system methylphenidate (OROS‐MPH).

Methods

102 children with attention‐deficit/hyperactivity disorder (ADHD) participated in an open label, 28 day trial, performing neurocognitive test at baseline and at 28 days after the switch from MPH‐IR to OROS‐MPH.

Results

There were significant improvements in the commission error and the reaction time of both visual and auditory continuous performance tests (CPTs) at 28 days after switching from MPH‐IR to OROS‐MPH. A positive correlation was observed between the improvement in parent/caregiver‐rated IOWA Conners total score (Δ IOWA) and the reduction in commission error (r = 0.3, p = 0.001) and reduction in reaction time variability (r = 0.3, p = 0.006) of visual CPT. In a linear regression model, the change in parent/caregiver‐rated IOWA Conners scale total scores were significant predictors of change in commission error (β = 0.3, p = 0.005, CI = 0.4–2.3, adjusted R2 = 0.12) and RT variability (β = 0.3, p = 0.004, CI = 0.5–2.4, adjusted R2 = 0.09) of visual CPT.

Conclusions

These data suggest that MPH‐IR may be successfully switched to OROS‐MPH treatment with associated improvements in neurocognitive performance. Large‐scale controlled trials are needed to replicate these findings. Copyright © 2009 John Wiley & Sons, Ltd.
In vitro induction of apoptosis and in vivo effects of a flavone nitroderivative in murine mammary adenocarcinoma cells
Authors: Cárdenas Mariano G. , Zotta Elsa , Marder Mariel , Roguin Leonor P.
Published: February 2009

We explored thein vitroandin vivomechanism of antitumor action of the synthetic flavonoid 2′‐nitroflavone on LM3 murine mammary adenocarcinoma cells.In vitroassays showed that 2′‐nitroflavone increased the population of LM3 hypodiploid cells and produced a typical ladder of DNA fragmentation. Apoptotic cell death was also characterized by the activation of caspase‐8, ‐9 and ‐3, by an increment in the expression levels of the proapoptotic protein Bax and by the release of cytochromecto cytosol. Thein vivoeffect of 2′‐nitroflavone on tumor growth was studied in BALB/c mice injected subcutaneously with LM3 cells. Results showed that tumor volume and weight were significantly reduced at doses of 10 and 40 mg/kg of 2′‐nitroflavone, respectively. Apoptotic cells were identified by TUNEL assay in tumor slices from mice treated with 10 mg/kg of 2′‐nitroflavone. Western blot analysis of tumor lysate supernatants from treated mice revealed an upregulation of the total levels of Bax and Fas receptor. In addition, administration of 40 mg/kg of 2′‐nitroflavone to nontumor‐bearing mice showed no histopathological effects on different organ tissues. This is the first report of thein vivogrowth inhibitory effect of 2′‐nitroflavone as an apoptotic agent likely useful for mammary adenocarcinoma treatment. © 2009 UICC
Childhood leukemias and other hematopoietic malignancies: Interdependence between an infectious event and chromosomal modifications
Authors: zur Hausen Harald
Published: February 2009

A large number of epidemiological observations suggest an infectious origin of hematopoietic malignancies, including various forms of leukemia, nonHodgkin's lymphomas, Hodgkin's lymphomas and multiple myelomas. Incidence of nonHodgkin's lymphomas and Hodgkin's lymphomas, although not of leukemias, is substantially increased under immunosuppression. Specific chromosomal modifications (translocations) resulting in fusion genes frequently emerge as early, but not sufficient, events for malignant progression in most of these conditions. Presently less than 10% of the global incidence of leukemias and lymphomas can be linked to infections (Epstein‐Barr virus, human T‐lymphotropic retrovirus, human herpesvirus type 8 and Helicobacter pylori). For individual tumor types of the remaining more than 90%, several risk factors have been identified. They include occupational hazards, such as engagement in community services and agriculture, as well as time–space clustering. In childhood leukemias, a protective effect was noted for multiple infections during the first year of life and for at least 6 months of breastfeeding. A high socioeconomic state and absence of multiple contacts during the early phase of life have been described as risk factors. A hypothesis is presented here which combines these observations. It postulates a wide‐spread viral infection, nontumorigenic when replication competent, but potentially leukemiogenic or carcinogenic when replication‐incompetent viral genomes infect cells with specific chromosomal modifications. Existing data on polyoma‐like virus types seem to render members of this or structurally related virus families as putative candidates for these malignancies. © 2009 UICC
WT1 IgG antibody for early detection of nonsmall cell lung cancer and as its prognostic factor
Authors: Oji Yusuke , Kitamura Yayoi , Kamino Eriko , Kitano Aiko , Sawabata Noriyoshi , Inoue Masayoshi , Mori Masahide , Nakatsuka Shin‐ichi , Sakaguchi Nao , Miyazaki Kaori , Nakamura Michiyo , Fukuda Ikuyo , Nakamura Junya , Tatsumi Naoya , Takakuwa Tetsuya , Nishida Sumiyuki , Shirakata Toshiaki , Hosen Naoki , Tsuboi Akihiro , Nezu Riichiro , Maeda Hajime , Oka Yoshihiro , Kawase Ichiro , Aozasa Katsuyuki , Okumura Meinoshin , Miyoshi Shinichiro , Sugiyama Haruo
Published: February 2009

There are urgent needs to develop methods for early detection of nonsmall cell lung cancer (NSCLC) because of its increasing incidence and poor prognosis. Here, we analyzed the production of IgG antibody (WT1 Ab) against WT1 (Wilms' tumor gene) protein that was overexpressed in the majority of NSCLC. Enzyme‐linked immuno‐sorbent assay showed that WT1 Ab was produced in all of 91 NSCLC patients and 70 healthy individuals and that WT1 Ab titers were significantly higher in NSCLC patients compared with healthy individuals. When the cut‐off level of WT1 Ab titers were fixed at mean + 3SD of those in healthy individuals, 26.4% of NSCLC patients had WT1 Ab titers over the cut‐off level, and positive rates of WT1 Ab at each clinical stage were 25.0, 30.8 and 38.4% in stage I, II and III NSCLC, respectively. When WT1 Ab was combined with CEA or CYFRA for detection of NSCLC, positive detection rates increased from 25.0 to 34.1 and 31.8%, respectively, in stage I and from 38.4 to 69.2 and 46.1%, respectively, in stage III, but not changed in stage II. Western blot analysis showed that dominant subclass of WT1 Ab was Th1‐type IgG2. Interestingly, elevation of WT1 Ab titers was significantly associated with longer disease‐free survival in patients with stages I–III NSCLC. These results showed that WT1 Ab could be a useful marker for early detection of NSCLC and its prognostic prediction. These results also suggested that WT1‐specific immune responses played an important role in anti‐cancer immunity in NSCLC. © 2009 UICC