bluuebunny/crossref_metadata_2025 huggingface dataset:
Beneficial effects of C36, a novel breaker of advanced glycation endproducts cross‐links, on the cardiovascular system of diabetic rats
Authors: Cheng G , Wang L‐L , Long L , Liu H‐Y , Cui H , Qu W‐S , Li S
Published: October 2007

Background and purpose:

Advanced glycation endproducts (AGE) have been implicated in the pathogenesis of diabetic complications, including diabetic cardiovascular dysfunctions. 3‐benzyloxycarbonylmethyl‐4‐methyl‐thiazol‐3‐ium bromide (C36), a novel AGE breaker, was investigated for its beneficial effects on the cardiovascular system of diabetic rats.

Experimental approach:

The in vitro breaking abilities of C36 on AGE cross‐links formed in vitro and in vivo were assessed. After 4 weeks' treatment with C36, cardiovascular and left ventricular functions in diabetic (streptozotocin–induced) rats were evaluated by haemodynamic studies. Effects of C36 on AGE accumulation, collagen distribution, and fibrosis‐associated gene expression were also investigated by biochemical and morphological methods and reverse transcription‐PCR, respectively.

Key results:

In vitro, C36 released bovine serum albumin (BSA) from preformed AGE‐BSA‐collagen complexes and decreased the IgG cross‐linked to red blood cell surface (RBC‐IgG). In vivo, C36 treatment of diabetic rats resulted in a significant increase in left ventricular systolic pressure and the maximal rate of left ventricular pressure rise and pressure fall, induction in cardiac output and systemic arterial compliance, decrease of total peripheral resistance, reduction of diabetes‐induced RBC‐IgG content, increase of myocardial and tail tendon collagen solubility, and normalization of collagen type III/I ratio in diabetic rats. In addition, C36 treatment attenuated mRNA levels of diabetes‐induced genes, including receptors for AGE, transforming growth factor β1, connective tissue growth factor, and collagen III.

Conclusions and implications:

C36 was an effective breaker of AGE cross‐links and had beneficial effects on the cardiovascular system of diabetic rats.

British Journal of Pharmacology (2007) 152, 1196–1206; doi:10.1038/sj.bjp.0707533; published online 29 October 2007
Anti‐angiogenic properties of a sulindac analogue
Authors: Pyriochou A , Tsigkos S , Vassilakopoulos T , Cottin T , Zhou Z , Gourzoulidou E , Roussos C , Waldmann H , Giannis A , Papapetropoulos A
Published: October 2007

Background and purpose:

Angiopoietins (Ang) are crucial for new blood vessel formation and exert their effects by acting on the Tie2 receptor. We have recently described a sulindac analogue 2‐((1E,Z)‐1‐benzylidene‐5‐bromo‐2‐methyl‐1H‐inden‐3‐yl)acetic acid; termed C‐18 from now onwards) that inhibits Tie2 receptor activity in kinase assays in vitro. Here, we have assessed the ability of C‐18 to inhibit angiogenesis‐related properties of endothelial cells and tested its selectivity for the Tie2 receptor.

Experimental approach:

For in vitro experiments human umbilical vein endothelial cells (HUVEC) were used. Proliferation was measured using the MTT assay; migration assays were performed in a modified Boyden chamber and tube‐like structure formation was determined on matrigel. The effects of C‐18 in vivo were evaluated in the chicken chorioallantoic membrane (CAM).

Key results:

Pre‐treatment of HUVEC with C‐18 blocked Ang‐1‐stimulated migration, but also abolished vascular endothelial cell growth factor (VEGF)‐ and fibroblast growth factor 2‐induced responses. Incubation with C‐18 inhibited serum‐induced proliferation in a concentration‐dependent manner; C‐18 was, however, without effect on Ang‐1‐induced survival. In addition, we observed that C‐18 did not inhibit ligand‐induced receptor phosphorylation of Tie2 or VEGFR2. On the other hand, C‐18 blocked activation of members of the mitogen‐activated protein kinase family and of the Ser/Thr kinase Akt induced by both VEGF and Ang‐1. Furthermore, incubation of CAMs with C‐18 led to a dose‐dependent inhibition of vascular length.

Conclusions and implications:

C‐18 did not act as a Tie2 inhibitor, as originally thought, but rather inhibited growth factor‐stimulated signalling pathways that regulate endothelial cell migration and potently reduces neovascularization in vivo.

British Journal of Pharmacology (2007) 152, 1207–1214; doi:10.1038/sj.bjp.0707534; published online 29 October 2007
Coexistence of hERG current block and disruption of protein trafficking in ketoconazole‐induced long QT syndrome
Authors: Takemasa H , Nagatomo T , Abe H , Kawakami K , Igarashi T , Tsurugi T , Kabashima N , Tamura M , Okazaki M , Delisle B P , January C T , Otsuji Y
Published: October 2007

Background and purpose:

Many drugs associated with acquired long QT syndrome (LQTS) directly block humanether‐a‐go‐go‐related gene (hERG) K+channels. Recently, disrupted trafficking of the hERG channel protein was proposed as a new mechanism underlying LQTS, but whether this defect coexists with the hERG current block remains unclear. This study investigated how ketoconazole, a direct hERG current inhibitor, affects the trafficking of hERG channel protein.

Experimental approach:

Wild‐type hERG andSCN5A/hNav1.5 Na+channels or the Y652A and F656C mutated forms of the hERG were stably expressed in HEK293 cells. The K+and Na+currents were recorded in these cells by using the whole‐cell patch‐clamp technique (23°C). Protein trafficking of the hERG was evaluated by Western blot analysis and flow cytometry.

Key results:

Ketoconazole directly blocked the hERG channel current and reduced the amount of hERG channel protein trafficked to the cell surface in a concentration‐dependent manner. Current density of the hERG channels but not of the hNav1.5 channels was reduced after 48 h of incubation with ketoconazole, with preservation of the acute direct effect on hERG current. Mutations in drug‐binding sites (F656C or Y652A) of the hERG channel significantly attenuated the hERG current blockade by ketoconazole, but did not affect the disruption of trafficking.

Conclusions and implications:

Our findings indicate that ketoconazole might cause acquired LQTS via a direct inhibition of current through the hERG channel and by disrupting hERG protein trafficking within therapeutic concentrations. These findings should be considered when evaluating new drugs.

British Journal of Pharmacology(2008)153, 439–447; doi:10.1038/sj.bjp.0707537; published online 29 October 2007
Curcumin inhibits connective tissue growth factor gene expression in activated hepatic stellate cellsin vitroby blocking NF‐κB and ERK signalling
Authors: Chen A , Zheng S
Published: October 2007

Background and purpose:

Gene expression of connective tissue growth factor (CTGF) is induced in activated hepatic stellate cells (HSC), the major effectors in hepatic fibrosis, and production of extracellular matrix (ECM) is consequently increased. We previously reported that curcumin, the yellow pigment in curry, suppressedctgfexpression, leading to decreased production of ECM by HSC. The purpose of this study is to evaluate signal transduction pathways involved in the curcumin suppression ofctgfexpression in HSC.

Experimental approaches:

Transient transfection assays were performed to evaluate effects of activation of signalling pathways on thectgfpromoter activity. Real‐time PCR and Western blotting analyses were conducted to determine expression of genes.

Results:

Suppression ofctgfexpression by curcumin was dose‐dependently reversed by lipopolysaccharide (LPS), an NF‐κB activator. LPS increased the abundance of CTGF and type I collagen in HSCin vitro. Activation of NF‐κB by dominant active IκB kinase (IKK), or inhibition of NF‐κB by dominant negative IκBα, caused the stimulation, or suppression of thectgfpromoter activity, respectively. Curcumin suppressed gene expression of Toll‐like receptor‐4, leading to the inhibition of NF‐κB. On the other hand, interruption of ERK signalling by inhibitors or dominant negative ERK, like curcumin, reduced NF‐κB activity and inctgfexpression. In contrast, the stimulation of ERK signalling by constitutively active ERK prevented the inhibitory effects of curcumin.

Conclusions and implications:

These results demonstrate that the interruption of NF‐κB and ERK signalling by curcumin results in the suppression ofctgfexpression in activated HSCin vitro.

British Journal of Pharmacology(2008)153, 557–567; doi:10.1038/sj.bjp.0707542; published online 29 October 2007
Targeting of FAK Ser910 by ERK5 and PP1δ in non-stimulated and phorbol ester-stimulated cells
Authors: Villa-Moruzzi Emma
Published: October 2007

Ser910 of FAK (focal adhesion kinase) was phosphorylated in fibroblasts treated with the phorbol ester PMA and dephosphorylated by PP1δ (protein phosphatase 1δ), as indicated by shRNA (small-hairpin RNA) gene silencing. Ser910 of FAK was reported previously to be an ERK (extracellular-signal-regulated kinase) 1/2 target in cells treated with phorbol esters. In contrast, various approaches, including the use of the MEK (mitogen-activated protein kinase/ERK kinase) inhibitors UO126 and CI-1040 to inhibit ERK1/2 pointed to the involvement of ERK5. This hypothesis was confirmed by: (i) shRNA ERK5 gene silencing, which resulted in complete pSer910 loss in non-stimulated and PMA-stimulated cells; (ii) direct phosphorylation of recombinant FAK by ERK5; and (iii) ERK5 activation by PMA. PMA stimulation and ERK5 silencing in MDA-MB 231 and MDA-MB 361 breast cancer cells indicated Ser910 targeting by ERK5 also in these cells. Given the proximity of Ser910 to the FAT (focal adhesion targeting) regulatory domain of FAK, cell proliferation and morphology were investigated in FAK−/− cells expressing S910A mutant FAK. The cell growth rate decreased and exposure to PMA induced peculiar morphological changes in cells expressing S910A, with respect to wild-type FAK, suggesting a role for Ser910 in these processes. The present study indicates, for the first time, the phosphorylation of Ser910 of FAK by ERK5 and its dephosphorylation by PP1δ, and suggested a role for Ser910 in the control of cell shape and proliferation.
The zinc finger transcription factor ZFHX1A is linked to cell proliferation by Rb–E2F1
Authors: Liu Yongqing , Costantino Mary E. , Montoya-Durango Diego , Higashi Yujiro , Darling Douglas S. , Dean Douglas C.
Published: October 2007

ZFHX1A is expressed in proliferating cells in the developing embryo, and in the present study we provide evidence that its expression is confined to proliferating cells through dependence on the Rb (retinoblastoma protein) family/E2F cell cycle pathway. Mutation of the Rb or E2F1 genes lead to induction of ZFHX1A mRNA, implying that the Rb–E2F1 repressor complex is important for repression of ZFHX1A. This repression is associated with recruitment of an E2F–Rb–histone deacetylase repressor complex to the promoter. A dominant-negative form of E2F1 inhibited ZFHX1A expression in p16INK4a(−) cells where Rb is constitutively hyperphosphorylated and inactive, suggesting that E2F can contribute to ZFHX1A transactivation in the absence of functional Rb. ZFHX1A is an E-box-binding transcription factor whose binding sites overlap with those bound by Snail1 and 2, and ZFHX1B/SIP1 (leading to at least partially overlapping function; for example, each of the proteins can repress E-cadherin expression). We found that expression of Snail1 and ZFHX1B/SIP1 is also regulated by E2Fs, but in contrast with ZFHX1A this regulation is Rb-family-independent. Snail2 expression was unaffected by either E2F or the Rb family. We propose that the differential effects of the Rb family/E2F pathway on expression of these E-box-binding proteins are important in maintaining their distinct patterns (and thus distinct functions) during embryogenesis.
DGA1 (diacylglycerol acyltransferase gene) overexpression and leucine biosynthesis significantly increase lipid accumulation in the Δsnf2 disruptant of Saccharomyces cerevisiae
Authors: Kamisaka Yasushi , Tomita Nao , Kimura Kazuyoshi , Kainou Kumiko , Uemura Hiroshi
Published: October 2007

We previously found that SNF2, a gene encoding a transcription factor forming part of the SWI/SNF (switching/sucrose non-fermenting) chromatin-remodelling complex, is involved in lipid accumulation, because the Δsnf2 disruptant of Saccharomyces cerevisiae has a higher lipid content. The present study was conducted to identify other factors that might further increase lipid accumulation in the Δsnf2 disruptant. First, expression of LEU2 (a gene encoding β-isopropylmalate dehydrogenase), which was used to select transformed strains by complementation of the leucine axotroph, unexpectedly increased both growth and lipid accumulation, especially in the Δsnf2 disruptant. The effect of LEU2 expression on growth and lipid accumulation could be reproduced by adding large amounts of leucine to the culture medium, indicating that the effect was not due to Leu2p (β-isopropylmalate dehydrogenase) itself, but rather to leucine biosynthesis. To increase lipid accumulation further, genes encoding the triacylglycerol biosynthetic enzymes diacylglycerol acyltransferase (DGA1) and phospholipid:diacylglycerol acyltransferase (LRO1) were overexpressed in the Δsnf2 disruptant. Overexpression of DGA1 significantly increased lipid accumulation, especially in the Δsnf2 disruptant, whereas LRO1 overexpression decreased lipid accumulation in the Δsnf2 disruptant. Furthermore, the effect of overexpression of acyl-CoA synthase genes (FAA1, FAA2, FAA3 and FAA4), which each supply a substrate for Dga1p (diacylglycerol acyltransferase), was investigated. Overexpression of FAA3, together with that of DGA1, did not further increase lipid accumulation in the Δsnf2 disruptant, but did enhance lipid accumulation in the presence of exogenous fatty acids. Lastly, the total lipid content in the Δsnf2 disruptant transformed with DGA1 and FAA3 overexpression vectors reached approx. 30%, of which triacylglycerol was the most abundant lipid. Diacylglycerol acyltransferase activity was significantly increased in the Δsnf2 disruptant strain overexpressing DGA1 as compared with the wild-type strain overexpressing DGA1; this higher activity may account for the prominent increase in lipid accumulation in the Δsnf2 disruptant with DGA1 overexpression. The strains obtained have a lipid content that is high enough to act as a model of oleaginous yeast and they may be useful for the metabolic engineering of lipid production in yeast.
Three-dimensional structure and ligand binding properties of trichosurin, a metatherian lipocalin from the milk whey of the common brushtail possum Trichosurus vulpecula
Authors: Watson Randall P. , Demmer Jerome , Baker Edward N. , Arcus Vickery L.
Published: October 2007

Lipocalins are extracellular proteins (17–25 kDa) that bind and transport small lipophilic molecules. The three-dimensional structure of the first lipocalin from a metatherian has been determined at different values of pH both with and without bound ligands. Trichosurin, a protein from the milk whey of the common brushtail possum, Trichosurus vulpecula, has been recombinantly expressed in Escherichia coli, refolded from inclusion bodies, purified and crystallized at two different pH values. The three-dimensional structure of trichosurin was solved by X-ray crystallography in two different crystal forms to 1.9 Å (1 Å=0.1 nm) and 2.6 Å resolution, from crystals grown at low and high pH values respectively. Trichosurin has the typical lipocalin fold, an eight-stranded anti-parallel β-barrel but dimerizes in an orientation that has not been seen previously. The putative binding pocket in the centre of the β-barrel is well-defined in both high and low pH structures and is occupied by water molecules along with isopropanol molecules from the crystallization medium. Trichosurin was also co-crystallized with a number of small molecule ligands and structures were determined with 2-naphthol and 4-ethylphenol bound in the centre of the β-barrel. The binding of phenolic compounds by trichosurin provides clues to the function of this important marsupial milk protein, which is highly conserved across metatherians.
Lactate favours the dissociation of skeletal muscle 6-phosphofructo-1-kinase tetramers down-regulating the enzyme and muscle glycolysis
Authors: Costa Leite Tiago , Da Silva Daniel , Guimarães Coelho Raquel , Zancan Patricia , Sola-Penna Mauro
Published: October 2007

For a long period lactate was considered as a dead-end product of glycolysis in many cells and its accumulation correlated with acidosis and cellular and tissue damage. At present, the role of lactate in several physiological processes has been investigated based on its properties as an energy source, a signalling molecule and as essential for tissue repair. It is noteworthy that lactate accumulation alters glycolytic flux independently from medium acidification, thereby this compound can regulate glucose metabolism within cells. PFK (6-phosphofructo-1-kinase) is the key regulatory glycolytic enzyme which is regulated by diverse molecules and signals. PFK activity is directly correlated with cellular glucose consumption. The present study shows the property of lactate to down-regulate PFK activity in a specific manner which is not dependent on acidification of the medium. Lactate reduces the affinity of the enzyme for its substrates, ATP and fructose 6-phosphate, as well as reducing the affinity for ATP at its allosteric inhibitory site at the enzyme. Moreover, we demonstrated that lactate inhibits PFK favouring the dissociation of enzyme active tetramers into less active dimers. This effect can be prevented by tetramer-stabilizing conditions such as the presence of fructose 2,6-bisphosphate, the binding of PFK to f-actin and phosphorylation of the enzyme by protein kinase A. In conclusion, our results support evidence that lactate regulates the glycolytic flux through modulating PFK due to its effects on the enzyme quaternary structure.
Comparative in vitro and ex vivo activities of selected inhibitors of transthyretin aggregation: relevance in drug design
Authors: Cardoso Isabel , Almeida Maria Rosário , Ferreira Nelson , Arsequell Gemma , Valencia Gregorio , Saraiva Maria João
Published: October 2007

Destabilization of the tetrameric fold of TTR (transthyretin) is important for aggregation of the protein which culminates in amyloid fibril formation. Many TTR mutations interfere with tetramer stability, increasing the amyloidogenic potential of the protein. The vast majority of proposed TTR fibrillogenesis inhibitors are based on in vitro assays with isolated protein, limiting their future use in clinical assays. In the present study we investigated TTR fibrillogenesis inhibitors using a cellular system that produces TTR intermediates/aggregates in the medium. Plasmids carrying wild-type TTR, V30M or L55P cDNA were transfected into a rat Schwannoma cell line and TTR aggregates were investigated in the medium using a dot-blot filter assay followed by immunodetection. Results showed that, in 24 h, TTR L55P forms aggregates in the medium, whereas, up to 72 h, wild-type TTR and V30M do not. A series of 12 different compounds, described in the literature as in vitro TTR fibrillogenesis inhibitors, were tested for their ability to inhibit L55P aggregate formation; in this system, 2-[(3,5-dichlorophenyl) amino] benzoic acid, benzoxazole, 4-(3,5-difluorophenyl) benzoic acid and tri-iodophenol were the most effective inhibitors, as compared with the reference iododiflunisal, previously shown by ex vivo and in vitro procedures to stabilize TTR and inhibit fibrillogenesis. Among these drugs, 2-[(3,5-dichlorophenyl) amino] benzoic acid and tri-iodophenol stabilized TTR from heterozygotic carriers of V30M in the same ex vivo conditions as those used previously for iododiflunisal. The novel cellular-based test herein proposed for TTR fibrillogenesis inhibitor screens avoids not only lengthy and cumbersome large-scale protein isolation steps but also artefacts associated with most current in vitro first-line screening methods, such as those associated with acidic conditions and the absence of serum proteins.
Identification and characterization of two closely related histone H4 arginine 3 methyltransferases in Arabidopsis thaliana
Authors: Yan Dongsheng , Zhang Yong , Niu Lifang , Yuan Yi , Cao Xiaofeng
Published: October 2007

Arginine methylation of histone H3 and H4 plays important roles in transcriptional regulation in eukaryotes such as yeasts, fruitflies, nematode worms, fish and mammals; however, less is known in plants. In the present paper, we report the identification and characterization of two Arabidopsis thaliana protein arginine N-methyltransferases, AtPRMT1a and AtPRMT1b, which exhibit high homology with human PRMT1. Both AtPRMT1a and AtPRMT1b methylated histone H4, H2A, and myelin basic protein in vitro. Site-directed mutagenesis of the third arginine (R3) on the N-terminus of histone H4 to lysine (H4R3N) completely abolished the methylation of histone H4. When fused to GFP (green fluorescent protein), both methyltransferases localized to the cytoplasm as well as to the nucleus. Consistent with their subcellular distribution, GST (glutathione transferase) pull-down assays revealed an interaction between the two methyltransferases, suggesting that both proteins may act together in a functional unit. In addition, we demonstrated that AtFib2 (Arabidopsis thaliana fibrillarin 2), an RNA methyltransferase, is a potential substrate for AtPRMT1a and AtPRMT1b, and, furthermore, uncovered a direct interaction between the protein methyltransferase and the RNA methyltransferase. Taken together, our findings implicate AtPRMT1a and AtPRMT1b as H4-R3 protein arginine N-methyltransferases in Arabidopsis and may be involved in diverse biological processes inside and outside the nucleus.
Oxidative switches in functioning of mammalian copper chaperone Cox17
Authors: Voronova Anastassia , Meyer-Klaucke Wolfram , Meyer Thomas , Rompel Annette , Krebs Bernt , Kazantseva Jekaterina , Sillard Rannar , Palumaa Peep
Published: October 2007

Cox17, a copper chaperone for cytochrome-c oxidase, is an essential and highly conserved protein in eukaryotic organisms. Yeast and mammalian Cox17 share six conserved cysteine residues, which are involved in complex redox reactions as well as in metal binding and transfer. Mammalian Cox17 exists in three oxidative states, each characterized by distinct metal-binding properties: fully reduced mammalian Cox170S–S binds co-operatively to four Cu+; Cox172S–S, with two disulfide bridges, binds to one of either Cu+ or Zn2+; and Cox173S–S, with three disulfide bridges, does not bind to any metal ions. The Em (midpoint redox potential) values for two redox couples of Cox17, Cox173S–S↔Cox172S–S (Em1) and Cox172S–S↔Cox170S–S (Em2), were determined to be −197 mV and −340 mV respectively. The data indicate that an equilibrium exists in the cytosol between Cox170S-S and Cox172S–S, which is slightly shifted towards Cox170S-S. In the IMS (mitochondrial intermembrane space), the equilibrium is shifted towards Cox172S–S, enabling retention of Cox172S–S in the IMS and leading to the formation of a biologically competent form of the Cox17 protein, Cox172S–S, capable of copper transfer to the copper chaperone Sco1. XAS (X-ray absorption spectroscopy) determined that Cu4Cox17 contains a Cu4S6-type copper–thiolate cluster, which may provide safe storage of an excess of copper ions.
Sirt1 interacts with transducin-like enhancer of split-1 to inhibit nuclear factor κB-mediated transcription
Authors: Ghosh Hiyaa S. , Spencer James V. , Ng Bobby , McBurney Michael W. , Robbins Paul D.
Published: October 2007

Sirt1 is an NAD+-dependent deacetylase that plays a role in cellular processes such as transcriptional regulation, stress response, longevity and apoptosis. Sirt1 deacetylates histone proteins and certain transcription factors such as p53, CTIP2 (chicken ovalbumin upstream promoter-transcription factor-interacting protein 2), FOXO (forkhead box O) and NF-κB (nuclear factor κB). To identify potential Sirt1-interacting factors, we performed a yeast two-hybrid screen. The screen identified TLE1 (transducin-like enhancer of split-1) as a possible Sirt1-interacting factor, which was then confirmed by co-immunoprecipitation. TLE1 is a non-DNA binding co-repressor for several transcriptional factors including NF-κB. We have demonstrated using co-transfection assays that Sirt1 and TLE1 repress NF-κB activity. The catalytic mutant of Sirt1, Sirt1-H363Y, and the N-terminal Sirt1 fragment (amino acids 1–270) also show similar repression activity, suggesting that the deacetylase activity of Sirt1 may not be critical for its effect on NF-κB activity. Furthermore, analysis in Sirt1-null MEFs (murine embryonic fibroblasts) and HeLa cells stably expressing siRNA (small interfering RNA) specific to Sirt1 or TLE1 demonstrate that both Sirt1 and TLE1 are required for negative regulation of NF-κB activity. Taken together, these results suggest that the interaction between Sirt1 and TLE1 is important for mediating repression of NF-κB activity.
Do mammalian NPC1 and NPC2 play a role in intestinal cholesterol absorption?
Authors: Dixit Sayali S. , Sleat David E. , Stock Ann M. , Lobel Peter
Published: October 2007

NPC1L1 (Niemann–Pick C1-like 1), the pharmacological target of the cholesterol-uptake inhibitor ezetimibe, is a transporter localized on the brush border of enterocytes. Although this protein plays a key role in intestinal uptake of sterols, multiple molecular events that underlie intestinal cholesterol absorption have not been fully characterized. Two proteins that might be involved in this process are NPC1 and NPC2 (Niemann–Pick disease type C proteins 1 and 2), which function in the endosomal/lysosomal cholesterol egress pathway and whose deficiency results in NPC (Niemann–Pick type C) disease. The involvement of these proteins in intestinal cholesterol absorption was examined in mutant mice lacking either NPC1 or NPC2. Our data indicate that deficiencies in either protein do not have an effect on cholesterol uptake or absorption. This contrasts with recent results obtained for the fruitfly Drosophila melanogaster, which indicate that a deficiency of NPC1 (dNPC1a being its Drosophila homologue) leads to activation of an NPC1L1 (Drosophila homologue dNPC1b)-independent cholesterol uptake pathway, underscoring fundamental differences in mammalian and non-mammalian cholesterol metabolism.
A quasichemical approach for protein-cluster free energies in dilute solution
Authors: Young Teresa M. , Roberts Christopher J.
Published: October 2007

Reversible formation of protein oligomers or small clusters is a key step in processes such as protein polymerization, fibril formation, and protein phase separation from dilute solution. A straightforward, statistical mechanical approach to accurately calculate cluster free energies in solution is presented using a cell-based, quasichemical (QC) approximation for the partition function of proteins in an implicit solvent. The inputs to the model are the protein potential of mean force (PMF) and the corresponding subcell degeneracies up to relatively low particle densities. The approach is tested using simple two and three dimensional lattice models in which proteins interact with either isotropic or anisotropic nearest-neighbor attractions. Comparison with direct Monte Carlo simulation shows that cluster probabilities and free energies of oligomer formation (ΔGi0) are quantitatively predicted by the QC approach for protein volume fractions ∼10−2 (weight/volume concentration ∼10gl−1) and below. For small clusters, ΔGi0 depends weakly on the strength of short-ranged attractive interactions for most experimentally relevant values of the normalized osmotic second virial coefficient (b2*). For larger clusters (i⪢2), there is a small but non-negligible b2* dependence. The results suggest that nonspecific, hydrophobic attractions may not significantly stabilize prenuclei in processes such as non-native aggregation. Biased Monte Carlo methods are shown to accurately provide subcell degeneracies that are intractable to obtain analytically or by direct enumeration, and so offer a means to generalize the approach to mixtures and proteins with more complex PMFs.
Shielding effects in polymer-polymer reactions. II. Reactions between linear and star-branched chains with up to six arms
Authors: Fröhlich Markus G. , Vana Philipp , Zifferer Gerhard
Published: October 2007

The shielding effect of surrounding arms and chains on the encounter probability of reactive sites located both at the end of a linear chain and at several positions along the arms of star-branched chains with up to six arms is calculated by means of exact enumeration of samples prepared by Monte Carlo simulation. The changes of parameters that characterize the size and the shape of chain configurations during the approach of reactive centers located at the end of the linear chain and at the center of the star are evaluated. In addition to this specific case, which represents the central reaction step in reversible addition-fragmentation chain transfer star polymerization following the Z-group approach, a general discussion is given on the chain-length dependence of shielding factors associated with distinct segment positions.
Instability of current sheets and formation of plasmoid chains
Authors: Loureiro N. F. , Schekochihin A. A. , Cowley S. C.
Published: October 2007

Current sheets formed in magnetic reconnection events are found to be unstable to high-wavenumber perturbations. The instability is very fast: its maximum growth rate scales as S1∕4vA∕LCS, where LCS is the length of the sheet, vA the Alfvén speed, and S the Lundquist number. As a result, a chain of plasmoids (secondary islands) is formed, whose number scales as S3∕8.
Time-dependent wave packet study on trans-cis isomerization of HONO driven by an external field
Authors: Richter Falk , Gatti Fabien , Léonard Céline , Le Quéré Frédéric , Meyer Hans-Dieter
Published: October 2007

The present paper is devoted to a full quantum mechanical study of the cis→trans isomerization of HONO. In contrast to our previous study [Richter et al., J. Chem. Phys. 120, 6072 (2004)], the dynamics is now performed in the presence of an external time-dependent field in order to be closer to experimental conditions. A six-dimensional dipole surface is computed. Using a previously developed potential energy surface [Richter et al., J. Chem. Phys. 120, 1306 (2004)], all eigenstates up to 4000cm−1 are calculated. We simulate the dynamics during and after excitation by an electromagnetic pulse whose parameters are chosen to efficiently trigger the isomerization. Our investigations show that there is a selective isomerization pathway.
Initial-value problem for small disturbances in an idealized one-dimensional detonation
Authors: Tumin Anatoli
Published: October 2007

The solution of the initial-value problem for linearized reactive Euler equations is presented as an expansion into modes of discrete and continuous spectra in the case of one-dimensional perturbations. The result provides a convenient tool to predict initial amplitudes of the unstable modes depending on the initial perturbation. Examples of initial perturbations introduced into the quiescent gas and into the reaction zone are discussed. It is shown that the discrete spectrum stemming from the solution of the initial-value problem for an idealized one-reaction detonation is equivalent to the spectrum of the conventional normal-mode approach.
Exact solutions for shapes of two-dimensional bubbles in a corner flow
Authors: Zubarev Nikolay M. , Zubareva Olga V.
Published: October 2007

A one-parameter family of exact solutions for the deformations of two-dimensional bubbles in a corner flow of an ideal liquid is obtained. The solutions correspond to the special case where the pressure inside the bubble equals the stagnation pressure. The parameter of the model is the corner angle. The solution family includes classical McLeod’s solution which corresponds to the corner of angle π. For the particular case of a right-angled corner, the solution describes the straining flow past a bubble. In view of the known analogy between the distributions of a planar electric field and the velocity field for a two-dimensional potential flow, our solutions give equilibrium configurations of the surface of a conducting liquid in an external electric field.
Optical tomographic reconstruction of ion beam induced refractive index changes in silica
Authors: Goh X. M. , Dragomir N. M. , Jamieson D. N. , Roberts A. , Belton D. X.
Published: October 2007

Refractive index changes induced by ion beam implantation can be used to produce photonic devices such as waveguides. Here, we relate the measured three-dimensional changes in refractive index produced by ion beam implantation to modeling of the implantation process. We use a quantitative phase microscopic method in conjunction with a tomographic reconstruction process to determine the change in the refractive index distribution within a silica optical fiber that has been selectively implanted with 2.4MeV H+ ions. The index profile is compared with numerical simulations of the ion vacancy and ionization using the stopping range of ions in matter program.
On the modulational stability of magnetic structures in electron drift turbulence
Authors: Jucker Martin , Pavlenko Vladimir P.
Published: October 2007

The generation of large-scale magnetic fields in magnetic electron drift mode turbulence is investigated. In particular, the mechanism of modulational instability caused by three-wave interactions is elucidated and the explicit increment is calculated. Also, a stability criterion similar to the known Lighthill criterion is found.
Photoluminescence phenomena of Ce3+-doped Y3Al5O12 nanophosphors
Authors: Su L. T. , Tok A. I. Y. , Boey F. Y. C. , Zhang X. H. , Woodhead J. L. , Summers C. J.
Published: October 2007

The photoluminescence phenomena of Ce3+-doped Y3Al5O12 nanophosphors synthesized by the chemical gelation were investigated and compared with bulk phosphors. The oxidation state of the cerium ions in the nanophosphors was determined to be trivalent. This is an essential characteristic of phosphor’s emission. The Stokes shift for the nanophosphors was less than the bulk phosphors, which indicates that the nanophosphors had restricted surroundings. The photoionization effect was observed for the nanophosphors where the 5d electrons were lost to the conduction band and trapped at the surface-defective sites. Another observation was the high concentration of surface defects on the nanophosphors. These surface defects were investigated using the high resolution transmission electron microscope.
Accurate ab initio potential energy curve of F2. I. Nonrelativistic full valence configuration interaction energies using the correlation energy extrapolation by intrinsic scaling method
Authors: Bytautas Laimutis , Nagata Takeshi , Gordon Mark S. , Ruedenberg Klaus
Published: October 2007

The recently introduced method of correlation energy extrapolation by intrinsic scaling (CEEIS) is used to calculate the nonrelativistic electron correlations in the valence shell of the F2 molecule at 13 internuclear distances along the ground state potential energy curve from 1.14Åto8Å, the equilibrium distance being 1.412Å. Using Dunning’s correlation-consistent double-, triple-, and quadruple-zeta basis sets, the full configuration interaction energies are determined, with an accuracy of about 0.3mhartree, by successively generating up to octuple excitations with respect to multiconfigurational reference functions that strongly change along the reaction path. The energies of the reference functions and those of the correlation energies with respect to these reference functions are then extrapolated to their complete basis set limits. The applicability of the CEEIS method to strongly multiconfigurational reference functions is documented in detail.
Comparative study of Ti and Ni clusters from first principles
Authors: Lee Byeongchan , Lee Geun Woo
Published: October 2007

Icosahedral clusters in Ti and Ni are studied with first-principles density functional calculations. We find significant distortion on the Ti icosahedron caused by the strong interaction between surface atoms on the icosahedron but not between the center atom and surface atoms, whereas no such distortion is observed on Ni clusters. In addition, distortion becomes more severe when atoms are added to the Ti13 cluster resulting in short bonds. Such distorted icosahedra having short bonds are essential in explaining the structure factor of Ti liquid obtained in experiment.
Photoluminescence in phosphorous-implanted ZnO films
Authors: Vaithianathan Veeramuthu , Hishita Shunichi , Park Jae Young , Kim Sang Sub
Published: October 2007

ZnO thin films prepared by pulsed laser deposition were implanted with phosphorous (P) using dose levels of 1012–1014ions∕cm2 at room temperature. The P-implanted films were subsequently annealed between 500 and 700°C in oxygen ambient. The Hall effect measurements revealed a substantial reduction in the electron concentration of the P-implanted films without annealing, whereas the reduction was more pronounced with optimized rapid thermal annealing treatment. The photoluminescence spectra showed emissions associated with the shallow P-related acceptors at ∼3.179, ∼3.256, and ∼3.325eV as well as a strong red emission centered at ∼1.85eV originating from a donor-acceptor pair transition after annealing at 600 and 700°C. These results indicate that the P dose level during ion implantation and the annealing temperature are key processing parameters that should be optimized to produce p-type ZnO films.
Rhodium coated mirrors deposited by magnetron sputtering for fusion applications
Authors: Marot L. , De Temmerman G. , Oelhafen P. , Covarel G. , Litnovsky A.
Published: October 2007

Metallic mirrors will be essential components of all optical spectroscopy and imaging systems for ITER plasma diagnostics. Any change in the mirror performance, in particular, its reflectivity, due to erosion of the surface by charge exchange neutrals or deposition of impurities will influence the quality and reliability of the detected signals. Due to its high reflectivity in the visible wavelength range and its low sputtering yield, rhodium appears as an attractive material for first mirrors in ITER. However, the very high price of the raw material calls for using it in the form of a film deposited onto metallic substrates. The development of a reliable technique for the preparation of high reflectivity rhodium films is therefore of the highest importance. Rhodium layers with thicknesses of up to 2μm were produced on different substrates of interest (Mo, stainless steel, Cu) by magnetron sputtering. Produced films exhibit a low roughness and crystallite size of about 10nm with a dense columnar structure. No impurities were detected on the surface after deposition. Scratch tests demonstrate that adhesion properties increase with substrate hardness. Detailed optical characterizations of Rh-coated mirrors as well as results of erosion tests performed both under laboratory conditions and in the TEXTOR tokamak are presented in this paper.
Measurement of the dc resistance of semiconductor thin film–gas systems: Comparison to several transport models
Authors: Carrico Barbara , Saredy J. , Tracy J. L. , Patel N. G. , Garner J. , Gasparov L.
Published: October 2007

Measurements have been made of the dc resistance of a thin film semiconductor, an indium tin oxide that has been exposed to various gases (acetylene, methane, and sulfur dioxide). The resistance versus time is found to be a characteristic that serves as a possible means for detecting and identifying a gas. Three simple dc transport models are used to determine the time-dependent resistance: resistor network, dynamic Maxwell-Garnett Theory (DMGT), and a dynamic effective medium approximation (DEMA) model. The resistor network model gives only the general trend of the experimental data. The DEMA and DMGT predictions are nearly identical and independent of dimensionality. This promising application of the historic EMA and MGT models yields results that are in good agreement with experimental resistance data presented in this paper. Future directions might include an extension of these dc resistance results to the finite frequency ac and optical conductivity.
Three-dimensional curvelets for coherent vortex analysis of turbulence
Authors: Ma Jianwei , Hussaini M. Yousuff
Published: October 2007

This letter presents a multiscale geometric method based on three-dimensional (3D) second-generation curvelet transform to extract coherent vortices out of 3D turbulent flows. Since the platelike elements of 3D curvelets satisfy the 3D parabolic scaling, and since they form a sparse basis, they optimally represent singular surfaces in three dimensions. This method preserves the edges and structures of extracted vortex tubes better than the conventional wavelets. The effectiveness of the present method is demonstrated in the case of simulation data of 3D homogeneous isotropic turbulence.
Piezoelectric properties of irradiation-crosslinked polypropylene ferroelectrets
Authors: Zhang Xiaoqing , Huang Jinfeng , Chen Jianbo , Wan Zhenmao , Wang Shu , Xia Zhongfu
Published: October 2007

The cellular irradiation-cross-linked polypropylene films treated by a hot-press process are corona charged to be piezoelectric. For the samples charged at room temperature, quasistatic piezoelectric d33 coefficients up to 400pC∕N are obtained. The d33 coefficients are slightly dependent on pressure in the range up to 50kPa. The d33 values decrease to 30% when the samples are exposed to 90°C for 1day; a preaging treatment improves the thermal stability of d33. The dominant drift path of the detrapped charges is from one void surface to the adjacent void surface through the bulk of the solid.
Pituitary and testicular endocrine responses to exogenous gonadotrophin-releasing hormone (GnRH) and luteinising hormone in male dogs treated with GnRH agonist implants
Authors: Junaidi A. , Williamson P. E. , Martin G. B. , Stanton P. G. , Blackberry M. A. , Cummins J. M. , Trigg T. E.
Published: October 2007

The present study tested whether exogenous gonadotrophin-releasing hormone (GnRH) and luteinising hormone (LH) can stimulate LH and testosterone secretion in dogs chronically treated with a GnRH superagonist. Twenty male adult dogs were assigned to a completely randomised design comprising five groups of four animals. Each dog in the control group received a blank implant (placebo) and each dog in the other four groups received a 6-mg implant containing a slow-release formulation of deslorelin (d-Trp6-Pro9-des-Gly10–LH-releasing hormone ethylamide). The same four control dogs were used for all hormonal challenges, whereas a different deslorelin-implanted group was used for each challenge. Native GnRH (5 μg kg–1 bodyweight, i.v.) was injected on Days 15, 25, 40 and 100 after implantation, whereas bovine LH (0.5 μg kg–1 bodyweight, i.v.) was injected on Days 16, 26, 41 and 101. On all occasions after Day 25–26 postimplantation, exogenous GnRH and LH elicited higher plasma concentrations of LH and testosterone in control than deslorelin-treated animals (P < 0.05). It was concluded that, in male dogs, implantation of a GnRH superagonist desensitised the pituitary gonadotrophs to GnRH and also led to a desensitisation of the Leydig cells to LH. This explains, at least in part, the profound reduction in the production of androgen and spermatozoa in deslorelin-treated male dogs.
Identification of novel genes associated with dominant follicle development in cattle
Authors: Zielak Anna E. , Forde Niamh , Park Stephan D. E. , Doohan Fiona , Coussens Paul M. , Smith George W. , Ireland James J. , Lonergan Pat , Evans Alexander C. O.
Published: October 2007

Follicle development is regulated by the interaction of endocrine and intrafollicular factors, as well as by numerous intracellular pathways, which involves the transcription of new genes, although not all are known. The aim of the present study was to determine the expression of a set of unknown genes identified by bovine cDNA microarray analysis in theca and granulosa cells of dominant and subordinate follicles, collected at a single stage of the first follicular wave using quantitative real-time polymerase chain reaction. Differences were further examined at three stages of the follicular wave (emergence, selection and dominance) and bioinformatics tools were used to identify these originally unknown sequences. The suggested name function and proposed role for the novel genes identified are as follows: MRPL41 and VDAC2, involved in apoptosis (dominant follicle development); TBC1D1 stimulates cell differentiation (growth associated with dominant follicle selection and development); STX7, promotes phagocytosis of cells (subordinate follicle regression); and SPC22 and EHD3, intracellular signalling (subordinate follicle regression). In conclusion, we have identified six novel genes that have not been described previously in ovarian follicles that are dynamically regulated during dominant follicle development and presumably help mediate intracellular signalling, cell differentiation, apoptosis and phagocytosis, events critical to follicular development.
Pulsatile release of luteinising hormone during the luteal phase in lactating and weaned sows
Authors: Langendijk P. , Dieleman S. J. , Gerritsen R. , Hazeleger W. , Mainsant M.-L. , Soede N. M. , Kemp B.
Published: October 2007

The present paper describes luteal phase luteinising hormone (LH) in sows that ovulated due to a limited nursing regimen (LN). The LN regimen was imposed either at Day 14 or at Day 21 of lactation. At ovulation, lactation was terminated (n = 8) or sows remained lactating throughout early pregnancy (n = 8). Blood samples were collected every 15 min for 8 h during the day, around Day 11 after ovulation. In addition, lactating sows were bled during the night, when piglets were allowed to suckle. The LH pattern was typical for the luteal phase, with one to five pulses per 8 h. The LH characteristics (frequency, base, average, pulse area) did not differ between lactating and weaned sows, except for the amplitude of LH pulses, which was higher in weaned sows compared with lactating sows (1.22 ± 0.15 v. 0.76 ± 0.11 ng mL–1, respectively; P < 0.05). In lactating sows, average LH, basal LH and the frequency of LH pulses were significantly lower during the night, when piglets were allowed to suckle. The sage of lactation at which LN was imposed did not influence LH. In conclusion, it is unlikely that the small difference in LH explains the considerable difference between lactating and weaned sows in progesterone at Day 12 of pregnancy (24.1 ± 1.3 v. 43.3 ± 4.0 ng mL–1, respectively; P < 0.01). Moreover, the difference in progesterone already exists during the early luteal phase (Day 0–10), when secretion of the corpora lutea is still independent of LH.
Analysis of σ
32
mutants defective in chaperone-mediated feedback control reveals unexpected complexity of the heat shock response
Authors: Yura Takashi , Guisbert Eric , Poritz Mark , Lu Chi Zen , Campbell Elizabeth , Gross Carol A.
Published: October 2007

Protein quality control is accomplished by inducing chaperones and proteases in response to an altered cellular folding state. In
Escherichia coli
, expression of chaperones and proteases is positively regulated by σ
32
. Chaperone-mediated negative feedback control of σ
32
activity allows this transcription factor to sense the cellular folding state. We identified point mutations in σ
32
altered in feedback control. Surprisingly, such mutants are resistant to inhibition by both the DnaK/J and GroEL/S chaperones
in vivo
and also show dramatically increased stability. Further characterization of the most defective mutant revealed that it has almost normal binding to chaperones and RNA polymerase and is competent for chaperone-mediated inactivation
in vitro
. We suggest that the mutants identify a regulatory step downstream of chaperone binding that is required for both inactivation and degradation of σ
32
.