bluuebunny/crossref_metadata_2025 huggingface dataset:
Central ghrelin gastroprotection involves nitric oxide/prostaglandin cross‐talk
Authors: Sibilia V , Pagani F , Rindi G , Lattuada N , Rapetti D , De Luca V , Campanini N , Bulgarelli I , Locatelli V , Guidobono F , Netti C
Published: April 2008

Background and purpose:

Ghrelin, a gut‐brain peptide, is considered a gastroprotective factor in gastric mucosa. We investigated the role of prostaglandins (PG) and the possible interplay between PGs and nitric oxide (NO) in ghrelin gastroprotection against ethanol (EtOH)‐induced gastric lesions.

Experimental approach:

We examined the effects of (1) central ghrelin (4 μg per rat) injection on PGE2 accumulation in normal or EtOH–lesioned gastric mucosa, (2) pretreatment with indomethacin (10 mg kg−1, p.o.), a non‐selective cyclooxygenase (COX) inhibitor, and with a selective COX‐1, SC560 (5 mg kg−1, p.o.) or COX‐2 inhibitor, celecoxib (3.5 mg kg−1, p.o.) on ghrelin gastroprotection against 50% EtOH (1 mL per rat)‐induced gastric lesions, (3) the NO synthase inhibitor, L‐NAME (70 mg kg−1, s.c), on gastric PGE2 content in ghrelin‐treated rats and (4) central ghrelin on the expression of constitutive and inducible NOS and COX mRNA and on the localization of the immunoreactivity for COX‐2 in the gastric mucosa exposed to EtOH.

Key results:

Ghrelin increased PGE2 in normal mucosa, whereas, it reversed the EtOH‐induced PGE2 surge. Ghrelin had no effect on mucosal COX‐1 expression but reduced the EtOH‐induced increase in COX‐2 expression and immunoreactivity. Indomethacin and SC560, but not celecoxib, removed ghrelin gastroprotection. L‐NAME prevented the PGE2 surge induced by ghrelin and, like indomethacin, reduced EtOH‐induced PGE2 increase. Ghrelin enhanced eNOS expression and reduced iNOS mRNA.

Conclusions and implications:

This study shows that COX‐1‐derived PGs are mainly involved in ghrelin gastroprotection and that the constitutive‐derived NO together with PGE2 are involved in ghrelin gastroprotective activity.

British Journal of Pharmacology (2008) 154, 688–697; doi:10.1038/bjp.2008.120; published online 14 April 2008
Diabetic cardiomyopathy: how much does it depend on AGE?
Authors: Montagnani M
Published: April 2008

Diabetic cardiomyopathy refers to dysfunction of cardiac muscle in patients with diabetes that cannot be directly ascribed to hypertension, coronary heart disease or other defined cardiac abnormalities per se. The development of diabetic cardiomyopathy may involve several distinct mechanisms, including increased formation of advanced glycation end products (AGEs) secondary to hyperglycaemia. AGEs may alter structural proteins and lead to increased arterial and myocardial stiffness. Therefore, therapies that prevent or retard development of AGEs in diabetes may be valuable strategies to treat or prevent diabetic cardiomyopathy. In this issue of British Journal of Pharmacology, Wu and colleagues demonstrate that aminoguanidine (inhibitor of AGE formation and protein cross‐linking) treatment of a rat model of type I diabetes (rats made insulin deficient with streptozotocin and nicotinamide treatment) ameliorates detrimental changes in left ventricular structure and function. Results from this study are in agreement with previous investigations, suggesting that aminoguanidine is effective in preventing cardiac hypertrophy and arterial stiffening in experimental animal models of diabetes and emphasize the potential pathogenic role of AGEs in diabetic cardiomyopathy.

British Journal of Pharmacology (2008) 154, 725–726; doi:10.1038/bjp.2008.121; published online 14 April 2008
Regression of aortic valve stenosis by ApoA‐I mimetic peptide infusions in rabbits
Authors: Busseuil D , Shi Y , Mecteau M , Brand G , Kernaleguen A‐E , Thorin E , Latour J‐G , Rhéaume E , Tardif J‐C
Published: April 2008

Background and purpose:

Aortic valve stenosis (AVS) is the most common valvular heart disease, and standard curative therapy remains open heart surgical valve replacement. The aim of our experimental study was to determine if apolipoprotein A‐I (ApoA‐I) mimetic peptide infusions could induce regression of AVS.

Experimental approach:

Fifteen New Zealand White male rabbits received a cholesterol‐enriched diet and vitamin D2 until significant AVS was detected by echocardiography. The enriched diet was then stopped to mimic cholesterol‐lowering therapy and animals were allocated randomly to receive saline (control group, n=8) or an ApoA‐I mimetic peptide (treated group, n=7), three times per week for 2 weeks. Serial echocardiograms and post mortem valve histology were performed.

Key results:

Aortic valve area increased significantly by 25% in the treated group after 14 days of treatment (P=0.012). Likewise, aortic valve thickness decreased by 21% in the treated group, whereas it was unchanged in controls (P=0.0006). Histological analysis revealed that the extent of lesions at the base of valve leaflets and sinuses of Valsalva was smaller in the treated group compared with controls (P=0.032). The treatment also reduced calcification, as revealed by the loss of the positive relationship observed in the control group (r=0.87, P=0.004) between calcification area and aortic valve thickness.

Conclusions and implications:

Infusions of ApoA‐I mimetic peptide lead to regression of experimental AVS. These positive results justify the further testing of high‐density lipoprotein (HDL)‐based therapies in patients with valvular aortic stenosis. Regression of aortic stenosis, if achieved safely, could transform the clinical treatment of this disease.

British Journal of Pharmacology (2008) 154, 765–773; doi:10.1038/bjp.2008.122; published online 14 April 2008
A neuropeptide‐centric view of psychostimulant addiction
Authors: Boutrel B
Published: April 2008

Drugs of abuse all share common properties classically observed in human beings and laboratory animals. They enhance neural firing and dopamine tone within the nucleus accumbens and produce progressively greater drug‐induced motor responses defined as behavioural sensitization. They produce conditioned place preference, a behavioural model of incentive motivation, which highlights the role of environmental cues in drug addiction. They increase brain reward function as seen by a lowering of intracranial self‐stimulation thresholds. And last but not least, they are self‐administered, and sometimes even abused, and can trigger reinstatement of drug‐seeking behaviour in animals extinguished from drug self‐administration. It has long been considered that the reinforcing properties of virtually all drugs of abuse, more specifically psychostimulants, are primarily dependent on activation of the mesolimbic dopamine system. However, recent evidence raises the importance of dopamine‐independent mechanisms in reward‐related behaviours. The overwhelming body of evidence that indicates a critical role for the mesolimbic dopamine system in the reinforcing effect of psychostimulants should not mask the key contribution of other modulatory systems in the brain. This review summarizes the complex and subtle role of several neuropeptidergic systems in various aspects of addictive behaviours observed in laboratory animals exposed to psychostimulants. A special emphasis is given to the cannabinoid, opioid, nociceptin/orphanin FQ, corticotropin‐releasing factor and hypocretin/orexin systems. The relevance of these systems viewed as potential therapeutic targets for drug addiction is discussed in the light of their narrow pharmacological profile and their effectiveness in preventing drug addiction at doses usually not accompanied by severe side effects.

British Journal of Pharmacology (2008) 154, 343–357; doi:10.1038/bjp.2008.133; published online 14 April 2008
Nitric oxide mediates NMDA-induced persistent inhibition of protein synthesis through dephosphorylation of eukaryotic initiation factor 4E-binding protein 1 and eukaryotic initiation factor 4G proteolysis
Authors: Petegnief Valérie , Font-Nieves Míriam , Martín M. Elena , Salinas Matilde , Planas Anna M.
Published: April 2008

Cerebral ischaemia causes long-lasting protein synthesis inhibition that is believed to contribute to brain damage. Energy depletion promotes translation inhibition during ischaemia, and the phosphorylation of eIF (eukaryotic initiation factor) 2α is involved in the translation inhibition induced by early ischaemia/reperfusion. However, the molecular mechanisms underlying prolonged translation down-regulation remain elusive. NMDA (N-methyl-D-aspartate) excitotoxicity is also involved in ischaemic damage, as exposure to NMDA impairs translation and promotes the synthesis of NO (nitric oxide), which can also inhibit translation. In the present study, we investigated whether NO was involved in NMDA-induced protein synthesis inhibition in neurons and studied the underlying molecular mechanisms. NMDA and the NO donor DEA/NO (diethylamine–nitric oxide sodium complex) both inhibited protein synthesis and this effect persisted after a 30 min exposure. Treatments with NMDA or NO promoted calpain-dependent eIF4G cleavage and 4E-BP1 (eIF4E-binding protein 1) dephosphorylation and also abolished the formation of eIF4E–eIF4G complexes; however, they did not induce eIF2α phosphorylation. Although NOS (NO synthase) inhibitors did not prevent protein synthesis inhibition during 30 min of NMDA exposure, they did abrogate the persistent inhibition of translation observed after NMDA removal. NOS inhibitors also prevented NMDA-induced eIF4G degradation, 4E-BP1 dephosphorylation, decreased eIF4E–eIF4G-binding and cell death. Although the calpain inhibitor calpeptin blocked NMDA-induced eIF4G degradation, it did not prevent 4E-BP1 dephosphorylation, which precludes eIF4E availability, and thus translation inhibition was maintained. The present study suggests that eIF4G integrity and hyperphosphorylated 4E-BP1 are needed to ensure appropriate translation in neurons. In conclusion, our data show that NO mediates NMDA-induced persistent translation inhibition and suggest that deficient eIF4F activity contributes to this process.
The roles of Tyr91 and Lys162 in general acid–base catalysis in the pigeon NADP+-dependent malic enzyme
Authors: Kuo Cheng-Chin , Lin Kuan-Yu , Hsu Yau-Jung , Lin Shu-Yu , Lin Yu-Tsen , Chang Gu-Gang , Chou Wei-Yuan
Published: April 2008

The role of general acid–base catalysis in the enzymatic mechanism of NADP+-dependent malic enzyme was examined by detailed steady-state kinetic studies through site-directed mutagenesis of the Tyr91 and Lys162 residues in the putative catalytic site of the enzyme. Y91F and K162A mutants showed approx. 200- and 27000-fold decreases in kcat values respectively, which could be partially recovered with ammonium chloride. Neither mutant had an effect on the partial dehydrogenase activity of the enzyme. However, both Y91F and K162A mutants caused decreases in the kcat values of the partial decarboxylase activity of the enzyme by approx. 14- and 3250-fold respectively. The pH-log(kcat) profile of K162A was found to be different from the bell-shaped profile pattern of wild-type enzyme as it lacked a basic pKa value. Oxaloacetate, in the presence of NADPH, can be converted by malic enzyme into L-malate by reduction and into enolpyruvate by decarboxylation activities. Compared with wild-type, the K162A mutant preferred oxaloacetate reduction to decarboxylation. These results are consistent with the function of Lys162 as a general acid that protonates the C-3 of enolpyruvate to form pyruvate. The Tyr91 residue could form a hydrogen bond with Lys162 to act as a catalytic dyad that contributes a proton to complete the enol–keto tautomerization.
Trp359 regulates flavin thermodynamics and coenzyme selectivity in Mycobacterium tuberculosis FprA
Authors: Neeli Rajasekhar , Sabri Muna , McLean Kirsty J. , Dunford Adrian J. , Scrutton Nigel S. , Leys David , Munro Andrew W.
Published: April 2008

Mtb (Mycobacterium tuberculosis) FprA (flavoprotein reductase A) is an NAD(P)H-dependent FAD-binding reductase that is structurally related to mammalian adrenodoxin reductase, and which supports the catalytic function of Mtb cytochrome P450s. Trp359, proximal to the FAD, was investigated in light of its potential role in controlling coenzyme interactions, as observed for similarly located aromatic residues in diflavin reductases. Phylogenetic analysis indicated that a tryptophan residue corresponding to Trp359 is conserved across FprA-type enzymes and in adrenodoxin reductases. W359A/H mutants of Mtb FprA were generated, expressed and the proteins characterized to define the role of Trp359. W359A/H mutants exhibited perturbed UV-visible absorption/fluorescence properties. The FAD semiquinone formed in wild-type NADPH-reduced FprA was destabilized in the W359A/H mutants, which also had more positive FAD midpoint reduction potentials (−168/−181 mV respectively, versus the standard hydrogen electrode, compared with −230 mV for wild-type FprA). The W359A/H mutants had lower ferricyanide reductase kcat and NAD(P)H Km values, but this led to improvements in catalytic efficiency (kcat/Km) with NADH as reducing coenzyme (9.6/18.8 μM−1·min−1 respectively, compared with 5.7 μM−1·min−1 for wild-type FprA). Stopped-flow spectroscopy revealed NAD(P)H-dependent FAD reduction as rate-limiting in steady-state catalysis, and to be retarded in mutants (e.g. limiting rate constants for NADH-dependent FAD reduction were 25.4 s−1 for wild-type FprA and 4.8 s−1/13.4 s−1 for W359A/H mutants). Diminished mutant FAD content (particularly in W359H FprA) highlighted the importance of Trp359 for flavin stability. The results demonstrate that the conserved Trp359 is critical in regulating FprA FAD binding, thermodynamic properties, catalytic efficiency and coenzyme selectivity.
Proteasome-dependent degradation of α-catenin is regulated by interaction with ARMc8α
Authors: Suzuki Takeyuki , Ueda Atsuhisa , Kobayashi Nobuaki , Yang Jun , Tomaru Koji , Yamamoto Masaki , Takeno Mitsuhiro , Ishigatsubo Yoshiaki
Published: April 2008

ARMc8 (armadillo-repeat-containing protein 8) is a key component of the CTLH (C-terminal to lissencephaly type-1-like homology motif) complex in mammalian cells. This complex is well conserved in Saccharomyces cerevisiae and has been characterized as a FBPase (fructose-1, 6-bisphosphatase)-degrading complex. The yeast homologue of ARMc8, Gid (glucose-induced degradation) 5p, plays an essential role in the ubiquitin- and proteasome-dependent degradation of FBPase. To elucidate the function of ARMc8, we used a yeast two-hybrid system to screen a human skeletal muscle cDNA library. α-Catenin was isolated as a binding protein of ARMc8α. This association was confirmed by co-immunoprecipitation assay using MDCK (Madin–Darby canine kidney) cells in which exogenous α-catenin and ARMc8α were overexpressed. The association was also confirmed by co-immunoprecipitation assay using endogenous proteins in untransfected MDCK cells. We then used immunofluorescence microscopy of MDCK cells and C2C12 cells to investigate the intracellular distribution of ARMc8. Exogenously expressed ARMc8 was co-localized with α-catenin and β-catenin along the cell membrane, suggesting an association between α-catenin and ARMc8 in the cells. To compare the binding domain of α-catenin with ARMc8α with that of β-catenin, we performed a co-immunoprecipitation assay, again using 5′- and 3′-deletion constructs of α-catenin. The N-terminal sequence (amino acids 82–148) of α-catenin was sufficient to bind to both ARMc8α and β-catenin. Next, we investigated the proteasome-dependent degradation of α-catenin by immunoblotting using proteasome inhibitors. Co-expression of ARMc8α with α-catenin resulted in rapid degradation of the exogenous α-catenin. Furthermore, ARMc8 knockdown inhibited α-catenin degradation and prolonged the half-life of α-catenin. We conclude that ARMc8α associates with α-catenin and up-regulates its degradation.
Role of a tryptophan anchor in human topoisomerase I structure, function and inhibition
Authors: Laco Gary S. , Pommier Yves
Published: April 2008

Human Top1 (topoisomerase I) relaxes supercoiled DNA during cell division and transcription. Top1 is composed of 765 amino acids and contains an unstructured N-terminal domain of 200 amino acids, and a structured functional domain of 565 amino acids that binds and relaxes supercoiled DNA. In the present study we examined the region spanning the junction of the N-terminal domain and functional domain (junction region). Analysis of several published Top1 structures revealed that three tryptophan residues formed a network of aromatic stacking interactions and electrostatic interactions that anchored the N-terminus of the functional domain to sub-domains containing the nose cone and active site. Mutation of the three tryptophan residues (Trp203/Trp205/Trp206) to an alanine residue, either individually or together, in silico revealed that the individual tryptophan residue's contribution to the tryptophan ‘anchor’ was additive. When the three tryptophan residues were mutated to alanine in vitro, the resulting mutant Top1 differed from wild-type Top1 in that it lacked processivity, exhibited resistance to camptothecin and was inactivated by urea. The results indicated that the tryptophan anchor stabilized the N-terminus of the functional domain and prevented the loss of Top1 structure and function.
ArHsp21, a developmentally regulated small heat-shock protein synthesized in diapausing embryos of Artemia franciscana
Authors: Qiu Zhijun , MacRae Thomas H.
Published: April 2008

Embryos of the crustacean, Artemia franciscana, undergo alternative developmental pathways, producing either larvae or encysted embryos (cysts). The cysts enter diapause, characterized by exceptionally high resistance to environmental stress, a condition thought to involve the sHSP (small heat-shock protein), p26. Subtractive hybridization has revealed another sHSP, termed ArHsp21, in diapause-destined Artemia embryos. ArHsp21 shares sequence similarity with p26 and sHSPs from other organisms, especially in the α-crystallin domain. ArHsp21 is the product of a single gene and its synthesis occurred exclusively in diapause-destined embryos. Specifically, ArHsp21 mRNA appeared 2 days post-fertilization, followed 1 day later by the protein, and then increased until embryo release at day 5. No ArHsp21 protein was detected in embryos developing directly into larvae, although there was a small amount of mRNA at 3 days post-fertilization. The protein was degraded during post-diapause development and had disappeared completely from second instar larvae. ArHsp21 formed large oligomers in encysted embryos and transformed bacteria. When purified from bacteria, ArHsp21 functioned as a molecular chaperone in vitro, preventing heat-induced aggregation of citrate synthase and reduction-driven denaturation of insulin. Sequence characteristics, synthesis patterns and functional properties demonstrate clearly that ArHsp21 is an sHSP able to chaperone other proteins and contribute to stress tolerance during diapause. As such, ArHsp21 would augment p26 chaperone activity and it may also possess novel activities that benefit Artemia embryos exposed to stress.
Computational and experimental studies on the catalytic mechanism of biliverdin-IXβ reductase
Authors: Smith Liam J. , Browne Seamus , Mulholland Adrian J. , Mantle Timothy J.
Published: April 2008

BVR-B (biliverdin-IXβ reductase) also known as FR (flavin reductase) is a promiscuous enzyme catalysing the pyridine-nucleotide-dependent reduction of a variety of flavins, biliverdins, PQQ (pyrroloquinoline quinone) and ferric ion. Mechanistically it is a good model for BVR-A (biliverdin-IXα reductase), a potential pharmacological target for neonatal jaundice and also a potential target for adjunct therapy to maintain protective levels of biliverdin-IXα during organ transplantation. In a commentary on the structure of BVR-B it was noted that one outstanding issue remained: whether the mechanism was a concerted hydride transfer followed by protonation of a pyrrolic anion or protonation of the pyrrole followed by hydride transfer. In the present study we have attempted to address this question using QM/MM (quantum mechanics/molecular mechanics) calculations. QM/MM potential energy surfaces show that the lowest energy pathway proceeds with a positively charged pyrrole intermediate via two transition states. These initial calculations were performed with His153 as the source of the proton. However site-directed mutagenesis studies with both the H153A and the H153N mutant reveal that His153 is not required for catalytic activity. We have repeated the calculation with a solvent hydroxonium donor and obtain a similar energy landscape indicating that protonation of the pyrrole is the most likely first step followed by hydride transfer and that the required proton may come from bulk solvent. The implications of the present study for the design of inhibitors of BVR-A are discussed.
A critical role in structure-specific DNA binding for the acetylatable lysine residues in HMGB1
Authors: Assenberg René , Webb Michelle , Connolly Edward , Stott Katherine , Watson Matthew , Hobbs Josie , Thomas Jean O.
Published: April 2008

The structure-specific DNA-binding protein HMGB1 (high-mobility group protein B1) which comprises two tandem HMG boxes (A and B) and an acidic C-terminal tail, is acetylated in vivo at Lys2 and Lys11 in the A box. Mutation to alanine of both residues in the isolated A domain, which has a strong preference for pre-bent DNA, abolishes binding to four-way junctions and 88 bp DNA minicircles. The same mutations in full-length HMGB1 also abolish its binding to four-way junctions, and binding to minicircles is substantially impaired. In contrast, when the acidic tail is absent (AB di-domain) there is little effect of the double mutation on four-way junction binding, although binding to minicircles is reduced ∼15-fold. Therefore it appears that in AB the B domain is able to substitute for the non-functional A domain, whereas in full-length HMGB1 the B domain is masked by the acidic tail. In no case does single substitution of Lys2 or Lys11 abolish DNA binding. The double mutation does not significantly perturb the structure of the A domain. We conclude that Lys2 and Lys11 are critical for binding of the isolated A domain and HMGB1 to distorted DNA substrates.
Structure and Cu(I)-binding properties of the N-terminal soluble domains of Bacillus subtilis CopA
Authors: Singleton Chloe , Banci Lucia , Ciofi-Baffoni Simone , Tenori Leonardo , Kihlken Margaret A. , Boetzel Ruth , Le Brun Nick E.
Published: April 2008

CopA, a P-type ATPase from Bacillus subtilis, plays a major role in the resistance of the cell to copper by effecting the export of the metal across the cytoplasmic membrane. The N-terminus of the protein features two soluble domains (a and b), that each contain a Cu(I)-binding motif, MTCAAC. We have generated a stable form of the wild-type two-domain protein, CopAab, and determined its solution structure. This was found to be similar to that reported previously for a higher stability S46V variant, with minor differences mostly confined to the Ser46-containing β3-strand of domain a. Chemical-shift analysis demonstrated that the two Cu(I)-binding motifs, located at different ends of the protein molecule, are both able to participate in Cu(I) binding and that Cu(I) is in rapid exchange between protein molecules. Surprisingly, UV–visible and fluorescence spectroscopy indicate very different modes of Cu(I) binding below and above a level of 1 Cu(I) per protein, consistent with a major structural change occurring above 1 Cu(I) per CopAab. Analytical equilibrium centrifugation and gel filtration results show that this is a result of Cu(I)-mediated dimerization of the protein. The resulting species is highly luminescent, indicating the presence of a solvent-shielded Cu(I) cluster.
Expression and function of ephrin-B1 and its cognate receptor EphB2 in human atherosclerosis: from an aspect of chemotaxis
Authors: Sakamoto Aiji , Ishibashi-Ueda Hatsue , Sugamoto Yuka , Higashikata Takeo , Miyamoto Susumu , Kawashiri Masa-aki , Yagi Kunimasa , Konno Tetsuo , Hayashi Kenshi , Fujino Noboru , Ino Hidekazu , Takeda Yoshiyu , Yamagishi Masakazu
Published: April 2008

Although several cytokines and chemokines have been demonstrated to play pivotal roles in the pathophysiological conditions of atherosclerosis, few findings exist regarding the expression and function of cytokine-modulating molecules such as ephrin-Bs and their cognate receptors, EphBs, in human atherosclerosis. Therefore, in the present study, we screened novel genes modulating atherogenesis by cDNA array and quantitatively determined them by real-time RT (reverse transcription)-PCR in human carotid atherosclerotic plaques. Ephrin-B1 and EphB2, key regulators of embryogenesis, were significantly up-regulated in plaques compared with those in adjacent control tissues [ephrin-B1, 0.638±0.106 compared with 0.831±0.152, or 130% (P<0.05); EphB2, 1.296±0.281 compared with 2.233±0.506, or 172% (P<0.05)]. Immunohistological analysis demonstrated that both ephrin-B1 and EphB2 were expressed in macrophages and T-lymphocytes in plaques as well as in monocytes, T-lymphocytes and arterial endothelial cells isolated from healthy adults. Interestingly, the extracellular domains of ephrin-B1 and EphB2, the expression of which were both enhanced in stimulated THP-1 cells, significantly inhibited spontaneous (22.5 and 27.6% respectively; P<0.01) and MCP-1 (monocyte chemoattractant protein-1)-dependent (29.7 and 22.6% respectively; P<0.01) migration of monocytes. In conclusion, these results demonstrate that ephrin-B1 and EphB2 are overexpressed in atherosclerotic tissue and might locally regulate cell migration, possibly through modulating cytokine-related chemotaxic activity; however, the functional role of these molecules in atherogenesis should be investigated further.
Decrease in oxidative stress through supplementation of vitamins C and E is associated with a reduction in blood pressure in patients with essential hypertension
Authors: Rodrigo Ramón , Prat Hernán , Passalacqua Walter , Araya Julia , Bächler Jean P.
Published: April 2008

Oxidative stress has been associated with mechanisms of EH (essential hypertension). The aim of the present study was to test the hypothesis that the antioxidant properties of vitamins C and E are associated with a decrease in BP (blood pressure) in patients with EH. A randomized double-blind placebo-controlled clinical trial was conducted in 110 men with grade 1 EH (35–60 years of age without obesity, dyslipidaemia and diabetes mellitus, non-smokers, not undergoing vigorous physical exercise, without the use of any medication and/or high consumption of fruit and vegetables). Participants were randomly assigned to receive either vitamins C+E [vitamin C (1 g/day) plus vitamin E (400 international units/day)] or placebo for 8 weeks. Measurements included 24 h ambulatory BP and blood analysis of oxidative-stress-related parameters in erythrocytes (GSH/GSSH ratio, antioxidant enzymes and malondialdehyde) and plasma [FRAP (ferric reducing ability of plasma)], and levels of 8-isoprostane, vitamins C and E were measured at baseline and after treatment. Following administration of vitamins C+E, patients with EH had significantly lower systolic BP, diastolic BP and mean arterial BP and higher erythrocyte and serum antioxidant capacity compared with either placebo-treated patients with EH or the patients with EH at baseline prior to treatment. BP correlated positively with plasma 8-isoprostane levels and negatively with plasma FRAP levels in the vitamins C+E- and placebo-treated groups. In conclusion, the present study supports the view that oxidative stress is involved in the pathogenesis of EH, and that enhancement of antioxidant status by supplementation with vitamins C and E in patients with EH is associated with lower BP. This suggests intervention with antioxidants as an adjunct therapy for hypertension.
Adaptive biasing force method for scalar and vector free energy calculations
Authors: Darve Eric , Rodríguez-Gómez David , Pohorille Andrew
Published: April 2008

In free energy calculations based on thermodynamic integration, it is necessary to compute the derivatives of the free energy as a function of one (scalar case) or several (vector case) order parameters. We derive in a compact way a general formulation for evaluating these derivatives as the average of a mean force acting on the order parameters, which involves first derivatives with respect to both Cartesian coordinates and time. This is in contrast with the previously derived formulas, which require first and second derivatives of the order parameter with respect to Cartesian coordinates. As illustrated in a concrete example, the main advantage of this new formulation is the simplicity of its use, especially for complicated order parameters. It is also straightforward to implement in a molecular dynamics code, as can be seen from the pseudocode given at the end. We further discuss how the approach based on time derivatives can be combined with the adaptive biasing force method, an enhanced sampling technique that rapidly yields uniform sampling of the order parameters, and by doing so greatly improves the efficiency of free energy calculations. Using the backbone dihedral angles Φ and Ψ in N-acetylalanyl-N′-methylamide as a numerical example, we present a technique to reconstruct the free energy from its derivatives, a calculation that presents some difficulties in the vector case because of the statistical errors affecting the derivatives.
X-ray diffraction study of the optimization of MgO growth conditions for magnetic tunnel junctions
Authors: O Se Young , Lee Chan-Gyu , Shapiro Alexander J. , Egelhoff William F. , Vaudin Mark D. , Ruglovsky Jennifer L. , Mallett Jonathan , Pong Philip W. T.
Published: April 2008

We have carried out a systematic study optimizing the MgO growth via preparation and sputtering conditions and underlayer structures. It was found that to prevent water vapor which is detrimental to MgO (200) growth, the chamber pressure needs to be reduced below 10−8Torr. Simple underlayers such as 5nm CoFeB tend to give better MgO, but we have also succeeded in growing MgO on more complicated underlayers such as 1 Ta/20 Au/5 Co40Fe40B20 and 1 Ta/20 conetic (Ni77Fe14Cu5Mo4)∕1.5 Co40Fe40B20 (units in nanometers). We accomplished this by extensive baking of the deposition chamber and use of Ti-getter films. Short sputtering distance and high sputtering power were found to optimize MgO deposition. We found that both preparation and sputtering conditions have important effects on the MgO growth. X-ray diffraction analysis was used as the characterization tool for optimizing the MgO growth conditions.
Spray deposition of nanocrystalline Ni1−xZnxFe2O4 (x⩽0.6) films from polyol-mediated sol: Microstructure and magnetic properties
Authors: Beji Z. , Ammar S. , Smiri L. S. , Vaulay M.-J. , Herbst F. , Gallas B. , Fiévet F.
Published: April 2008

Static-spray deposition of a polyol-based sol, containing nanoparticles of NiZn ferrite, on a moderately heated glass support, has been used to generate crystalline thin films. The films exhibit superparamagnetic behavior with a blocking temperature, which decreases as the zinc content increases, due to their nanocrystalline character. At low temperature, the films are ferrimagnetic; the saturation magnetization and the coercivity depend markedly on both the zinc content and the microstructure.
Finding important anharmonic terms in the sixth-order potential energy function by the scaled hypersphere search method: An application to vibrational analyses of molecules and clusters
Authors: Maeda Satoshi , Watanabe Yu , Ohno Koichi
Published: April 2008

A fitting method of the sixth-order potential energy function is proposed, where ab initio potential energy data for the fitting are sampled in directions containing maximal anharmonic downward distortions detected by the scaled hypersphere search (SHS) method. This technique has been applied to H2O, HCHO, HCOOH, C2H4, CH3OH, CH3CHO, CH3NH2, B2H6, (H2O)2, and (H2O)3, where, without using the symmetry, 176, 904, 1432, 2992, 2520, 2760, 3608, 6232, 768, and 1456 times single-point energy calculations, respectively, were required for obtaining anharmonic terms. Experimental IR peak positions of not only fundamentals but also overtones and combinations in the excitation energy range of 1000–4000cm−1 could be reproduced very accurately by the post-vibrational self-consistent field theory employing potential functions obtained by the present SHS based polynomial fitting method.
The structure and energetics of (GaAs)n, (GaAs)n−, and (GaAs)n+ (n=2–15)
Authors: Gutsev G. L. , Johnson E. , Mochena M. D. , Bauschlicher C. W.
Published: April 2008

Electronic and geometrical structures of neutral, negatively, and positively charged (GaAs)n clusters are computed using density functional theory with generalized gradient approximation. All-electron computations are performed on (GaAs)2–(GaAs)9 while effective core potentials (ECPs) are used for (GaAs)9–(GaAs)15. Calibration calculations on GaAs and (GaAs)9 species support the use of the ECP for the larger clusters. The ground-state geometries of (GaAs)n− and/or (GaAs)n+ are different from the corresponding neutral ground-state geometry, except for n=7, 9, 12, 14, and 15, where the neutral and ions have similar structures. Beginning with n=6, all atoms are three coordinate, except for (GaAs)10+ and (GaAs)13+. For the larger species, there is a competition between fullerenes built from hexagons and rhombi and geometrical configurations where Ga–Ga and As–As bonds are formed, which results in the formation of pentagons. As expected, the static polarizability varies in the order of anion>neutral>cation, but the values are rather similar for all three charge states. The thermodynamic stability for the loss of GaAs is reported.
Quantum theory of (femtosecond) time-resolved stimulated Raman scattering
Authors: Sun Zhigang , Lu J. , Zhang Dong H. , Lee Soo-Y.
Published: April 2008

We present a complete perturbation theory of stimulated Raman scattering (SRS), which includes the new experimental technique of femtosecond stimulated Raman scattering (FSRS), where a picosecond Raman pump pulse and a femtosecond probe pulse simultaneously act on a stationary or nonstationary vibrational state. It is shown that eight terms in perturbation theory are required to account for SRS, with observation along the probe pulse direction, and they can be grouped into four nonlinear processes which are labeled as stimulated Raman scattering or inverse Raman scattering (IRS): SRS(I), SRS(II), IRS(I), and IRS(II). Previous FSRS theories have used only the SRS(I) process or only the “resonance Raman scattering” term in SRS(I). Each process can be represented by an overlap between a wave packet in the initial electronic state and a wave packet in the excited Raman electronic state. Calculations were performed with Gaussian Raman pump and probe pulses on displaced harmonic potentials to illustrate various features of FSRS, such as high time and frequency resolution; Raman gain for the Stokes line, Raman loss for the anti-Stokes line, and absence of the Rayleigh line in off-resonance FSRS from a stationary or decaying v=0 state; dispersive line shapes in resonance FSRS; and the possibility of observing vibrational wave packet motion with off-resonance FSRS.
Extracting maximum information from polarized surface vibrational spectra: Application to etched, H-terminated Si(110) surfaces
Authors: Clark Ian T. , Aldinger Brandon S. , Gupta Ankush , Hines Melissa A.
Published: April 2008

A general method to maximize the information extracted from polarized surface absorption spectra is developed and applied to the study of etched Si(110) surfaces. In essence, this technique transforms spectra from the experimental reference frame, which is defined by the direction of the surface electric field during irradiation by s- and p-polarized light, into a more appropriate Cartesian reference frame defined by the surface normal and the plane of incidence. If the Cartesian reference frame is aligned with high symmetry directions of the system, significant spectral simplification can result. This analysis relies on the well-known boundary conditions on interfacial electric fields and is independent of any adsorbate screening or the effective dielectric constant of the adsorbate layer. The validity of this analysis is demonstrated on the spectra of NH4F-etched, H-terminated Si(110). The transition dipole moments of the symmetric and antisymmetric SiH stretch modes associated with flat terraces are polarized along the [110] and [001] directions, respectively. Two additional modes with transition dipoles polarized along the [001] and [11¯0] directions are assigned to defect species associated with microfaceting and other surface roughness. Data taken in two different experimental geometries are shown to be in excellent quantitative agreement, confirming the validity of the technique. Additionally, the measured adsorbate layer dielectric constant is in good agreement with previously reported values for hydrogen-terminated silicon surfaces.
Measuring current by counting electrons in a nanowire quantum dot
Authors: Gustavsson S. , Shorubalko I. , Leturcq R. , Schön S. , Ensslin K.
Published: April 2008

We measure current by counting single electrons tunneling through an InAs nanowire quantum dot (QD). The charge detector is realized by fabricating a quantum point contact in close vicinity to the nanowire. The results based on electron counting compare well to a direct measurements of the QD current, when taking the finite bandwidth of the detector into account. The ability to detect single electrons also opens up possibilities for manipulating and detecting individual spins in nanowire QDs.
Pressure effects on CrCl63− embedded in cubic Cs2NaMCl6 (M=Sc,Y) lattices: Study through periodic and cluster calculations
Authors: García-Lastra J. M. , Moreno M. , Barriuso M. T.
Published: April 2008

The structural, elastic, vibrational, and optical properties of cubic elpasolites Cs2NaMCl6 (M=Sc,Y) containing CrCl63− complexes have been investigated by means of both periodic and cluster calculations as a function of pressure in the framework of density functional theory. Aside from calculating the host lattice bulk modulus BH and the local modulus B1 associated with the CrCl63−, complex particular attention is paid to the pressure dependence of Huang–Rhys factors, Sa and Se (related to local a1g and eg modes), and the Stokes shift associated with the first electronic excited state T2g4 (t2g2eg) of CrCl63−. The present calculations provide a big difference between BH=231kbars and B1=676kbars derived for Cs2NaScCl6:Cr3+ at zero pressure which plays a key role for a right interpretation of pressure effects on vibration frequencies and optical parameters due to CrCl63−. The significant decrease of Huang–Rhys factors, Sa and Se, due to the pressure observed experimentally is well accounted for by the present work which supports that ∂Sa∕∂P is determined by the Grüneisen constant γa of the a1g local mode (whose frequency is νa) and the dependence of 10Dq on the metal-ligand distance. At the same time, the present results point out that the Stokes shift would be little pressure dependent in the range of 0–50kbars. Accordingly the Ham effect in the T2g4 (t2g2eg) state of CrCl63− in the cubic elpasolites would also happen for a pressure up to 50kbars but the spin-orbit constant would increase with respect to that at zero pressure. From the analysis carried out in this work it is also concluded that the figures dνa∕dP=0.55cm−1∕kbar and dSa∕dP=−7.2×10−3kbar−1 extracted from the complex emission band of Cs2NaScCl6:Cr3+ are hardly compatible. This fact underlines the usefulness of ab initio calculations for helping in the analysis of complex experimental findings. Finally, as the CrCl63− unit is found to be to a good extent elastically decoupled from the rest of the elpasolite lattice, a model is shown to lead to an approximate relation between the pressure derivative of the local modulus and the Grüneisen constant γa.
Toward accurate thermochemical models for transition metals: G3Large basis sets for atoms Sc–Zn
Authors: Mayhall Nicholas J. , Raghavachari Krishnan , Redfern Paul C. , Curtiss Larry A. , Rassolov Vitaly
Published: April 2008

An augmented valence triple-zeta basis set, referred to as G3Large, is reported for the first-row transition metal elements Sc through Zn. The basis set is constructed in a manner similar to the G3Large basis set developed previously for other elements (H–Ar, K, Ca, Ga–Kr) and used as a key component in Gaussian-3 theory. It is based on a contraction of a set of 15s13p5d Gaussian primitives to 8s7p3d, and also includes sets of f and g polarization functions, diffuse spd functions, and core df polarization functions. The basis set is evaluated with triples-augmented coupled cluster [CCSD(T)] and Brueckner orbital [BD(T)] methods for a small test set involving energies of atoms, atomic ions, and diatomic hydrides. It performs well for the low-lying s→d excitation energies of atoms, atomic ionization energies, and the dissociation energies of the diatomic hydrides. The Brueckner orbital-based BD(T) method performs substantially better than Hartree–Fock–based CCSD(T) for molecules such as NiH, where the starting unrestricted Hartree–Fock wavefunction suffers from a high degree of spin contamination. Comparison with available data for geometries of transition metal hydrides also shows good agreement. A smaller basis set without core polarization functions, G3MP2Large, is also defined.
A mode-coupling theory treatment of the transport coefficients of the Lennard–Jones fluid
Authors: Egorov S. A.
Published: April 2008

We apply mode-coupling theory to study shear viscosity and self-diffusion coefficient of the Lennard–Jones fluid throughout the entire fluid region of the phase diagram. Theoretical results are compared with the extensive simulation data and good agreement is found. In addition, theory is compared to the experimental data on the transport coefficients of inert gas fluids.
Cage and tube structures of medium-sized zinc oxide clusters (ZnO)n (n=24, 28, 36, and 48)
Authors: Wang Baolin , Wang Xiaoqiu , Chen Guibin , Nagase Shigeru , Zhao Jijun
Published: April 2008

Following our recent work which revealed that the lowest-energy structures of (ZnO)n (n=9–18) follow cage and tube structural growth patterns with stacks of small subunits of (ZnO)2 and (ZnO)3 [Wang et al., J. Phys. Chem. C 111, 4956 (2007)], we have extended the search for the most stable structures to some larger clusters, i.e., (ZnO)n (n=24, 28, 36, and 48) by using gradient-corrected density-functional theory (DFT). A number of starting configurations belonging to different structural motifs were generated from handmade constructions with chemical intuition and then optimized via DFT calculations. Within the size range studied, cage and tube structures were found to be the most preferred structural motifs for the (ZnO)n clusters.
Prediction of metastable metal-rare gas fluorides: FMRgF (M=Be and Mg; Rg=Ar, Kr and Xe)
Authors: Jayasekharan T. , Ghanty T. K.
Published: April 2008

The structure, stability, charge redistribution, bonding, and harmonic vibrational frequencies of rare gas containing group II-A fluorides with the general formula FMRgF (where M=Be and Mg; Rg=Ar, Kr, and Xe) have been investigated using second order Møller–Plesset perturbation theory, density functional theory, and coupled cluster theory [CCSD(T)] methods. The species, FMRgF show a quasilinear structure at the minima and a bent structure at the transition state. The predicted species are unstable with respect to the two-body dissociation channel, leading to the global minima (MF2+Rg) on the singlet potential energy surface. However, with respect to other two-body dissociation channel (FM+RgF), they are found to be stable and have high positive energies on the same surface. The computed binding energy for the two-body dissociation channels are 94.0, 164.7, and 199.7kJmol−1 for FBeArF, FBeKrF, FBeXeF, respectively, at CCSD(T) method. The corresponding energy values are 83.4, 130.7, and 180.1kJmol−1 for FMgArF, FMgKrF, and FMgXeF, respectively, at the same level of theory. With respect to the three-body dissociation (FM+Rg+F) channel as well as dissociation into atomic constituent, they are also found to be stable and have high positive energies. The dissociation of the predicted species typically proceeds via MRgF bending mode at the transition state. The computed barrier heights for the transition states are 11.4, 32.2, and 57.6kJmol−1 for FBeArF, FBeKrF, and FBeXeF, respectively, at the CCSD(T) method. The corresponding barrier heights for the Mg containing species are 2.1, 9.2, and 32.1kJmol−1 along the series ArKrXe, respectively. The MRg bond energies of the FMRgF species is significantly higher than the corresponding bond energies of the M+Rg species (∼53 and ∼15kJmol−1 for Be+Ar and Mg+Ar, respectively). The computed energy diagram as well as the geometrical parameters along with the AIM results suggest that the species are metastable with partial covalent character in the MRg bonding. Thus, it may be possible to prepare and to characterize these species using low temperature matrix isolation technique.
Three-dimensional hydrodynamic focusing in a microfluidic Coulter counter
Authors: Scott R. , Sethu P. , Harnett C. K.
Published: April 2008

Electrical impedance-based particle detection or Coulter counting, offers a lab-on-chip compatible method for flow cytometry. Developments in this area will produce devices with greater portability, lower cost, and lower power requirements than fluorescence-based flow cytometry. Because conventional Coulter apertures are prone to clogging, hydrodynamic focusing improves the device by creating fluid-walled channels with variable width to increase sensitivity without the associated risk of blocking the channel. We describe a device that focuses the sample in three dimensions, creating a narrow sample stream on the floor of the channel for close interaction with sensing electrodes. The key to this design is a stepped outlet channel fabricated in a single layer with soft lithography. In contrast to previous impedance-based designs, the new design requires minimal alignment with the substrate. Three-dimensional focusing maximizes the sensitivity of the device to cell-size particles within much larger channels. Impedance-based particle sensing experiments within this device show an increase in percentage conductivity change by a factor of 2.5 over devices that only focus the sample in the horizontal direction.
Mode-selective symmetry control for indirect-drive inertial confinement fusion hohlraums
Authors: Vesey R. A. , Slutz S. A. , Herrmann M. C. , Mehlhorn T. A. , Campbell R. B.
Published: April 2008

Achieving a high degree of radiation symmetry is a critical feature of target designs for indirect-drive inertial confinement fusion. Typically, the radiation flux incident on the capsule is required to be uniform to 1% or better. It is generally possible to design a hohlraum that provides low values of higher-order asymmetry (Legendre mode P10 and above) due to geometric averaging effects. Because low-order intrinsic asymmetry (e.g., Legendre modes P2 and P4) are less strongly reduced by geometric averaging alone, the development of innovative control techniques has been an active area of research in the inertial fusion community over the years. Shields placed inside the hohlraum are one example of a technique that has often been proposed and incorporated into hohlraum target designs. Simple mathematical considerations are presented indicating that radiation shields may be designed to specifically tune lower-order modes (e.g., P4) without deleterious effects on the higher order modes. Two-dimensional view factor and radiation-hydrodynamics simulations confirm these results and support such a path to achieving a highly symmetric x-ray flux. The term “mode-selective” is used because these shields, essentially ring structures offset from the capsule, are designed to affect only a specific Legendre mode (or multiple modes) of interest.