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A 5 MHz phase stabilizing system and beam current monitor for the superconducting linac ALPI at Laboratori Nazionali di Legnaro (LNL) was designed, constructed and tested. The system, based on a 5 MHz resonant phase detector, provides stabilization of the phase of the beam bunches produced by the LNL double drift buncher. In addition, the system gives a non-destructive reading of the pulsed beam current in the range between 0.3 and 140 nA. The high impedance coupling of the preamplifier to the resonant phase detector allows for a sensitivity of 1 mV/nA, which is two orders of magnitude higher than previously reported for this kind of devices. The fast phase stabilization is performed by means of a voltage controlled phase shifter; the long term drifts are corrected using a digitally controlled delay. An automatic phase adjustment of the resonator amplifier output was included, in order to correct for any phase shift generated by the amplifiers due to changes of the input signal level. A general expression of the phase response in resonant phase detectors is evaluated and discussed.

Nitro-fatty acids (NO(2)-FA) are electrophilic signaling mediators formed by reactions of nitric oxide and nitrite. NO(2)-FA exert anti-inflammatory signaling actions through post-translational protein modifications. We report that nitro-oleic acid (OA-NO(2)) stimulates proMMP-7 and proMMP-9 proteolytic activity via adduction of the conserved cysteine switch domain thiolate. Biotin-labeled OA-NO(2) showed this adduction occurs preferentially with latent forms of MMP, confirming a role for thiol alkylation by OA-NO(2) in MMP activation. In addition to regulating pro-MMP activation, MMP expression was modulated by OA-NO(2) via activation of peroxisome proliferator-activated receptor-γ. MMP-9 transcription was decreased in phorbol 12-myristate 13-acetate-stimulated THP-1 macrophages to an extent similar to that induced by the peroxisome proliferator-activated receptor-γ agonist Rosiglitazone. This was affirmed using a murine model of atherosclerosis, ApoE(-/-) mice, where in vivo OA-NO(2) administration suppressed MMP expression in atherosclerotic lesions. These findings reveal that electrophilic fatty acid derivatives can serve as effectors during inflammation, first by activating pro-MMP proteolytic activity via alkylation of the cysteine switch domain, and then by transcriptionally inhibiting MMP expression, thereby limiting the further progression of inflammatory processes.

Vibrocompacted fuel should be seen not only as an unusual method, useful only for testing fuel rods containing sphere-pac fuel. In fact, the liquid metal cooled FBR BOR-60 was completely fueled with vipac fuel rods, produced in an automated pilot plant. The vipac technology was developed and studied on a laboratory scale using granulated uranium oxide with properties comparable to the original fuel. The fuel rods showed good performance and some superior aspects compared to the pellet fuel. These aspects refer to a better thermomechanical stability of the fuel, a higher degree of automation and flexibility to meet special conditions of the fuel cycle. A special condition could be the direct insertion of small amounts of granular metallic getter into the fuel rod to influence the physico-chemical properties of the fuel. A basic condition for further improvement is the use of a programmable dosing facility which we are developing and applying. The aim is to establish an automated fuel cycle technology for the minor actinide transmutation.

Transfer reactions at two near-barrier energies for the systems32S +100,101Ru have been studied. Differential cross sections have been extracted for a large variety of channels, with a set-up yielding good mass, nuclear charge and energy resolutions. A steeper decrease of the measured angular distributions at backward angles with respect to the prediction of a semiclassical theory is interpreted as a loss of transfer flux feeding more complex channels and/or fusion. Coupled channels calculations, which use the transfer form factors derived from the experiment, reproduce the fusion cross sections at sub-barrier energies. Multi-nucleon transfer seems to play an essential role for the fusion process, as evidenced by the found strong correlations. A systematic comparison is made with the systems33S +90,91,92Zr, which have been the object of a previous experimental study with the same set-up.

Redox-sensitive posttranslational modification emerged as important signaling mechanisms. Besides other posttranslational modifications nitroalkylation by nitrated fatty acids mediate favorable anti-inflammatory effects. This review gives an overview of the generation and the reactivity of nitrated fatty acids. Additionally, it provides insights into the so far described pathways regulated by nitrated fatty acids. This article is part of a Special Issue entitled Regulation of Cellular Processes by S-nitrosylation.

The recent increase in fungal infections, especially among AIDS patients, has resulted in the need for more effective antifungal agents. In our search for such agents, we focused on developing compounds which inhibit fungal dihydrofolate reductase (DHFR). A series of 25 5-(arylthio)-2,4-diaminoquinazolines were synthesized as potentially selective inhibitors of Candida albicans DHFR. The majority of the compounds were potent inhibitors of C. albicans DHFR and much less active against human DHFR. High selectivity, as defined by the ratio of the I50 values for human and C. albicans DHFR, was achieved by compounds with bulky and rigid 4-substituents in the phenylthio moiety. For example, 5-[(4-morpholinophenyl)thio]-2,4-diaminoquinazoline displayed a selectivity ratio of 540 and was the most selective inhibitor synthesized to date. Substitution in the 2- or 3-position of the 5-phenylthio group provided only marginal selectivity. 6-Substituted-5-[(4-tert-butylphenyl)thio]-2,4-diaminoquinazolines showed potent activity against the C. albicans enzyme but were equally active against human DHFR. Most of the selective compounds were also good inhibitors of C. albicans cell growth, with minimum inhibitory concentration values as low as 0.05 microgram/ mL.

A series of 7,8-dialkylpyrrolo[3,2-f]quinazolines were prepared as inhibitors of dihydrofolate reductase (DHFR). On the basis of an apparent inverse relationship between compound size and antifungal activity, the compounds were designed to be relatively small and compact. Inhibitor design was aided by a GRID analysis of the three-dimensional structure of Candida albicans DHFR, which suggested that relatively small, branched alkyl groups at the 7- and 8-positions of the pyrroloquinazoline ring system would provide optimal interactions with a hydrophobic region of the protein. The compounds were potent inhibitors of fungal and human DHFR, with Ki values as low as 7.1 and 0.1 pM, respectively, and were highly active against C. albicans and an array of tumor cell lines. In contrast to known lipophilic inhibitors of DHFR such as trimetrexate and piritrexim, members of this series of pyrroloquinazolines were not susceptible to P-glycoprotein-mediated multidrug resistance and also showed significant distribution...

The decay of the238U superdeformed shape isomer has been reinvestigated by detecting for the first time simultaneously the fission and the gamma-back decay. An electrostatic deflection system has been used to transport the238mU recoils, produced in a238U(d, pn) reaction with a pulsed beam of 18 MeV deuterons, in front of a detector set-up consisting of three ion-implanted solidstate detectors and a Ge(Li) gamma-detector. The gamma-back decay has been measured in coincidence with conversion electrons of the 2+ → 0+ transition deexciting the first rotational state in238U. Two gamma-transitions of 2.513 MeV and 1.878 MeV have been observed with half-lives consistent with the result obtained for the decay by delayed fissionT1/2=(298±18) ns.

A test for quantitative fit testing of dust/mist and dust/mist/fume respirators has been developed. Currently, respirators with filters of these approval classes have to be modified so they resemble HEPA respirators before quantitative fit testing can be done. With the developed test, such modification is unnecessary. The test uses an aerosol which reduces filter penetration through the respirators while allowing leaks through the face seal to be detected and measured. A test for quantitative fit testing of dust/mist and dust/mist/fume respirators has been developed. Currently, respirators with filters of these approval classes have to be modified so they resemble HEPA respirators before quantitative fit testing can be done. With the developed test, such modification is unnecessary. The test uses an aerosol which reduces filter penetration through the respirators while allowing leaks through the face seal to be detected and measured.

Over the last 50 years, the posttranslational modification (PTM) of proteins has emerged as a central mechanism for cells to regulate metabolism, growth, differentiation, cell-cell interactions, and immune responses. By influencing protein structure and function, PTM leads to a multiplication of proteome diversity. Redox-dependent PTMs, mediated by environmental and endogenously generated reactive species, induce cell signaling responses and can have toxic effects in organisms. PTMs induced by the electrophilic by-products of redox reactions most frequently occur at protein thiols; other nucleophilic amino acids serve as less favorable targets. Advances in mass spectrometry and affinity-chemistry strategies have improved the detection of electrophile-induced protein modifications both in vitro and in vivo and have revealed a high degree of amino acid and protein selectivity of electrophilic PTM. The identification of biological targets of electrophiles has motivated further study of the functional impact of various PTM reactions on specific signaling pathways and how this might affect organisms.

Observational clinical and ex vivo studies have established a strong association between atrial fibrillation and inflammation1. However, whether inflammation is the cause or the consequence of atrial fibrillation and which specific inflammatory mediators may increase the atria's susceptibility to fibrillation remain elusive. Here we provide experimental and clinical evidence for the mechanistic involvement of myeloperoxidase (MPO), a heme enzyme abundantly expressed by neutrophils, in the pathophysiology of atrial fibrillation. MPO-deficient mice pretreated with angiotensin II (AngII) to provoke leukocyte activation showed lower atrial tissue abundance of the MPO product 3-chlorotyrosine, reduced activity of matrix metalloproteinases and blunted atrial fibrosis as compared to wild-type mice. Upon right atrial electrophysiological stimulation, MPO-deficient mice were protected from atrial fibrillation, which was reversed when MPO was restored. Humans with atrial fibrillation had higher plasma concentrations of MPO and a larger MPO burden in right atrial tissue as compared to individuals devoid of atrial fibrillation. In the atria, MPO colocalized with markedly increased formation of 3-chlorotyrosine. Our data demonstrate that MPO is a crucial prerequisite for structural remodeling of the myocardium, leading to an increased vulnerability to atrial fibrillation.

Electrophilic fatty acids are generated during inflammation by non-enzymatic reactions and can modulate inflammatory responses. We used a new mass spectrometry-based electrophile capture strategy to reveal the formation of electrophilic oxo-derivatives (EFOX) from the omega-3 fatty acids docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA). These EFOX were generated by a cyclooxygenase-2 (COX-2)-catalyzed mechanism in activated macrophages. Modulation of COX-2 activity by aspirin increased the rate of EFOX production and their intracellular levels. Owing to their electrophilic nature, EFOX adducted to cysteine and histidine residues of proteins and activated Nrf2-dependent anti-oxidant gene expression. We confirmed the anti-inflammatory nature of DHA- and DPA-derived EFOX by showing that they can act as peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists and inhibit pro-inflammatory cytokine and nitric oxide production, all within biological concentration ranges. These data support the idea that EFOX are signaling mediators that transduce the beneficial clinical effects of omega-3 fatty acids, COX-2 and aspirin.

Nitrated fatty acids (NO(2)-FA) have been identified as endogenous anti-inflammatory signalling mediators generated by oxidative inflammatory reactions. Herein the in vivo generation of nitro-oleic acid (OA-NO(2)) and nitro-linoleic acid (LNO(2)) was measured in a murine model of myocardial ischaemia and reperfusion (I/R) and the effect of exogenous administration of OA-NO(2) on I/R injury was evaluated.In C57/BL6 mice subjected to 30 min of coronary artery ligation, endogenous OA-NO(2) and LNO(2) formation was observed after 30 min of reperfusion, whereas no NO(2)-FA were detected in sham-operated mice and mice with myocardial infarction without reperfusion. Exogenous administration of 20 nmol/g body weight OA-NO(2) during the ischaemic episode induced profound protection against I/R injury with a 46% reduction in infarct size (normalized to area at risk) and a marked preservation of left ventricular function as assessed by transthoracic echocardiography, compared with vehicle-treated mice. Administration of OA-NO(2) inhibited activation of the p65 subunit of nuclear factor kappaB (NFkappaB) in I/R tissue. Experiments using the NFkappaB inhibitor pyrrolidinedithiocarbamate also support that protection lent by OA-NO(2) was in part mediated by inhibition of NFkappaB. OA-NO(2) inhibition of NFkappaB activation was accompanied by suppression of downstream intercellular adhesion molecule 1 and monocyte chemotactic protein 1 expression, neutrophil infiltration, and myocyte apoptosis.This study reveals the de novo generation of fatty acid nitration products in vivo and reveals the anti-inflammatory and potential therapeutic actions of OA-NO(2) in myocardial I/R injury.

Circulating levels of myeloperoxidase (MPO), a heme enzyme released upon activation of polymorphonuclear neutrophils, predict adverse outcome in patients with impaired left ventricular (LV) function. The MPO −463 G/A promoter polymorphism (rs 2333227) regulates MPO transcription, with the G allele being linked to increased protein expression. The aim of this study was to assess the prognostic information derived from the −463 G/A MPO polymorphism on outcomes of patients with impaired LV function. The −463 G/A promoter MPO genotype as well as MPO plasma levels were determined in 116 patients with impaired LV function. Patients were prospectively followed for a median of 1050 days. The GG genotype was associated with a decrease in overall survival (χ 2 5.80; p = 0.016). This association remained after multivariate adjustment for plasma levels of NT-proBNP, creatinine, hsCRP, and MPO; leukocyte count; and LV function (hazard ratio 3.16 (95% CI 1.17–8.53), p = 0.024) and for classical cardiovascular risk factors (hazard ratio 2.88 (95% CI 1.13–7.33), p = 0.026). Interestingly, we observed no association of the MPO polymorphism with total MPO protein concentration or MPO activity in plasma. The −463 G/A MPO polymorphism is linked to adverse clinical outcome of patients with impaired LV function. Further studies are needed to elucidate the value of this polymorphism for risk stratification.

Nitrated derivatives of fatty acids (NO2-FA) are pluripotent cell-signaling mediators that display anti-inflammatory properties. Current understanding of NO2-FA signal transduction lacks insight into how or if NO2-FA are modified or metabolized upon formation or administration in vivo. Here the disposition and metabolism of nitro-9-cis-octadecenoic (18:1-NO2) acid was investigated in plasma and liver after intravenous injection in mice. High performance liquid chromatography-tandem mass spectrometry analysis showed that no 18:1-NO2 or metabolites were detected under basal conditions, whereas administered 18:1-NO2 is rapidly adducted to plasma thiol-containing proteins and glutathione. NO2-FA are also metabolized via β-oxidation, with high performance liquid chromatography-tandem mass spectrometry analysis of liver lipid extracts of treated mice revealing nitro-7-cis-hexadecenoic acid, nitro-5-cis-tetradecenoic acid, and nitro-3-cis-dodecenoic acid and corresponding coenzyme A derivatives of 18:1-NO2 as metabolites. Additionally, a significant proportion of 18:1-NO2 and its metabolites are converted to nitroalkane derivatives by saturation of the double bond, and to a lesser extent are desaturated to diene derivatives. There was no evidence of the formation of nitrohydroxyl or conjugated ketone derivatives in organs of interest, metabolites expected upon 18:1-NO2 hydration or nitric oxide (•NO) release. Plasma samples from treated mice had significant extents of protein-adducted 18:1-NO2 detected by exchange to added β-mercaptoethanol. This, coupled with the observation of 18:1-NO2 release from glutathione-18:1-NO2 adducts, supports that reversible and exchangeable NO2-FA-thiol adducts occur under biological conditions. After administration of [3H]18:1-NO2, 64% of net radiolabel was recovered 90 min later in plasma (0.2%), liver (18%), kidney (2%), adipose tissue (2%), muscle (31%), urine (6%), and other tissue compartments, and may include metabolites not yet identified. In aggregate, these findings show that electrophilic FA nitroalkene derivatives (a) acquire an extended half-life by undergoing reversible and exchangeable electrophilic reactions with nucleophilic targets and (b) are metabolized predominantly via saturation of the double bond and β-oxidation reactions that terminate at the site of acyl-chain nitration.

Etude des changements des spectres d'absorption acoustiques basses temperatures de ces ceramiques, en fonction de la teneur en oxygene dans l'intervalle 6

Standardized methods were developed to determine the pathogenicity and the degree of virulence of Xanthomonas campestris pv. glycines (Xcg) as well as the reaction of soybean plants in the greenhouse. A glass atomizer is described which allowed uniform inoculation without damaging the leaves. Optimum bacterial concentration was determined as 6 × 106 CFU/ml for the pathogenicity test and 1.3 × 105 CFU/ml for the virulence test. A total of 64 isolates were tested. Forty-five strains were designated as pathogenic, six of which were considered highly virulent. It was shown, for the first time, that large differences in the virulence of Xcg strains exist. All the highly virulent strains of Xcg were fresh isolates from diseased soybean leaves collected in Thailand. On the other hand, all the “old” cultures from bacterial collections possessed a low or very low virulence. Decrease of virulence of the pathogen did not occur very fast, however, that is: not within 2 years when stored on YDC-agar slants. Therefore, the bacteria may be kept on slants at 15 °C for short time storage, but the strains should be preserved permanently as lyophilized cultures. Zusammenfassung Es wurden standardisierte Methoden erarbeitet, um die Pathogenitat und den Virulenzgrad von Xanthomonas campestris pv. glycines, sowie die Reaktion von Sojabohnensorten im Gewachshaus zu erfassen. Hierzu wurde ein Glasspruher hergestellt, der eine gleichmasige Inokulation der Sojabohnenblatter ohne Verletzungen ermoglicht. Als optimale Bakterienkonzentrationen wurden 6×106 GFU/ml fur die Pathogenitatsprufung und 1,3×105 GFU/ml fur die Virulenzprufung ermittelt. Insgesamt wurden 64 Stamme getestet, von denen 45 als pathogen und davon 6 als hoch virulent eingestuft wurden. Es konnte so zum ersten Mal gezeigt werden, das grose Unterschiede in der Virulenz von X. c. pv. glycines-Stammen bestehen. Samtliche hoch virulenten Stamme reprasentierten frische Isolate von befallenen Sojablattern aus Thailand. Andererseits besasen alle alten Kulturen aus Bakteriensammlungen nur eine niedrige oder sehr niedrige Virulenz. Die Abnahme der Virulenz wahrend der Lagerung verlief jedoch nicht sehr schnell. Es wird eine Aufbewahrung der Stamme auf YDC-Agar bei 15 °C oder – noch besser – als lyophilisierte Kulturen empfohlen.

The efficacy of sodium hypochlorite (NaOCl) for restraining cotton seed infestation by Xanthomonas campestris pv. malvacearum was studied. Seeds of three cotton cultivars were artificially inoculated by soaking in suspensions (ca. 5.10 8 CFU/ml) of different strains of Xcm. Twelve h after soaking (at 30°C) various dilutions of NaOCl were added to the soaking suspensions and incubated for another 12 h. The infestation rate of cotyledons and effect on germination were determined 14 and 21 days after treatment under the standardized conditions of a growth chamber (12 h 20,000 Lux at plant height, 30/20 °C day/night, ca. 100 % relative humidity). Cbncentrations below 0.15 % of active chlorine in the soaking-water had no marked effect on reduction of the disease. Goncentrations between 0.45 % to 0.60 % appeared to be most effective without reducing germination rate. Seed germination was affected, however, by concentration of active chlorine above 0.6 %. Seed quality during sodium hypochlorite treatment obviously influenced the effectivity of this measure. Zusammenfassung Es wurde untersucht, ob der Befall von Baumwollsaatgut mit Xanthomonas campestm pv. malvacearum durch Natriumhypochlorit (NaOGl) reduziert werden binn. Zu diesem Zweck wurden die Samen von 3 hoch anfalligen Baumwollsorten kunstlich inokuliert. 12 h nach Einweichen der Samen (bei 30 °C) in Suspensionen von zwei verschiedenen Rassen von Xcm (ca. 5 108 CFU/tnl) wurden unterschiedliche Konzentrationeii von NaOCl der Suspension zugefugt und die Samen fur weitere 12 h eingeweicht. Die Befalls- und Aufgangsraten wurden 14 und 21 Tage nach der Inokulation ermittelt. Konzentrationen imterhalb von 0,15 % aktivem Chlor bewirkten keinen spiirbaren Einflus auf den Befall. Mit weiter ansteigenden Konzentrationen wurde ein deutlicher Befallsruckgang (zwischen 50 bis 100 %) festgestellt. Oberhalb von 0,6 % aktivem Chlor in der Losung wurde jedoch auch ein negativer Einflus auf die Keimfahigkeit der Samen festgestellt, wobei sich Unterschiede zwischen den einzelnen Baumwollsorten fur den NaOCl-Einflus auf Befall und Keimfahigkeit ergaben. Es wird angenommen, das der unterschiedliche Befallsruckgang im Zusammenhang mit dem Entwicklungszustand der Samen einzelner Sorten zur Zeit der Infektion stand.

Smoking remains the leading cause of cardiovascular disease, accounting for almost one third of cardiac deaths in the Western industrialized countries. Atherosclerosis in general, and coronary disease in particular, is now considered an inflammatory disease. Recent research has tried to better characterize the subcellular mechanisms of smoke and nicotine on the vessel wall and circulating mediators of disease. Whereas nicotine-dependent receptor activation on endothelial cells has long been considered to elicit antiinflammatory actions, recent observations reveal that nicotine evokes close interactions between the endothelium and proinflammatory cells: namely, leukocytes. Besides monocytes and macrophages, nicotine has been shown to stimulate neutrophils, a cell species long been considered irrelevant for the progression of atherosclerotic disease. Being stimulated by nicotine, neutrophils generate reactive oxygen species and release prooxidant enzymes like myeloperoxidase, which are capable of entering the vessel wall independently. Central mechanisms by which these enzymes can modulate the structural and functional integrity of the vessel wall have been characterized and increased our understanding of neutrophil-derived changes in vascular homeostasis in response to smoking and nicotine, respectively.

Background: Observational clinical and ex-vivo studies have established a strong association between atrial fibrillation (AF) and inflammation. However, whether inflammation is cause or consequence of AF and which specific inflammatory mediators increase atrial susceptibility to fibrillate remain elusive. Herein, we provide evidence for mechanistic involvement of myeloperoxidase (MPO), a heme enzyme abundantly expressed by neutrophils, in the pathophysiology of AF. Methods and Results: Patients with AF assessed by pacemaker interrogation not only exhibited higher circulating plasma levels of MPO (503.1 [IR:404.6 –880.7] vs. 437.8 [IR:348.9 – 488.0 pmol/l; p=0.03; n=42), they also revealed an increased MPO burden in explanted left atrial tissue as compared to patients devoid of AF. In AF-patients MPO co-localized with markedly increased formation of 3-nitro and 3-chlorotyrosin, protein oxidations known to be catalyzed by MPO. Myeloperoxidase knock-out mice, pretreated with angiotensin II infusion for 2 weeks yielding increased neutrophil activation, revealed strikingly attenuated vulnerability for AF during right atrial electrophysiological stimulation as compared to wild type mice (probability of AF-induction: 3.0 vs. 12.7%; p Conclusion: In conclusion, the current findings not only underscore the significance of neutrophil activation as a critical pathophysiological prerequisite of AF, but reveal that MPO - by oxidatively modifying protein residues and increasing fibrosis of atrial myocytes - is causally linked to the initiation and perpetuation of AF.

In 1962, Menkes et al1 first described a pediatric disorder characterized by hypopigmented brittle hair, doughy skin, connective tissue fragility, failure to thrive, progressive neurological damage, and various defects of the arterial wall. This was termed “kinky hair syndrome” and later was found to be associated with a disturbance in copper metabolism due to mutations in the ATP7A gene. The ATP7A (or Menkes ATPase) is 1 of 2 membrane-bound copper-transporting ATPases (ATP7A and ATP7B) essential for controlling intracellular copper homeostasis. ATP7A is of particular importance for the transfer of copper through the membrane of the trans-Golgi network and hence is important for the so-called secretory pathway of copper.2 In Menkes syndrome, in which the function of the ATP7A transporter is disturbed, systemic copper levels are low because copper export from enterocytes is greatly impaired and copper thus accumulates in the intestine. A critical manifestation of impaired ATP7A function is the limited incorporation of copper, an essential catalytic residue in a variety of enzymes. An early example of this defect was highlighted by insufficient insertion of copper into the tyrosinase of patients with Menkes disease.3 Tyrosinase is the rate-limiting enzyme of melanin formation with defects in its activity leading to low melanin levels in skin, albinism, and the hypopigmentation that is a clinical hallmark of Menkes syndrome. The study by Qin et al,4 published in the current issue of Hypertension , is of interest and significance because a critical linkage has been made between cardiovascular function and the biochemical defects in copper trafficking that are a hallmark of altered ATP7A function. Qin …

Bivalirudin, a direct thrombin inhibitor, has emerged as an important alternative to heparin in patients undergoing percutaneous coronary intervention. However, it remains elusive if potentially adverse extracoagulant properties are responsible for the fact that its favorable effects in clinical studies are mainly driven by a reduction in bleeding events. The aim of the current study was to determine the effects and mechanisms of acute treatment with bivalirudin in comparison to heparin on NO bioavailability, an important factor for the pathogenesis of ischemic events. In particular, we studied the interaction between bivalirudin and myeloperoxidase (MPO), a leukocyte-derived enzyme that consumes endothelial-derived nitric oxide (NO), modifies a variety of biological targets, and thus affects the integrity of the vessel wall. In patients undergoing elective percutaneous coronary intervention, bivalirudin, in contrast to heparin, exhibited a significant decrease in plasma MPO levels (p = 0.03) accompanied by a deterioration of flow-mediated dilation (p = 0.02), a surrogate for endothelial NO bioavailability. In vitro experiments revealed avid binding of bivalirudin to both bovine aortic endothelial cells (BAEC) and MPO. Methylation of bivalirudin carboxyl groups at the carboxyl-terminal end revealed the specific binding site of bivalirudin to MPO. Bivalirudin-facilitated binding of MPO to BAEC resulted also in functional changes in terms of increased NO consumption as well as enhanced MPO-mediated redox modifications. These results illustrate dichotomous extracoagulant properties of heparins and thrombin inhibitors and suggest that bivalirudin acutely impairs endothelial NO bioavailability, thereby underscoring the potentially critical role of MPO as a mediator of vascular function.

Inhibition of the vascular endothelial growth factor (VEGF) signaling pathway has emerged as one of the most promising new approaches for cancer therapy. We describe herein the key steps starting from an initial screening hit leading to the discovery of pazopanib, N(4)-(2,3-dimethyl-2H-indazol-6-yl)-N(4)-methyl-N(2)-(4-methyl-3-sulfonamidophenyl)-2,4-pyrimidinediamine, a potent pan-VEGF receptor (VEGFR) inhibitor under clinical development for renal-cell cancer and other solid tumors.

If left untreated, the common inherited metabolic disorder phenylketonuria (PKU) presents with mental retardation and reduced brain weight. The underlying molecular reasons for these deficits are unknown so far. Using human neuroblastoma cells as a model for normal human neuroblasts elevated phenylalanine, concentrations suppressed proliferation of these cells in culture. Furthermore, microarray and functional assays of these cells revealed that both phenylalanine and the known PPAR gamma agonist rosiglitazone regulated the same set of genes causing subsequently similar changes in the functional assays. The lowered brain weight of PKU patients may thus be the result of reduced neuroblast proliferation caused by phenylalanine-induced stimulation of PPAR gamma receptors. The observation that high concentrations of small substrates can activate receptors may serve as a new paradigm for other metabolic diseases and provides a new approach for the treatment of these disorders by application of specific receptor antagonists. (C) 2008 Elsevier Inc. All rights reserved.

We report on the ``safe'' Coulomb excitation of neutron-rich Cd, Xe, and Ba isotopes in the vicinity of the doubly-magic nucleus 132Sn. The radioactive nuclei have been produced by ISOLDE at CERN and postaccelerated by the REX-ISOLDE facility. The gamma-decay of excited states has been detected by the MINIBALL array. The presented preliminary results for the B(E2) values are consistent with expectations from phenomenological systematics and will be compared with theoretical calculations. Book subtitle: FINUSTAR 2 ispartof: pages:84-88 ispartof: AIP Conference Proceedings vol:1012 issue:1 pages:84-88 ispartof: Frontiers in NUclear STructure, Astrophysics and Reactions: FINUSTAR location:Kos, Greece date:10 Sep - 14 Sep 2007 status: published

A new isomeric state in237Np has been discovered at an excitation energy of (945.3±0.2) keV withT1/2 =(711±40) ns. Six gamma-ray lines have been measured depopulating the isomeric state to known levels in237Np. The comparison of the measured absolute gamma-ray transition probabilities with empirical values yields as most probable spinI andK assignmentI=K=13/2 for this isomeric state. It is most likely a 1-proton-2-neutron quasiparticle state 13/2−π5/2+ [642] +ν7/2− [743] + ν 1/2+ [631]. However, a one-quasiparticle 11/2− [505] configuration for the isomer cannot be excluded.

According to a central composite design samples with deviations from stoichiometry YBa2Cu3O7−x of ±2.5 wt% in the ingredients were prepared. The influence of these deviations on phase content, superconducting properties and microstructure of the ceramics was studied. Entsprechend einem zentral zusammengesetzten Versuchsplan wurden Proben mit Stochiometrieab-weichungen von ±2.5 Gew. % in den Ausgangssubstanzen von YBa2Cu3O7−x hergestellt. Der Einflus dieser Abweichungen auf Phasenzusammensetzung, supraleitende Eigenschaften und Mikrostruktur der Keramik wurden untersucht.

By varying the content ratio of the initial products, nine compounds of the YBaCuO system have been produced. These were studied to find their Tc values, critical currents jc at 77 K and effects of compression stress on the U(j)-curves. Mechanical loading has been found to result in a shift of the U(j)-curve towards a larger current. A correlation between the critical current value, the slope of the U(j)-curve, and the stress induced shift is shown to exist. Samples with equal absolute deviations from the stoichiometric composition reveal close properties, the better the smaller is the deviation.

Double differential cross sections of all prominent transfer channels have been measured in the systems33S +99,91,92Zr at two energies close to the nominal Coulomb barrier. In addition the fusion excitation functions of these systems have been measured below and around the barrier. The angular- andQ-distributions of the most important transfer reactions have been analysed in the framework of a simple semiclassical formalism. Particularly the two-nucleon transfer angular distributions exhibit strong multi step coupling effects which manifest themselves in reduced cross sections at large angles corresponding to close distances. From the angular distributions at forward angles, where a single step character of the transfer reaction can be assumed, approximate form factors have been extracted employing a first order perturbation theory. Within the uncertainties of a schematic coupled channels calculation the isotopic differences of the sub-barrier fusion enhancement can be understood on the basis of the isotopic differences of the transfer form factors andQ-values.

The project of a superconducting linac acting as booster of the LNL-XTU tandem is briefly discussed. Experience with lead plated quarter wave resonators is discussed together with the machine configuration.

The diagnosis and treatment of hepatocellular carcinoma (HCC) have witnessed major changes over the past decade. Until the early 1990s, HCC was a relatively rare malignancy, typically diagnosed at an advanced stage in a symptomatic patient, and there were no known effective palliative or therapeutic options. However, the rising incidence of HCC in several regions around the world coupled with emerging evidence for efficacy of screening in high-risk patients, liver transplantation as a curative option in select patients, ability to make definitive diagnosis using high-resolution imaging of the liver, less dependency on obtaining tissue diagnosis, and proven efficacy of transarterial chemoembolization and sorafenib as palliative therapy have improved the outlook for HCC patients. In this article, we present a summary of the most recent information on screening, diagnosis, staging, and different treatment modalities of HCC, as well as our recommended management approach.

With the development of targeted therapeutics, especially for small-molecule inhibitors, it is important to understand whether the observed in vivo efficacy correlates with the modulation of desired/intended target in vivo. We have developed a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors (VEGFR), platelet-derived growth factor receptor, and c-Kit tyrosine kinases, pazopanib (GW786034), which selectively inhibits VEGF-induced endothelial cell proliferation. It has good oral exposure and inhibits angiogenesis and tumor growth in mice. Because bolus administration of the compound results in large differences in Cmax and Ctrough, we investigated the effect of continuous infusion of a VEGFR inhibitor on tumor growth and angiogenesis. GW771806, which has similar enzyme and cellular profiles to GW786034, was used for these studies due to higher solubility requirements for infusion studies. Comparing the pharmacokinetics by two different routes of administration (bolus p.o. dosing and continuous infusion), we showed that the antitumor and antiangiogenic activity of VEGFR inhibitors is dependent on steady-state concentration of the compound above a threshold. The steady-state concentration required for these effects is consistent with the concentration required for the inhibition of VEGF-induced VEGFR2 phosphorylation in mouse lungs. Furthermore, the steady-state concentration of pazopanib determined from preclinical activity showed a strong correlation with the pharmacodynamic effects and antitumor activity in the phase I clinical trial. [Mol Cancer Ther 2007;6(7):2012–21]

Activation of leukocytes and in particular polymorphonuclear neutrophils (PMN) has emerged as a critical confounder in the pathophysiology of cardiovascular disease: Myeloperoxidase (MPO), one of the principal proteins hosted in and secreted by activated PMN, has been mechanistically linked to endothelial and left ventricular (LV) dysfunction in rodent models of sepsis and ischemic cardiomyopathy. Whether PMN activation is also overt in patients with LV dysfunction of ischemic and nonischemic origin, however, remains elusive. Prospectively, 447 consecutive, stable outpatients were included in this single-center study. In 113 patients with impaired left ventricular function (ejection fraction

The objective of this discussion is to provide a broad overview of Integrated Reservoir Management, using examples from fields around the world. Reservoir management can be viewed as a three component learning system. The first component is reservoir characterization based on the analysis and interpretation of fundamental geoscience and engineering data. The second is quantification of the subsurface via a geologic model, reservoir simulation, and facility model, providing the basis for future depletion plans. The third stage of learning follows production start up as we collect production surveillance data to evaluate the accuracy of the geologic interpretation and development plan. This repeated cycle of interpretation, modeling, and production feedback drives continuous improvement of the subsurface model and depletion plan, maximizing value from both new and mature fields, and cost-effectively recovering more oil and gas

The11,9Be +209Bi subbarrier fusion cross-sections were measured. The good quality of the9Be data allowed also to extract the fusion barrier distribution. The data are in good agreement with the theoretical predictions above the barrier but not below, where the cross-sections are similar, in contradiction with present theories. The barrier distribution for9Be does not evidence fusion processes originating from breakup.

We hypothesized that the level of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide (NO) synthase (eNOS), might determine the endothelial effects of statins.Endothelial NO synthase is up-regulated by statins. However, statins failed to improve endothelial function in some studies. Asymmetric dimethylarginine inhibits eNOS by a mechanism that is reversible by L-arginine.Ninety-eight clinically asymptomatic elderly subjects had their plasma ADMA levels screened. Those in the highest (high ADMA, n = 15) and lowest quartiles of the ADMA distribution (low ADMA, n = 13) were eligible to receive, in a randomized order, simvastatin (40 mg/day), L-arginine (3 g/day), or a combination of both, each for 3 weeks. Endothelium-dependent vasodilation (EDD) was assessed by brachial artery ultrasound.Simvastatin had no effect on EDD in subjects with high ADMA (6.2 +/- 1.2% vs. 6.1 +/- 0.9%), whereas simvastatin plus L-arginine significantly improved EDD (9.8 +/- 1.5% vs. 5.3 +/- 0.8%; p0.01). In subjects with low ADMA, simvastatin improved endothelial function when given alone (9.5 +/- 3.2% vs. 6.1 +/- 3.8%; p0.001) or in combination with L-arginine (9.0 +/- 3.1% vs. 6.3 +/- 3.3%; p = 0.001). L-arginine alone improved endothelial function in both groups. Endothelium-independent vasodilation was not affected.Simvastatin does not enhance endothelial function in subjects with elevated ADMA, whereas it does so in patients with low ADMA. Combination of simvastatin with oral L-arginine improves endothelial function in subjects with high ADMA, but has no additional effect in subjects with low ADMA. As NO-mediated effects may play a major role in the therapeutic effects of statins, ADMA concentration is an important factor that influences the "pleiotropic" effects of simvastatin.

Anilinoalkynylpyrimidines were prepared and evaluated as dual EGFR/ErbB2 kinase inhibitors. A preference was found for substituted phenyl and heteroaromatic rings attached to the alkyne. In addition, the presence of a potential hydrogen bond donor appended to this ring was favored. Selected molecules in the series demonstrated some activity against human tumor cell lines.

We report on the first radioactive beam experiment performed at the recently commissioned REX-ISOLDE facility at CERN in conjunction with the highly efficient γ spectrometer MINIBALL. Using Mg-30 ions accelerated to an energy of 2.25 MeV/u together with a thin Ni-nat target, Coulomb excitation of the first excited 2(+) states of the projectile and target nuclei well below the Coulomb barrier was observed. From the measured relative deexcitation γ-ray yields the B(E2;0(gs)(+)R 2(1)(+)) value of Mg-30 was determined to be 241(31)e(2) fm(4). Our result is lower than values obtained at projectile fragmentation facilities using the intermediate-energy Coulomb excitation method, and confirms the theoretical conjecture that the neutron-rich magnesium isotope Mg-30 resides outside the "island of inversion."

Relatively few clues have been uncovered to elucidate the cell biological role(s) of mammalian ATP2C1 encoding an inwardly directed secretory pathway Ca2+/Mn2+ pump that is ubiquitously expressed. Deficiency of ATP2C1 results in a human disease ( Hailey-Hailey), which primarily affects keratinocytes. ATP2C1-encoded protein is detected in the Golgi complex in a calcium-dependent manner. A small interfering RNA causes knockdown of ATP2C1 expression, resulting in defects in both post-translational processing of wild-type thyroglobulin ( a secretory glycoprotein) as well as endoplasmic reticulum-associated protein degradation of mutant thyroglobulin, whereas degradation of a nonglycosylated misfolded secretory protein substrate appears unaffected. Knockdown of ATP2C1 is not associated with elevated steady state levels of ER chaperone proteins, nor does it block cellular activation of either the PERK, ATF6, or Ire1/XBP1 portions of the ER stress response. However, deficiency of ATP2C1 renders cells hypersensitive to ER stress. These data point to the important contributions of the Golgi-localized ATP2C1 protein in homeostatic maintenance throughout the secretory pathway.

19 pages, 12 figures, 2 tables.-- PACS nrs.: 25.60.-t; 25.45.-z; 27.20.+n.-- et al. ISOLDE Collaborattion and REX-ISOLDE Collaboration., At the newly constructed postaccelerator REX-ISOLDE (Radioactive beam Experiment at ISOLDE) we have investigated reactions induced by a Li-9 beam incident on a deuterium target at an energy of 2.36 MeV/u. Most reaction channels were recorded. From one-neutron transfer the differential cross-section for the low lying Li-10 spectrum is found. The results from the other channels demonstrate the great applicability and many possibilities that REX-ISOLDE opens up.

In 2002 the dominant experiment at CERN/ISOLDE was REX-ISOLDE. The LINAC delivered beams of radioactive isotopes at energies of 0.3, 2 and 2.2 MeV/u towards the two target stations. Due to the charge state breeder very different mass regions of the nuclear chart could be addressed from Li to Sm. In order to perform Coulomb excitation and particle transfer experiments in the mass region up to A = 150, an energy of the LINAC is required, which is foreseen in two steps. The first step of the upgrade to 3.1 MeV/u will be done by using the MAFF 202.56 MHz IH-cavity. The second step to energies close to 4.2 MeV/u will be a major change of the LINAC structure. The two 7-gap spiral resonators of REX-ISOLDE will be exchanged by a 202 MHz IH-cavity. Design calculations, cavity design and first measurements with the cavity dedicated for the first step of the upgrade will be presented.

At REX-ISOLDE at ISOLDE/CERN radioactive ions are post accelerated with a 10 meters linac for experiments in nuclear-, astro- and solid state physics. For the efficient acceleration to energies between 0.8 and 2.3 MeV/u the principles of charge breeding of radioactive ions by an electron beam source was introduced at REX. The linac in its current stage consists of a 4-rod RFQ, a 20-gap IH drift tube cavity and three seven-gap splitting resonators. It is able to accelerate up to a mass to charge ratio of 4.5. 2002 has been the first year of nuclear physics experiments with REX-ISOLDE. The experiments done so far using Coulomb excitation and particle transfer reactions require good beam quality at the two target stations. Therefore commissioning measurements of the linac were made and are still being done. The results of those measurements will be presented showing the current energy spreads and radial emittances of the different cavities.

After the successful commissioning of the Radioactive beam EXperiment (REX) at ISOLDE (CERN) in 2002, first physics experiments were performed in 2003 which focussed on the neutron-rich Mg isotopes in the vicinity of the “island of inversion”. After introducing the REX facility and the modern γ spectrometer MINIBALL first preliminary results will be presented showing the high potential and physics opportunities offered by this new radioactive beam facility.