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BACKGROUND: The treatment of metastatic castration-resistant prostate cancer has changed with the introduction of radium-223, cabazitaxel, abiraterone and enzalutamide. To assess value for money, their cost effectiveness in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel from the Dutch societal perspective was investigated.METHODS: A cost-effectiveness analysis was conducted using efficacy, symptomatic skeletal-related event and safety data obtained from indirect treatment comparisons. Missing skeletal-related event data for cabazitaxel were conservatively assumed to be identical to radium-223. A Markov model combined these clinical inputs with Dutch-specific resource use and costs for metastatic castration-resistant prostate cancer treatment from a societal perspective. Total quality-adjusted life-years and costs in 2017 euros were calculated over a 5-year (lifetime) time horizon.RESULTS: Radium-223 resulted in €6092 and €4465 lower costs and 0.02 and 0.01 higher quality-adjusted life-years compared with abiraterone and cabazitaxel, respectively, demonstrating dominance of radium-223. Sensitivity analyses reveal a 64% (54%) chance of radium-223 being cost effective compared with abiraterone (cabazitaxel) at the informal €80,000 willingness-to-pay threshold. Compared with enzalutamide, radium-223 resulted in slightly lower quality-adjusted life-years (-0.06) and €7390 lower costs, revealing a 61% chance of radium-223 being cost effective compared with enzalutamide. The lower costs of radium-223 compared with abiraterone and enzalutamide are driven by lower drug costs and prevention of expensive skeletal-related events. Compared with cabazitaxel, the lower costs of radium-223 are driven by lower costs of the drug, administration and adverse events.CONCLUSION: Radium-223 may be a less costly treatment strategy offering similar gains in health benefits compared with abiraterone, cabazitaxel and enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel from the Dutch societal perspective.

Poor translation from animal studies to human clinical trials is one of the main hurdles in the development of new drugs. Here, we used precision-cut kidney slices (PCKS) as a translational model to study renal fibrosis and to investigate whether inhibition of tyrosine kinase receptors, with the selective inhibitor nintedanib, can halt fibrosis in murine and human PCKS. We used renal tissue of murine and human origins to obtain PCKS. Control slices and slices treated with nintedanib were studied to assess viability, activation of tyrosine kinase receptors, cell proliferation, collagen type I accumulation, and gene and protein regulation. During culture, PCKS spontaneously develop a fibrotic response that resembles in vivo fibrogenesis. Nintedanib blocked culture-induced phosphorylation of platelet-derived growth factor receptor and vascular endothelial growth factor receptor. Furthermore, nintedanib inhibited cell proliferation and reduced collagen type I accumulation and expression of fibrosis-related genes in healthy murine and human PCKS. Modulation of extracellular matrix homeostasis was achieved already at 0.1 μM, whereas high concentrations (1 and 5 μM) elicited possible nonselective effects. In PCKS from human diseased renal tissue, nintedanib showed limited capacity to reverse established fibrosis. In conclusion, nintedanib attenuated the onset of fibrosis in both murine and human PCKS by inhibiting the phosphorylation of tyrosine kinase receptors; however, the reversal of established fibrosis was not achieved.

Imaging modalities using tumor-directed monoclonal antibodies may be of value to improve the pre- and intraoperative detection and resection of lymph node (LN) metastatic disease in penile squamous cell carcinoma (PSCC). We investigated the expression of prostate-specific membrane antigen (PSMA), vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) and epithelial cell adhesion molecule (EpCAM) to analyze their potency for diagnostic applications. Antigen expression was determined in primary tumors and LNs with and without metastases of 22 patients with PSCC. The total immunostaining score (TIS, 0–12) was determined as the product of a proportion score (PS, 0–4) and an intensity score (IS, 0–3). EGFR and VEGF expression were high in primary tumor (median TIS 8) and LN metastases (median TIS 6 and 8, respectively). No EGFR expression was seen in LNs without metastases. However, LNs without metastases did show VEGF expression (median TIS 6). No EpCAM or PSMA expression was seen in PSCC. This study shows that VEGF and EGFR expression is moderate to high in LN metastases of PSCC. Both VEGF and EGFR warrant further clinical evaluation to determine their value as a target for pre- and intraoperative imaging modalities in the detection of LN metastases in PSCC.

Genetic studies have established a role of disrupted-in-schizophrenia-1 (DISC1) in chronic mental diseases (CMD). Limited experimental data are available on the domain structure of the DISC1 protein although multiple interaction partners are known including a self-association domain within the middle part of DISC1 (residues 403-504). The DISC1 C-terminal domain is deleted in the original Scottish pedigree where DISC1 harbors two coiled-coil domains and disease-associated polymorphisms at 607 and 704, as well as the important nuclear distribution element-like 1 (NDEL1) binding site at residues 802-839. Here, we performed mutagenesis studies of the C-terminal domain of the DISC1 protein (residues 640-854) and analyzed the expressed constructs by biochemical and biophysical methods. We identified novel DISC1 self-association motifs and the necessity of their concerted action for orderly assembly: the region 765-854 comprising a coiled-coil domain is a dimerization domain and the region 668-747 an oligomerization domain; dimerization was found to be a prerequisite for orderly assembly of oligomers. Consistent with this, disease-associated polymorphism C704 displayed a slightly higher oligomerization propensity. The heterogeneity of DISC1 multimers in vitro was confirmed with a monoclonal antibody binding exclusively to HMW multimers. We also identified C-terminal DISC1 fragments in human brains, suggesting that C-terminal fragments could carry out DISC1-dependent functions. When the DISC1 C-terminal domain was transiently expressed in cells, it assembled into a range of soluble and insoluble multimers with distinct fractions selectively binding NDEL1, indicating functionality. Our results suggest that assembly of the C-terminal domain is controlled by distinct domains including the disease-associated polymorphism 704 and is functional in vivo.

Raman microspectroscopy was used to study the preparation of industrial MoS2/Al2O3 extrudates. Using this technique, the influence of the impregnation solution composition on the nature and macrodistribution of Mo complexes inside these catalyst bodies was evaluated during their preparation process (impregnation, drying, and calcination). It was found that poor dispersion of the MoOx phase in the calcined samples can be brought about by the formation of bulk (NH4)3[Al(OH)6Mo6O18] during impregnation or redistribution of Mo complexes during drying. The formation of crystalline MoO3 and Al2(MoO4)3 in the oxidic precursors leads to a poorly dispersed MoS2 phase in the final catalyst and significantly lower hydrodesulfurization activity. The spatially resolved information that can be obtained, and its inherent sensitivity for the detection of crystalline phases make Raman microspectroscopy a powerful characterization technique for studying the preparation of industrial supported metal oxide catalysts.

Spatially resolved Raman and UV-vis-NIR microspectroscopy have been used as tools to study the preparation process of supported catalyst bodies. Detailed spectroscopic information on the local coordination geometry of two different metallic species along with their macro-distribution over the catalyst body has been obtained, enabling a good understanding of the physicochemical processes occurring during the drying process of impregnated gamma-Al(2)O(3) bodies. The formation and decomposition of the Keggin-type complex H(x)PMo(11)CoO(40)((7-)(x)-), which is considered to be a potential precursor for CoMoS(2)/gamma-Al(2)O(3) HDS catalysts, inside gamma-Al(2)O(3) bodies is shown to be a function of the composition of the impregnation solutions, the aging time, and the drying conditions applied. This knowledge has been successfully applied to prepare samples with a well-defined distribution of the bimetallic complex, that is, either egg-shell, egg-yolk, or homogeneous distributions. The Raman results are presented in a semiquantitative way by subtraction of a reference spectrum of a sample containing a known amount of H(x)PMo(11)CoO(40)((7-)(x)-) from the spectra recorded along the cross-section of the catalyst bodies.

Raman microscopy has been applied to study the preparation of shaped Mo/Al(2)O(3) catalysts. The speciation of different Mo complexes over gamma-Al(2)O(3) support bodies was followed in time after pore volume impregnation with aqueous solutions containing different Mo complexes. The addition of NO(3-) to the impregnation solutions allows for a quantitative Raman analysis of the distribution of different complexes over the catalyst bodies as this ion can be used as an internal standard. After impregnation with an acidic ammonium heptamolybdate (AHM) solution, the strong interaction between Mo(7)O(24)(6-) and Al(2)O(3) results in slow transport of this complex through the support and extensive formation of Al(OH)(6)Mo(6)O(18)(3-) near the outer surface of the support bodies. This may be prevented by decreasing the interaction between Mo and Al(2)O(3). In this way, transport is facilitated and a homogeneous distribution of Mo is obtained on a reasonable time scale. A decrease in interaction between Mo and Al(2)O(3) can be achieved by using alkaline impregnation solutions or by the addition of complexing agents, such as citrate and phosphate, to the impregnation solution. In general, time-resolved in situ Raman microscopy can be a valuable tool to study the physicochemical processes during the preparation of supported catalysts.

Recombinant, bacterially expressed apoptin protein induces apoptosis in human tumour cell lines but not in normal cells, mimicking the behaviour of ectopically expressed apoptin. Recombinant apoptin is isolated exclusively as a highly stable multimeric complex of 30-40 monomers, with little, if any, alpha-helical and beta-sheet structure. Despite its apparent disorder, multimeric apoptin is biologically active. Here, we present evidence that most of the apoptin moieties within the complex may well share a similar conformation. Furthermore, the multimer has extensive and uniform hydrophobic patches and conformationally stable domains. Only a small fraction of apoptin subunits can exchange between multimers under physiologically relevant conditions. These results prompt a model in which the apoptin multimer has a highly stable core of nonexchangeable subunits to which exchangeable subunits are attached through hydrophobic interactions. In combination with previous findings, our results lead us to propose that the stable core of apoptin is the biologically relevant structure.

The chicken anaemia virus-derived protein apoptin is a tumour-specific cell-killing agent. It is biologically active as a highly stable, multimeric complex, consisting of 30-40 monomers. In tumour cells, but negligibly in normal cells, apoptin is imported into the nucleus prior to the induction of apoptosis. Immunoelectron microscopic data we report here indicate that apoptin predominantly co-localises with heterochromatin and nucleoli within tumour cells. Apoptin's preference for these DNA-dense nuclear bodies may be explained by our finding that apoptin cooperatively forms distinct superstructures with DNA in vitro. These superstructures do not grow beyond a diameter of approximately 200 nm, containing up to 20 multimeric apoptin complexes and approximately 3 kb of DNA. Furthermore, we show a single apoptin multimer to have eight independent, non-specific DNA-binding sites which preferentially bind strand ends, but which can also collaborate to bind longer stretches of DNA. Apoptin's high affinity for naked, undecorated double- and single-stranded DNA and for DNA fibre ends suggests that it may also capture such DNA in superstructures in vivo. Since these forms of DNA are predominantly found in transcriptionally active, replicating and damaged DNA, apoptin could be triggering apoptosis by interfering with DNA transcription and synthesis.

The influence of the Si/Al ratio of the support of (Co)Mo/saponite catalysts on the performance in the hydrodesulfurisation of thiophene and hydrocracking of n-decane has been studied. The initial thiophene HDS activity of the sulfided Co catalysts increased with increasing support acidity, while with the CoMo catalysts the opposite effect was observed. The large drop in activity at lower Si/Al ratios is ascribed to the occurrence of two separate cobalt and molybdenum sulfide phases instead of the “Co‐Mo‐S” phase. In the hydrocracking of n-decane both the Co and the CoMo catalysts displayed an almost linear relationship between the first-order rate constant and the number of Bronsted acid sites. As with zeolite catalysts the Si/Al ratio was also found to affect the product selectivity. At low Si/Al ratios the relative amount of secondary cracking products increased due to a changing balance between the number of cracking and hydrogenation sites. Remarkably, it was found that in the presence of H2S between 423 and 573 K the n-decane conversion passes through a maximum. The observed relation between this “low-temperature” activity and the number of Bronsted acid sites seem to indicate the involvement of both H2S and the acid sites on the support. c ∞ 1999 Academic Press

Background: The treatment landscape of metastatic castration resistant prostate cancer (mCRPC) has changed with the introduction of abiraterone acetate (AA), enzalutamide (EN) and radium-223 (Ra-223). Little is known about the cost-effectiveness of these novel agents. This study investigates the cost-effectiveness of Ra-223 in the Netherlands. First, the costeffectiveness of Ra-223 will be evaluated against best supportive care (BSoC) in the mCRPC population. Second, the cost-effectiveness of Ra-223 in the post-chemo setting will be evaluated against the active comparators AA and EN. Material and Methods: A Markov model with five health states is used to describe disease progression and evaluate the cost-effectiveness. The health states are: progression-free survival (PFS) without a symptomatic skeletal event (SSE), progressed disease without SSE, PFS after experiencing a SSE, progressed disease after experiencing a SSE, and death. Disease progression is measured by alkaline phosphatase (comparator=BSoC) or prostate specific antigen. Efficacy, safety and quality adjusted life year (QALY) data were extracted from Phase III RCT's. Efficacy and safety of Ra-223 versus AA and EN was obtained by indirect treatment comparisons. The model has been validated by specialists treating mCRPC. Analyses were performed from a societal perspective, including costs outside the health care budget. Results: Compared to BSoC, Ra-223 has higher quality adjusted survival (0.29 QALYs) and lifetime costs (€22.485) in mCRPC patients, resulting in an incremental cost-effectiveness ratio of €78.642 per QALY. This is below the proposed Dutch threshold of €80.000. Probabilistic sensitivity analyses reveal a 33% chance for Ra-223 to be cost-effective compared to BSoC at this threshold. Cost-effectiveness of Ra-223 in the postchemo setting compared to active comparators is as follows. While quality adjusted survival of Ra-223 is similar to AA, Ra-223 has lower lifetime costs (€5.905), which are mainly driven by lower drug and SSE treatment costs. Probabilistic sensitivity analyses show a 78% chance for Ra-223 to be cost-effective compared to AA at a threshold of €80.000. Compared to EN, Ra-223 has a slightly lower QALY gain (-0.06) and lower lifetime costs (-€7.255), resulting in only a 19% chance of EN to be cost-effective compared to Ra-223 at a €80.000 threshold. Conclusions: Our model suggests that Ra-223 may be cost-effective compared to BSoC and AA in the Netherlands, with Ra-223 even dominating AA (evaluated in post-chemo patients only). Although EN may lead to slightly more health in post-chemo patients, this health gain is accompanied by extra costs resulting in EN not being considered costeffective compared to Ra-223 according to the Dutch threshold. Ra-223's cost-effectiveness compared to AA and EN should be interpreted with caution due to indirect treatment comparisons.

This work demonstrates that non-physiological electron transfer (ET) can occur in solution between wild type D. vulgaris flavodoxin (Fld) and horse heart cytochrome c (cyt-c), D. vulgaris cytochrome c553 (cyt-c553) and the haem domain of B. megaterium cytochrome P450 (cyt-P450 BMP). Second order rate constants of the ET reaction between [Fld]sq/[cyt-c]ox, [Fld]sq/[cyt-c553]ox and [Fld]sq/[cyt-P450 BMP]ox, were found to be 6.16 x 10(5), 1.80 x 10(4) and in the region of 10(5) respectively. These data are interpreted in terms of complementarity between the surfaces of the two proteins, their surface and redox potentials. Analysis of the ET results obtained from the separate wild type proteins supported the rational design approach in the creation of Fld-based chimeras. The preliminary design of the chimeras reported here is a 3D prototype for an artificial flavo-cytochrome obtained by covalent linkage of a Fld module to cyt-c553 via a disulphide bond. Theoretical ET rates calculated on the modelled flavo-cytochrome are encouraging the construction of these chimeric systems at DNA level. This work is now underway. The relevance of this molecular lego approach is to be seen in the long term goal of producing engineered multi-domain systems to be applied in the field of biosensors and bioelectronics to fulfil specific requirements. Novel catalytic devices can be obtained by using natural redox proteins in different combinations: this process mimics the natural evolution of proteins such as gene shuffling and gene fusion.

The Vilsmeier–Haack formylation of aromatic compounds is a well-established process in organic synthesis, largely driven by the fact that the resulting aldehydes are generally useful intermediates for the synthesis of fine chemicals and pharmaceutical products. Industrial-scale production, however, is often hampered by laborious procedures requiring the use of hazardous chemicals to produce the highly reactive intermediates. In order to circumvent these issues, a flow chemistry approach was developed. This article describes the design and semiautomated optimization of the Vilsmeier–Haack formylation in continuous flow and subsequent scale-up to preparative volumes in an intrinsically safe manner.

Acoustophoresis has been used to investigate the interaction between suspended mineral oxides (SiO2 and Al2O3) and aqueous solutions of cobalt (II) chloride, molybdenum (III) chloride and ammonium heptamolybdate (AHM) as a function of the pH. The measured electrokinetic sonic amplitude (ESA) is directly related to the ζ-potential and gives information on the iso-electric point of the mineral oxides, that are used as supports for catalysts. The interaction between the solutes and the suspended mineral oxides is an important parameter for the preparation of supported catalysts, which can be studied perfectly by means of acoustophoresis. The specific adsorption of cobalt and molybdenum on silica and alumina has been considered.

The (dis)similarities between the Selective Catalytic Reduction (SCR) of NO and the Selective Catalytic Oxidation (SCO) of NH3 are briefly reviewed. Since the SCO reaction acts counterproductively in the SCR reaction the two processes are related. A series of V2O5, MoO3, and WO3 catalysts on various supports have been tested in the SCO reaction. It appears that an acid metal oxide in combination with an acid support gives the most active catalysts. The main byproduct is NO; minor amounts of N2O are formed. NO formation occurs in the temperature regime where the reduction of oxide lattice is faster than the recombination of two nitrogen atoms. High partial pressures of NH3 give rise to elevated selectivity to N2. This can be understood by assuming that the recombination probability of two nitrogen atoms becomes higher. A reaction mechanism, entitled the ‘internal SCR mechanism’ is proposed to explain the formation of N2O.

The prion protein, PrP, exists in several stable conformations, with the presence of one conformation, PrPSc, associated with transmissible neurodegenerative diseases. Targeting PrP by high-affinity ligands has been proven to be an effective way of preventing peripheral prion infections. Here, we have generated bacterially expressed single chain fragments of the variable domains (scFv) of a monoclonal antibody in Escherichia coli, originally raised against purified PrPSc that recognizes both PrPc and PrPSc. This scFv fragment had a dissociation constant (K-D) with recombinant PrP of 2 nM and cleared prions in ScN2a cells at 4 nM, as demonstrated by a mouse prion bioassay. A peptide corresponding to the complementarity determining region 3 of the heavy chain (CDR3H) selectively bound PrPSc but had lost antiprion activity. However, synthesis and application of an improved peptide mimicking side chain topology of CDR3H while exhibiting increased protease resistance, a retro-inverso D-peptide of CDR3H, still bound PrPSc and reinstated antiprion activity. We conclude that (1) scFvW226 is so far the smallest polypeptide with bioassay confirmed antiprion activity, and (2) differential conformation specificity and bioactivity can be regulated by orchestrating the participation of different CDRs. (C) 2008 Elsevier Ltd. All rights reserved

The use of conformation-specific ligands has been closely linked to progress in the molecular characterization of neurodegenerative diseases. Deposition of misfolded or misprocessed proteins is now recognized as a hallmark of all neurodegenerative diseases. Initially, dyes like Congo red and thioflavin T were used as crudely conformation-specific ligands for staining the beta-sheeted protein components of amyloid deposits in neurodegenerative diseases such as Alzheimer disease (AD) and prion disease, the two diseases in which protein conformations were distinguished early on. This conformational characterization of extracellular protein deposits with dyes ultimately led to the identification of key players in the disease processes. The recent discovery of intermediate conformational species, i.e., soluble oligomers for AD and PK-sensitive PrP(Sc) for prion disease, whose conformation and assembly are thought to be distinct from both the physiological and the fibrillar conformational states, replaced the former notion that the microscopic protein deposits themselves caused disease. This insight and the generation of conformation-specific monoclonal antibodies to these conformers further advanced diagnosis and the understanding of molecular mechanisms of AD and are likely to do so in other neurodegenerative diseases. Here we review how conformer distinction performed by a variety of different techniques, including biophysical, biochemical, and antibody-based methods, led to the current molecular concepts of AD and the prion diseases. We provide an outlook on the application of these techniques in advancing the understanding of molecular mechanisms of other neurodegenerative diseases or degenerative brain conditions.

Prion diseases are invariably fatal neurodegenerative diseases, in which the infectious agent consists of PrP(Sc), a pathogenic misfolded isoform of the normal cellular prion protein (PrP(C)). Until now, no pharmacological options exist for these novel pathogens. Here we describe the screening of a series of polyquinolines and quinolines linked to a large variety of terminal groups for their ability to cure a persistently prion infected cell line (ScN2a). Several compounds showed antiprion activity in the nanomolar range. The most active molecule, named 42, had a half-effective concentration (EC50) for antiprion activity of 50 nM. In a library of quinoline derivatives we were able to identify several structure-activity relationships (SAR). Remarkably, antiprion SAR in ScN2a cells were similar to antimalarial SAR in a cell model of malaria, particularly for the sulfonamide quinoline derivatives, suggesting that some molecular targets of antiprion and antimalarial substances overlap.

Apoptin induces apoptosis specifically in tumour cells, where Apoptin is enriched in the DNA-dense heterochromatin and nucleoli. In vitro, Apoptin interacts with dsDNA, forming large nucleoprotein superstructures likely to be relevant for apoptosis induction. Its N- and C-terminal domains also have cell-killing activity, although they are less potent than the full-length protein. Here, we report that both Apoptin's N- and C-terminal halves separately bound DNA, indicating multiple independent binding sites. The reduced cell killing activity of both truncation mutants was mirrored in vitro by a reduced affinity compared to full-length Apoptin. However, none of the truncation mutants cooperatively bound DNA or formed superstructures, which suggests that cooperative DNA binding by Apoptin is required for the formation of nucleoprotein superstructures. As Apoptin's N- and C-terminal fragments not only share apoptotic activity, but also affinity for DNA, we propose that both properties are functionally linked. © 2003 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Raman microscopy has been applied to study the preparation of shaped Mo/Al2O3 catalysts. The speciation of different Mo complexes over gamma-Al2O3 support bodies was followed in time after pore volume impregnation with aqueous solutions containing different Mo complexes. The addition of NO3- to the impregnation solutions allows for a quantitative Raman analysis of the distribution of different complexes over the catalyst bodies as this ion can be used as an internal standard. After impregnation with an acidic ammonium heptamolybdate (AHM) solution, the strong interaction between Mo7O246- and Al2O3 results in slow transport of this complex through the support and extensive formation of Al(OH)(6)Mo6O183- near the outer surface of the support bodies. This may be prevented by decreasing the interaction between Mo and Al2O3. In this way, transport is facilitated and a homogeneous distribution of Mo is obtained on a reasonable time scale. A decrease in interaction between Mo and Al2O3 can be achieved by using alkaline impregnation solutions or by the addition of complexing agents, such as citrate and phosphate, to the impregnation solution. In general, time-resolved in situ Raman microscopy can be a valuable tool to study the physicochemical processes during the preparation of supported catalysts.

The chicken anemia virus-derived Apoptin protein induces tumor-specific apoptosis. Here, we show that recombinant Apoptin protein spontaneously forms non-covalent globular aggregates comprising 30 to 40 subunits in vitro. This multimerization is robust and virtually irreversible, and the globular aggregates are also stable in cell extracts, suggesting that they remain intact within the cell. Furthermore, studies of Apoptin expressed in living cells confirm that Apoptin indeed exists in large complexes in vivo. We map the structural motifs responsible for multimerization in vitro and aggregation in vivo to the N-terminal half of the protein. Moreover, we show that covalently fixing the Apoptin monomers within the recombinant protein multimer by internal cross-linking does not affect the biological activity of Apoptin, as these fixed aggregates exhibit similar tumor-specific localization and apoptosis-inducing properties as non-cross-linked Apoptin. Taken together, our results imply that recombinant Apoptin protein is a multimer when inducing apoptosis, and we propose that this multimeric state is an essential feature of its ability to do so. Finally, we determine that Apoptin adopts little, if any, regular secondary structure within the aggregates. This surprising result would classify Apoptin as the first protein for which, rather than the formation of a well defined tertiary and quaternary structure, semi-random aggregation is sufficient for activity.

Heavier feedstocks, and increasingly stringent sulfur, specifications lead to laborious operation in resid hydroprocessing units. Asphaltene, in particular, is a dominant component influencing catalyst deactivation, oil stability and sediment formation. It is necessary to treat asphaltene properly to prevent sediment formation and to ensure a longer catalyst, life. To meet such requirements, Nippon Ketjen and Akzo Nobel Catalysts have developed new heavy residual oil upgrading catalysts, KFR 22 for fixed-bed, and KF 1312, 1311, 1302T and 1302T2 for ebullated-bed processes. These new products enable better sediment control combined with excellent desulfurization and asphaltene cracking performance.

The sulfidation of∞ -alumina- and titania-supported (cobalt)molybdenum oxide catalysts has been studied with X-ray absorption spectroscopy and temperature programmed sulfidation (TPS). The catalysts were stepwise sulfided at temperatures between 298 and 673 K and their structure was determined with EXAFS spectroscopy. On alumina oxygen‐sulfur exchange starts at a temperature just above room temperature resulting in the formation of monomeric and dimeric molybdenum sulfide species containing disulfide ligands. Between 448 and 523 K the disulfide ligands are reduced with hydrogen and only dimeric molybdenum sulfide species with a Mo‐Mo distance of 2.77 ˚ A remain. Above 523 K these dimers aggregate to larger MoS2 particles. In contrast, on titania molybdenum oxide is sulfided to yield isolated molybdenum sulfide monomers at 523 K, which similarly aggregate to MoS2 particles between 523 and 623 K. No molybdenum sulfide dimers are observed as intermediates. Both on alumina and titania all intermediates are anchored to the support via Mo‐O linkages with a bond distance of 2.0 ˚ A. The addition of Co to Mo/Al2O3 accelerates the rate of sulfidation, demonstrated by the TPS patterns. However, on titania a lowering of the sulfidation rate is observed next to the presence of molybdenum sulfide dimers, that are not present in the unpromoted catalyst. These observations can be ascribed to the presence of CoMoO4 in the oxidic catalyst. c ∞ 1997 Academic Press

Saponites with Co, Ni, Zn, Mg and combinations of Co and Mg in the octahedral layer were synthesised. Their applicability as catalysts and supports for hydrotreating catalysts was investigated. The stability of these clays in a sulfidic environment was studied using Temperature Programmed Sulfidation. The catalytic performance of the saponites both bare and impregnated with Co/Mo was tested in the hydrodesulfurisation of thiophene.

The genesis of sulfur vacancies on sulfided (Co)Mo/Al2O3 catalysts was studied with EXAFS at the reaction temperature (673 K) in a H2 and H2/thiophene gas atmosphere. For Mo no significant changes in the sulfur coordination were observed for either the Co-promoted or the unpromoted sample. The experiments indicated that in Co-promoted Mo/Al2O3 vacancies are primarily formed on the Co atom. The sulfur coordination of the cobalt changed from 6.0 to 5.2 upon reduction with H2, followed by a slight increase to 5.4 by treatment with H2/thiophene. The reaction of selenophene (a structural analogue of thiophene) in hydrogen with sulfided (Co)Mo/Al2O3 catalysts was also investigated with EXAFS. It was possible to monitor the incorporation of Se in the metal sulfide phase. Characterization of the promoted catalyst after HD-Se at 473 K showed that Se was exclusively coordinated to the Co atoms. In contrast, data obtained after HD-Se at 673 K revealed that the Se atoms were located in the position of the bridging sulfur atoms between Co and Mo. Accordingly, a structural model is proposed that involves two types of active sites for hydrodesulfurization on the sulfided Co-promoted Mo catalyst. The first type consists of a sulfur vacancy that is only associated with the promoter atoms, which is created at low temperatures. At higher temperatures, a second type of site is produced by removal of sulfur atoms that are bonded to both Co and Mo atoms.

Prion diseases are invariably fatal, neurodegenerative diseases transmitted by an infectious agent, PrPSc, a pathogenic, conformational isoform of the normal prion protein (PrPC). Heterocyclic compounds such as acridine derivatives like quinacrine abolish prion infectivity in a cell culture model of prion disease. Here, we report that these compounds execute their antiprion activity by redistributing cholesterol from the plasma membrane to intracellular compartments, thereby destabilizing membrane domains. Our findings are supported by the fact that structurally unrelated compounds with known cholesterol-redistributing effects – U18666A, amiodarone, and progesterone – also possessed high antiprion potency. We show that tricyclic antidepressants (e.g. desipramine), another class of heterocyclic compounds, displayed structure-dependent antiprion effects and enhanced the antiprion effects of quinacrine, allowing lower doses of both drugs to be used in combination. Treatment of ScN2a cells with quinacrine or desipramine induced different ultrastructural and morphological changes in endosomal compartments. We synthesized a novel drug from quinacrine and desipramine, termed quinpramine, that led to a fivefold increase in antiprion activity compared to quinacrine with an EC50 of 85 nm. Furthermore, simvastatin, an inhibitor of cholesterol biosynthesis, acted synergistically with both heterocyclic compounds to clear PrPSc. Our data suggest that a cocktail of drugs targeting the lipid metabolism that controls PrP conversion may be the most efficient in treating Creutzfeldt-Jakob disease.

The performance of sulfided (Co)Mo/alumina catalysts was studied in the conversion of thiophene between 423 and 773 K at atmospheric pressure. Reaction orders for thiophene, H2, and H2S were determined at several temperatures. The reaction order in thiophene increases with rising temperature, indicating a Langmuir‐ Hinshelwood mechanism. Beyond 550 K the conversion curve deviates from pseudo-first-order kinetics, demonstrating the influence of the surface coverage of thiophene on the reaction rate. Above 673 K the reaction rate rises exponentially with temperature which can be ascribed to the presence of a second type of active site that is only active at high temperatures. These catalytic data can be combined with recent structural studies using EXAFS spectroscopy to derive an activity‐structure relation. It is proposed that at low temperature the active sites are terminal sulphur vacancies on the Co-promotor atom. In addition around 673 K a second type of sites becomes active, which is believed to consist of bridging sulphur vacancies in between Co and Mo atoms on the MoS2 edges. c ∞ 1998

The acidity of synthetic Zn and Mg saponites exchanged with H+, Al3+, Na+ and K+ has been studied using DRIFTS of adsorbed pyridine and TPD–TG measurements of adsorbed n-propylamine. The characterisation with IR of adsorbed pyridine revealed the presence of a large amount of Lewis acid sites owing to coordinatively unsaturated metal atoms at the edges of the clay platelets. Hardly any Bronsted sites were observed. However, with TPD–TG measurements of n-propylamine it was possible to quantify the number of Bronsted acid sites. In the H+ exchanged clays with high Si/Al ratios the amine/Al molar ratio was found to be near unity. At lower Si/Al ratios the number of acid sites increased non-linearly with the Al content. This study demonstrates that pyridine is a useful probe for determining Lewis acidity. However, to study the Bronsted acidity of H+ exchanged synthetic saponites, reliable quantitative information can only be obtained using n-propylamine.

The metal-support interaction in oxidic and sulfided (Co)Mo/Al{2}O{3}and (Co)Mo/TiO{2}catalysts has been studied with X-ray absorption spectroscopy. Analysis of the oxidic catalysts showed that on both Mo/Al{2}O{3}and Mo/TiO{2}the molybdenum oxide particles possess a highly distorted octahedral structure with Mo-O distances ranging from 1.71 A to 1.94 A. The second shell Mo-Mo coordination number of less than 1.0 indicated that the size of the molybdenum oxide particles is very small. Upon addition of Co the particle size is increased to approximately four Mo atoms per particle. EXAFS data analysis showed the presence of second shell Al and Ti neighbours indicating a linkage of the molybdenum oxide particles to the support via Mo-O-X(X=Al or Ti) bonds. Upon sulfidation of the oxidic catalysts small MoS{2}particles are formed with second shell Mo-Mo coordination numbers ranging from 0.8 to 3.9. A Mo-O contribution at 2.0 A was found in the first coordination shell of Mo in the sulfided catalysts. Since the coordination number of this Mo-O contribution correlated with the MoS{2}particle size, deduced from the second shell Mo-Mo coordination number, this Mo-O contribution was assigned as an interfacial Mo-O{s}{u}{p}{p}{o}{r}{t}linkage. This Mo-O{s}{u}{p}{p}{o}{r}{t}linkage stabilises the small MoS{2}particles and prevents them from sintering. It is proposed that the activity of these catalysts can be controlled by optimising the molybdenum sulfide-support interaction, which consists of the observed Mo-O{s}{u}{p}{p}{o}{r}{t}bonds.

Die Thiiren-Ll-dioxide (I) reagieren mit Triphenylphosphin-Ubergangsmetallkomplexen zu den Thiiren-1,1-dioxid-Komplexen (II).

The preparation and properties of platinum, palladium, and iridium complexes of thiiren 1,1-dioxides are described.