153 research outputs found
NS11394 [3ā²-[5-(1-Hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile], a Unique Subtype-Selective GABA A
Genome-wide copy number variation (CNV) in patients with autoimmune Addison's disease
<p>Abstract</p> <p>Background</p> <p>Addison's disease (AD) is caused by an autoimmune destruction of the adrenal cortex. The pathogenesis is multi-factorial, involving genetic components and hitherto unknown environmental factors. The aim of the present study was to investigate if gene dosage in the form of copy number variation (CNV) could add to the repertoire of genetic susceptibility to autoimmune AD.</p> <p>Methods</p> <p>A genome-wide study using the Affymetrix GeneChip<sup>Ā® </sup>Genome-Wide Human SNP Array 6.0 was conducted in 26 patients with AD. CNVs in selected genes were further investigated in a larger material of patients with autoimmune AD (n = 352) and healthy controls (n = 353) by duplex Taqman real-time polymerase chain reaction assays.</p> <p>Results</p> <p>We found that low copy number of <it>UGT2B28 </it>was significantly more frequent in AD patients compared to controls; conversely high copy number of <it>ADAM3A </it>was associated with AD.</p> <p>Conclusions</p> <p>We have identified two novel CNV associations to <it>ADAM3A </it>and <it>UGT2B28 </it>in AD. The mechanism by which this susceptibility is conferred is at present unclear, but may involve steroid inactivation (<it>UGT2B28</it>) and T cell maturation (<it>ADAM3A</it>). Characterization of these proteins may unravel novel information on the pathogenesis of autoimmunity.</p
Targeting a Newly Established Spontaneous Feline Fibrosarcoma Cell Line by Gene Transfer
Fibrosarcoma is a deadly disease in cats and is significantly more often located at classical vaccine injections sites. More rare forms of spontaneous non-vaccination site (NSV) fibrosarcomas have been described and have been found associated to genetic alterations. Purpose of this study was to compare the efficacy of adenoviral gene transfer in NVS fibrosarcoma. We isolated and characterized a NVS fibrosarcoma cell line (Cocca-6A) from a spontaneous fibrosarcoma that occurred in a domestic calico cat. The feline cells were karyotyped and their chromosome number was counted using a Giemsa staining. Adenoviral gene transfer was verified by western blot analysis. Flow cytometry assay and Annexin-V were used to study cell-cycle changes and cell death of transduced cells. Cocca-6A fibrosarcoma cells were morphologically and cytogenetically characterized. Giemsa block staining of metaphase spreads of the Cocca-6A cells showed deletion of one of the E1 chromosomes, where feline p53 maps. Semi-quantitative PCR demonstrated reduction of p53 genomic DNA in the Cocca-6A cells. Adenoviral gene transfer determined a remarkable effect on the viability and growth of the Cocca-6A cells following single transduction with adenoviruses carrying Mda-7/IL-24 or IFN-Ī³ or various combination of RB/p105, Ras-DN, IFN-Ī³, and Mda-7 gene transfer. Therapy for feline fibrosarcomas is often insufficient for long lasting tumor eradication. More gene transfer studies should be conducted in order to understand if these viral vectors could be applicable regardless the origin (spontaneous vs. vaccine induced) of feline fibrosarcomas
Synthesis of reaction-adapted zeolites as methanol-to-olefins catalysts with mimics of reaction intermediates as organic structure-directing agents
[EN] Catalysis with enzymes and zeolites have in common the presence of well-defined single active sites and pockets/cavities where the reaction transition states can be stabilized by longer-range interactions. We show here that for a complex reaction, such as the conversion of methanol-to-olefins (MTO), it is possible to synthesize reaction-adapted zeolites by using mimics of the key molecular species involved in the MTO mechanism. Effort has focused on the intermediates of the paring mechanism because the paring is less favoured energetically than the side-chain route. All the organic structure-directing agents based on intermediate mimics crystallize cage-based small-pore zeolitic materials, all of them capable of performing the MTO reaction. Among the zeolites obtained, RTH favours the whole reaction steps following the paring route and gives the highest propylene/ethylene ratio compared to traditional CHA-related zeolites (3.07 and 0.86, respectively).Li, C.; Paris, C.; MartĆnez-Triguero, J.; Boronat Zaragoza, M.; Moliner Marin, M.; Corma CanĆ³s, A. (2018). Synthesis of reaction-adapted zeolites as methanol-to-olefins catalysts with mimics of reaction intermediates as organic structure-directing agents. Nature Catalysis. 1(7):547-554. https://doi.org/10.1038/s41929-018-0104-7S54755417Stocker, M. Methanol-to-hydrocarbons: catalytic materials and their behavior. Micro. Mesopor. Mater. 29, 3ā48 (1999).Tian, P., Wei, Y., Ye, M. & Liu, Z. Methanol to olefins (MTO): from fundamentals to commercialization. ACS Catal. 5, 1922ā1938 (2015).Ilias, S. & Bhan, A. Mechanism of the catalytic conversion of methanol to hydrocarbons. ACS Catal. 3, 18ā31 (2013).Olsbye, U. et al. Conversion of methanol to hydrocarbons: how zeolite cavity and pore size controls product selectivity. Angew. Chem. Int. Ed. 24, 5810ā5831 (2012).Hemelsoet, K., Van der Mynsbrugge, J., De Wispelaere, K., Waroquier, M. & Van Speybroeck, V. Unraveling the reaction mechanisms governing methanol-to-olefins catalysis by theory and experiment. ChemPhysChem 14, 1526ā1545 (2013).Song, W., Haw, J. F., Nicholas, J. B. & Heneghan, C. S. Methylbenzenes are the organic reaction centers for methanol-to-olefin catalysis on HSAPO-34. J. Am. Chem. Soc. 122, 10726ā10727 (2000).Arstad, B. & Kolboe, S. The reactivity of molecules trapped within the SAPO-34 cavities in the methanol-to-hydrocarbons reaction. J. Am. Chem. Soc. 123, 8137ā8138 (2001).Xu, T. et al. Synthesis of a benzenium ion in a zeolite with use of a catalytic flow reactor. J. Am. Chem. Soc. 120, 4025ā4026 (1998).Song, W., Nicholas, J. B., Sassi, A. & Haw, J. F. Synthesis of the heptamethylbenzene cation in zeolite beta: in situ NMR and theory. Catal. Lett. 81, 49ā53 (2002).Xu, S. et al. Direct observation of cyclic carbenium ions and their role in the catalytic cycle of the metahnol-to-olefin reaction over chabazite zeolites. Angew. Chem. Int. Ed. 52, 11564ā11568 (2013).Chen, J. et al. Elucidating the olefin formation mechanism in the methanol to olefin reaction over AlPO-18 and SAPO-18. Catal. Sci. Tech. 4, 3268ā3277 (2014).Haw, J. F. et al. Roles for cyclopentenyl cations in the synthesis of hydrocarbons from methanol on zeolite catalyst HZSM-5. J. Am. Chem. Soc. 122, 4763ā4775 (2000).Svelle, S. et al. Conversion of methanol into hydrocarbons over zeolite H-ZSM-5:āethene formation is mechanistically separated from the formation of higher alkenes. J. Am. Chem. Soc. 128, 14770ā14771 (2006).Teketel, S., Olsbye, U., Lillerud, K. P., Beato, P. & S., S. Selectivity control through fundamental mechanistic insight in the conversion of methanol to hydrocarbons over zeolites. Micro. Mesopor. Mater. 136, 33ā41 (2010).Zhang, M. et al. Methanol conversion on ZSM-22, ZSM-35 and ZSM-5 zeolites: effects of 10-membered ring zeolite structures on methylcyclopentenyl cations and dual cycle mechanism. RSC Adv. 6, 95855ā95864 (2016).Sassi, A. et al. Methylbenzene chemistry on zeolite HBeta:āmultiple insights into methanol-to-olefin catalysis. J. Phys. Chem. B 106, 2294ā2303 (2002).Sassi, A., Wildman, M. A. & Haw, J. F. Reactions of butylbenzene isomers on zeolite HBeta:āmethanol-to-olefins hydrocarbon pool chemistry and secondary reactions of olefins. J. Phys. Chem. B 106, 8768ā8773 (2002).BjĆørgen, M., Olsbye, U., Petersen, D. & Kolboe, S. The methanol-to-hydrocarbons reaction: insight into the reaction mechanism from [12C]benzene and [13C]methanol coreactions over zeolite H-beta. J. Catal. 221, 1ā10 (2004).McCann, D. M. et al. A complete catalytic cycle for supramolecular methanol-to-olefins conversion by linking theory with experiment. Angew. Chem. Int. Ed. 47, 5179ā5182 (2008).Arstad, B., Kolboe, S. & Swang, O. Theoretical study of the heptamethylbenzenium ion. intramolecular isomerizations and C2, C3, C4 alkene elimination. J. Phys. Chem. A 109, 8914ā8922 (2005).De Wispelaere, K., Hemelsoet, K., Waroquier, M. & Van Speybroeck, V. Complete low-barrier side-chain route for olefin formation during methanol conversion in H-SAPO-34. J. Catal. 305, 76ā80 (2013).Wang, C. M., Wang, Y. D. & Xie, Z. K. Verification of the dual cycle mechanism for methanol-to-olefin conversion in HSAPO-34: a methylbenzene-based cycle from DFT calculations. Catal. Sci. Technol. 4, 2631ā2638 (2014).Wang, C. M., Wang, Y. D., Liu, H. X., Xie, Z. K. & Liu, Z. P. Theoretical insight into the minor role of paring mechanism in the methanol-to-olefins conversion within HSAPO-34 catalyst. Micro. Mesopor. Mater. 158, 264ā271 (2012).Ilias, S. & Bhan, A. The mechanism of aromatic dealkylation in methanol-to-hydrocarbons conversion on H-ZSM-5: What are the aromatic precursors to light olefins? J. Catal. 311, 6ā16 (2014).Erichsen, M. W. et al. Conclusive evidence for two unimolecular pathways to zeolite-catalyzed de-alkylation of the heptamethylbenzenium cation. ChemCatChem 7, 4143ā4147 (2015).Bhawe, Y. et al. Effect of cage size on the selective conversion of methanol to light olefins. ACS Catal. 2, 2490ā2495 (2012).Kang, J. H. et al. Further studies on how the nature of zeolite cavities that are bounded by small pores influences the conversion of methanol to light olefins. ChemPhysChem 19, 412ā419 (2018).Martin, N. et al. Nanocrystalline SSZ-39 zeolite as an efficient catalyst for the methanol-to-olefin (MTO) process. Chem. Commun. 52, 6072ā6075 (2016).Dusselier, M., Deimund, M. A., Schmidt, J. E. & Davis, M. E. Methanol-to-olefins catalysis with hydrothermally treated zeolite SSZ-39. 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CuāSSZ-39, an active and hydrothermally stable catalyst for the selective catalytic reduction of NOx. Chem. Commun. 48, 8264ā8266 (2012).Zhao, Y. & Truhlar, D. G. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor. Chem. Acc. 120, 215ā241 (2008).Ditchfield, R., Hehre, W. J. & Pople, J. A. Self-consistent molecular orbital methods. 9. Extended Gaussian-type basis for molecular-orbital studies of organic molecules. J. Chem. Phys. 54, 724ā728 (1971).Hehre, W. J., Ditchfield, R. & Pople, J. A. Self-consistent molecular orbital methods. 12. Further extensions of Gaussian-type basis sets for use in molecular-orbital studies of organic-molecules. J. Chem. Phys. 56, 2257ā2261 (1972).Frisch, M. J. et al. Gaussian 09, Revision C.01. (Gaussian, Wallingford, 2009).Van Speybroeck, V. et al. First principle chemical kinetics in zeolites: the methanol-to-olefin process as a case study. Chem. Soc. Rev. 43, 7326ā7357 (2014)
StructureāActivity Relationship Study of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitor 2-Amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101) and Absolute Configurational Assignment Using Infrared and Vibrational Circular Dichroism Spectroscopy in Combination with ab Initio HartreeāFock Calculations
Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia
<p>Abstract</p> <p>Background</p> <p>Hereditary Spastic Paraplegias (HSP) are characterized by progressive spasticity and weakness of the lower limbs. At least 45 loci have been identified in families with autosomal dominant (AD), autosomal recessive (AR), or X-linked hereditary patterns. Mutations in the <it>SPAST </it>(<it>SPG4</it>) and <it>ATL1 </it>(<it>SPG3A</it>) genes would account for about 50% of the ADHSP cases.</p> <p>Methods</p> <p>We defined the <it>SPAST </it>and <it>ATL1 </it>mutational spectrum in a total of 370 unrelated HSP index cases from Spain (83% with a pure phenotype).</p> <p>Results</p> <p>We found 50 <it>SPAST </it>mutations (including two large deletions) in 54 patients and 7 <it>ATL1 </it>mutations in 11 patients. A total of 33 of the <it>SPAST </it>and 3 of the <it>ATL1 </it>were new mutations. A total of 141 (31%) were familial cases, and we found a higher frequency of mutation carriers among these compared to apparently sporadic cases (38% vs. 5%). Five of the <it>SPAST </it>mutations were predicted to affect the pre-mRNA splicing, and in 4 of them we demonstrated this effect at the cDNA level. In addition to large deletions, splicing, frameshifting, and missense mutations, we also found a nucleotide change in the stop codon that would result in a larger ORF.</p> <p>Conclusions</p> <p>In a large cohort of Spanish patients with spastic paraplegia, <it>SPAST </it>and <it>ATL1 </it>mutations were found in 15% of the cases. These mutations were more frequent in familial cases (compared to sporadic), and were associated with heterogeneous clinical manifestations.</p
Temporal changes in the epidemiology, management, and outcome from acute respiratory distress syndrome in European intensive care units: a comparison of two large cohorts
Background: Mortality rates for patients with ARDS remain high. We assessed temporal changes in the epidemiology and management of ARDS patients requiring invasive mechanical ventilation in European ICUs. We also investigated the association between ventilatory settings and outcome in these patients. Methods: This was a post hoc analysis of two cohorts of adult ICU patients admitted between May 1ā15, 2002 (SOAP study, n = 3147), and May 8ā18, 2012 (ICON audit, n = 4601 admitted to ICUs in the same 24 countries as the SOAP study). ARDS was defined retrospectively using the Berlin definitions. Values of tidal volume, PEEP, plateau pressure, and FiO2 corresponding to the most abnormal value of arterial PO2 were recorded prospectively every 24 h. In both studies, patients were followed for outcome until death, hospital discharge or for 60 days. Results: The frequency of ARDS requiring mechanical ventilation during the ICU stay was similar in SOAP and ICON (327[10.4%] vs. 494[10.7%], p = 0.793). The diagnosis of ARDS was established at a median of 3 (IQ: 1ā7) days after admission in SOAP and 2 (1ā6) days in ICON. Within 24 h of diagnosis, ARDS was mild in 244 (29.7%), moderate in 388 (47.3%), and severe in 189 (23.0%) patients. In patients with ARDS, tidal volumes were lower in the later (ICON) than in the earlier (SOAP) cohort. Plateau and driving pressures were also lower in ICON than in SOAP. ICU (134[41.1%] vs 179[36.9%]) and hospital (151[46.2%] vs 212[44.4%]) mortality rates in patients with ARDS were similar in SOAP and ICON. High plateau pressure (> 29 cmH2O) and driving pressure (> 14 cmH2O) on the first day of mechanical ventilation but not tidal volume (> 8 ml/kg predicted body weight [PBW]) were independently associated with a higher risk of in-hospital death. Conclusion: The frequency of and outcome from ARDS remained relatively stable between 2002 and 2012. Plateau pressure > 29 cmH2O and driving pressure > 14 cmH2O on the first day of mechanical ventilation but not tidal volume > 8 ml/kg PBW were independently associated with a higher risk of death. These data highlight the continued burden of ARDS and provide hypothesis-generating data for the design of future studies
The Rotterdam Study: 2012 objectives and design update
The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, oncological, and respiratory diseases. As of 2008, 14,926 subjects aged 45Ā years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in over a 1,000 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods
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