165 research outputs found
Synthetic and spectrometric investigation of 1,4-benzoxazepines
Flavanone (2,3-dihydro-2-phenyl-4H-benzopyran-4-one) and a series of 4'- and 7-halogeno derivatives were prepared from the corresponding 2'-hydroxychalcones [1-(2-hydroxyphenyl)-3-phenyl-2-propen-l-ones], which, in turn, were synthesized by aldol condensation of substituted 2'-hydroxacetophenones with various benzaldehydes. A series of 2,3-dihydro-2-phenyl-l,4-benzoxazepin-5(4H)-ones were prepared by ring expansion of the corresponding flavanones, via the Schmidt reaction, using trimethylsilylazide and trifluoroacetic acid. A series of tetrazoles {2,3-dihydro-2-phenyl-tetrazolo[1,5-d]-1,4-benzoxazepines} were also isolated as by-products of the Schmidt reaction. Flavanone oxime was synthesized for use in Beckmann reactions, and its molecular structure was determined by x-ray crystallography. Attempts to prepare 1,4-benzoxazepinone or its 1,5-analogue via Beckmann rearrangement of flavanone oxime, with polyphosphoric acid or phosphorus pentachloride catalysts, however, were unsuccessful. Several methods for introducing ÎÂČ-unsaturation into the benzoxazepinone system were also examined. High resolution ÂčH n.m.r., computer modelling, and molecular mechanics techniques were used to determine the conformations of the heterocycles of the benzoxazepinones and tetrazoles and results are compared with earlier studies in this field. Certain trends in the fragmentation patterns were observed in the low resolution mass spectra of the benzoxazepinones and tetrazoles, and high resolution mass spectrometric data were used to explore the major fragmentation patterns of these compounds
(η5-CycloÂpentaÂdienÂyl){[3-(2,2-dicyanoÂethenÂyl)bicycloÂ[2.2.1]hepta-2,5-dien-2-yl]ethynÂyl}(triphenylÂphosphine)nickel(II)
The title compound, [Ni(C5H5)(C13H7N2)(C18H15P)] or (η5-C5H5)(PPh3)NiâC CâC7H6âC(H)=C(CN)2, contains an unusual disubstituted norbornadienyl (NBD) ligand containing ethynyl (âC Câ) and dicyanoÂvinyl [âC(H)=C(CN)2] groups. Disorder is present in the NBD group with site occupancies of 0.636â
(10) and 0.364â
(10) for two distinct orientations. There are no strong hydrogen bonds and the primary interÂactions are weak CâHâŻÏ(arene) interÂactions
Cognitive therapy for compulsive checking in obsessive-compulsive disorder: A pilot trial
We evaluated a novel, empirically-based cognitive therapy for compulsive checking â a common form of obsessive-compulsive disorder. Twelve adults completed 12 sessions of the therapy. Significant reductions in checking-related symptoms were found pre- to post-treatment, and pre-treatment to 6-month follow-up (moderate to large effect sizes). Participants reported high treatment acceptability after the third session, which was maintained at post-treatment. This pilot trial provides preliminary support for treating compulsive checking using this novel cognitive approach
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Electrospray mass spectrometry of NeuAc oligomers associated with the C fragment of the tetanus toxin
The Clostridial neurotoxins, botulinum and tetanus, gain entry into neuronal cells by protein recognition involving cell specific binding sites. The sialic or N-acetylneuraminic acid (NeuAc) residues of gangliosides attached to the surface of motor neurons are the suspected recognition and interaction points with Clostridial neurotoxins, although not necessarily the only ones. We have used electrospray ionization mass spectrometry (ESIMS) to examine formation of complexes between the tetanus toxin C fragment, or targeting domain, and carbohydrates containing NeuAc groups to determine how NeuAc residues contribute to ganglioside binding. ESI-MS was used to rapidly and efficiently measure dissociation constants for a number of related NeuAc-containing carbohydrates and NeuAc oligomers, information that has helped identify the structural features of gangliosides that determine their binding to tetanus toxin. The strength of the interactions between the C fragment and (NeuAc){sub n}, are consistent with the topography of the targeting domain of tetanus toxin and the nature of its carbohydrate binding sites. The results suggest that the targeting domain of tetanus toxin contains two binding sites that can accommodate NeuAc (or a dimer). This study also shows that NeuAc must play an important role in ganglioside binding and molecular recognition, a process critical for normal cell function and one frequently exploited by toxins, bacteria and viruses to facilitate their entrance into cells
Spallation Neutron Production by 0.8, 1.2 and 1.6 GeV Protons on various Targets
Spallation neutron production in proton induced reactions on Al, Fe, Zr, W,
Pb and Th targets at 1.2 GeV and on Fe and Pb at 0.8, and 1.6 GeV measured at
the SATURNE accelerator in Saclay is reported. The experimental
double-differential cross-sections are compared with calculations performed
with different intra-nuclear cascade models implemented in high energy
transport codes. The broad angular coverage also allowed the determination of
average neutron multiplicities above 2 MeV. Deficiencies in some of the models
commonly used for applications are pointed out.Comment: 20 pages, 32 figures, revised version, accepted fpr publication in
Phys. Rev.
Knowledge and competency standards for specialized cognitive behavior therapy for adult obsessive-compulsive disorder
Obsessive-Compulsive Disorder (OCD) is a leading cause of disability world-wide (World Health Organization, 2008). Treatment of OCD is a specialized field whose aim is recovery from illness for as many patients as possible. The evidence-based psychotherapeutic treatment for OCD is specialized cognitive behavior therapy (CBT, NICE, 2005, Koran and Simpson, 2013). However, these treatments are not accessible to many sufferers around the world. Currently available guidelines for care are deemed to be essential but insufficient because of highly variable clinician knowledge and competencies specific to OCD. The phase two mandate of the 14 nation International OCD Accreditation Task Force (ATF) created by the Canadian Institute for Obsessive Compulsive Disorders is development of knowledge and competency standards for specialized treatments for OCD through the lifespan deemed by experts to be foundational to transformative change in this field. This paper presents knowledge and competency standards for specialized CBT for adult OCD developed to inform, advance, and offer a model for clinical practice and training for OCD. During upcoming ATF phases three and four criteria and processes for training in specialized treatments for OCD through the lifespan for certification (individuals) and accreditation (sites) will be developed based on the ATF standards
Calorimetric Investigation of Copper Binding in the N-Terminal Region of the Prion Protein at Low Copper Loading: Evidence for an Entropically Favorable First Binding Event
Although
the Cu<sup>2+</sup>-binding sites of the prion protein have been well
studied when the protein is fully saturated by Cu<sup>2+</sup>, the
Cu<sup>2+</sup>-loading mechanism is just beginning to come into view.
Because the Cu<sup>2+</sup>-binding modes at low and intermediate
Cu<sup>2+</sup> occupancy necessarily represent the highest-affinity
binding modes, these are very likely populated under physiological
conditions, and it is thus essential to characterize them in order
to understand better the biological function of copperâprion
interactions. Besides binding-affinity data, almost no other thermodynamic
parameters (e.g., Î<i>H</i> and Î<i>S</i>) have been measured, thus leaving undetermined the enthalpic and
entropic factors that govern the free energy of Cu<sup>2+</sup> binding
to the prion protein. In this study, isothermal titration calorimetry
(ITC) was used to quantify the thermodynamic parameters (<i>K</i>, Î<i>G</i>, Î<i>H</i>, and <i>T</i>Î<i>S</i>) of Cu<sup>2+</sup> binding to
a peptide, PrPÂ(23â28, 57â98), that encompasses the majority
of the residues implicated in Cu<sup>2+</sup> binding by full-length
PrP. Use of the buffer <i>N</i>-(2-acetomido)-aminoethanesulfonic
acid (ACES), which is also a well-characterized Cu<sup>2+</sup> chelator,
allowed for the isolation of the two highest affinity binding events.
Circular dichroism spectroscopy was used to characterize the different
binding modes as a function of added Cu<sup>2+</sup>. The <i>K</i><sub>d</sub> values determined by ITC, 7 and 380 nM, are
well in line with those reported by others. The first binding event
benefits significantly from a positive entropy, whereas the second
binding event is enthalpically driven. The thermodynamic values associated
with Cu<sup>2+</sup> binding by the AÎČ peptide, which is implicated
in Alzheimerâs disease, bear striking parallels to those found
here for the prion protein
Methods for Analysis of Matrix Metalloproteinase Regulation of Neutrophil-Endothelial Cell Adhesion
Recent evidence indicates novel role for matrix metalloproteinases (MMPs), in particular gelatinase A (MMP-2), in the regulation of vascular biology that are unrelated to their well-known proteolytic breakdown of matrix proteins. We have previously reported that MMP-2 can modulate vascular reactivity by cleavage of the Gly32-Leu33 bound in big endothelin-1 (ET-1) yielding a novel vasoactive peptide ET-1[1-32]. These studies were conducted to investigate whether gelatinolytic MMPs could affect neutrophil-endothelial cell attachment. ET-1[1-32] produced by MMP-2 up-regulated CD11b/CD18 expression on human neutrophils, thereby promoted their adhesion to cultured endothelial cells. ET-1[1-32] evoked release of gelatinase B (MMP-9), which in turn cleaved big ET-1 to yield ET-1[1-32], thus revealing a self-amplifying loop for ET-1[1-32] generation. ET-1[1-32] was rather resistant to cleavage by neutrophil proteases and further metabolism of ET-1[1-32] was not a prerequisite for its biological actions on neutrophils. The neutrophil responses to ET-1[1-32] were mediated via activation of ET(A)receptors through activation of the Ras/Raf-1/MEK/ERK signaling pathway. These results suggest a novel role for gelatinase A and B in the regulation of neutrophil functions and their interactions with endothelial cells. Here we describe the methods in detail as they relate to our previously published work
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