Optimization of an ether series of mGluR5 positive allosteric modulators: Molecular determinants of MPEP site interaction crossover

We report the optimization of a series of non-MPEP site metabotropic glutamate receptor 5 (mGlu5) pos. allosteric modulators (PAMs) based on a simple acyclic ether series. Modifications led to a gain of MPEP site interaction through incorporation of a chiral amide in conjunction with a nicotinamide core. A highly potent PAM, 8v (VU0404251), was shown to be efficacious in a rodent model of psychosis. These studies suggest that potent PAMs within topol. similar chemotypes can be developed to preferentially interact or not interact with the MPEP allosteric binding site.

Discovery and SAR of a novel series of non-MPEP site mGlu(5) PAMs based on an aryl glycine sulfonammide scaffold

Herein we report the discovery and SAR of a novel series of non-MPEP site metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) based on an aryl glycine sulfonamide scaffold. This series represents a rare non-MPEP site mGlu(5) PAM chemotype.

Fluoroscopic and electrical assessment of a series of defibrillation leads:prevalence of externalized conductors

Introduction : Insulation defects with externalized conductors have been reported in the St. Jude Riata(®) family of defibrillation leads (St. Jude Medical, Sylmar, CA, USA). The objective of the Northern Ireland Riata(®) lead screening program was to identify insulation defects and externalized conductors by systematic fluoroscopic and electrical assessment in a prospectively defined cohort of patients. We sought to estimate the prevalence, identify risk factors, and determine the natural history of this abnormality. Methods : All patients with a Riata(®) lead under follow-up at the Royal Victoria Hospital were invited for fluoroscopic imaging and implantable cardioverter-defibrillator lead parameter checks. Fluoroscopic images were read independently by two cardiologists and the presence of externalized conductors was classified as positive, negative, or borderline. Results: One hundred and sixty-five of 212 patients with a Riata lead were evaluated by fluoroscopy and lead parameter measurements. The mean duration after implantation was 3.98+/-1.43 years. After screening 25 (15%) patients were classified as positive, 137 (83%) negative, and three (1.8%) borderline. Time since implantation (P = 0.001), presence of a single coil lead (P = 0.042), and patient age (P = 0.034) were significantly associated with externalized conductors. The observed rate of externalized conductors was 26.9% for 8-French and 4.7% for 7-French leads. No leads that were identified prospectively with externalized conductors had electrical abnormalities. Seven of 25 (28%) patients had a defective lead extracted by the end of this screening period. Conclusion: A significant proportion (15%) of patients with a Riata lead had an insulation breach 4 years after implantation. High-resolution fluoroscopic imaging in at least two orthogonal views is required to identify this abnormality. (PACE 2012;35:1498-1504).

64-point Fourier transform chip for digital television applications

A 64-point Fourier transform chip is described that performs a forward or inverse, 64-point Fourier transform on complex two's complement data supplied at a rate of 13.5MHz and can operate at clock rates of up to 40MHz, under worst-case conditions. It uses a 0.6µm double-level metal CMOS technology, contains 535k transistors and uses an internal 3.3V power supply. It has an area of 7.8×8mm, dissipates 0.9W, has 48 pins and is housed in a 84 pin PLCC plastic package. The chip is based on a FFT architecture developed from first principles through a detailed investigation of the structure of the relevant DFT matrix and through mapping repetitive blocks within this matrix onto a regular silicon structure.

Modified Information Criteria and Selection of Long Memory Time Series Models

The problem of model selection of a univariate long memory time series is investigated once a semi parametric estimator for the long memory parameter has been used. Standard information criteria are not consistent in this case. A Modified Information Criterion (MIC) that overcomes these difficulties is introduced and proofs that show its asymptotic validity are provided. The results are general and cover a wide range of short memory processes. Simulation evidence compares the new and existing methodologies and empirical applications in monthly inflation and daily realized volatility are presented.

Bloodlines

A three-part BBC television drama series

Transnational Fantômas: The Influence of Feuillade’s Series on International Cinema during the 1910s

The influence of Fantômas novels and films on global popular culture is widely acknowledged. From the 1915 Spanish musical "Cine-fantomas" to the 1960s Italian comic book series "Diabolik," "Kriminal" and "Satanik," from Turkish B-movies such as "Fantoma Istanbulda Bulusalim" (dir. Natuk Baytan, 1967) to Julio Cortazar’s anti-imperialist pamphlet "Fantômas contra los vampiros multinacionales" (1975), Pierre Souvestre and Marcel Allain’s original literary series have engendered uncountable translations, adaptations, imitations and plagiarisms that have spread the character’s fame worldwide since its first appearance in 1911.
By focusing on the influence of Louis Feuillade’s film adaptations during the first decade of Fantômas’ long history as a transnational and transmedia icon, this paper aims to contribute to the growing interdisciplinary field that deals with the history of the supranational cultural sphere created by modern media culture. As a sort of archaeology of contemporary cultural globalization, this form of study intends to enrich previous historical surveys that had only taken into consideration specific national contexts. Moreover, it might also rebalance certain “colonizing” accounts that overemphasize the role of the cultural superpowers such as France, the UK or the US, often forgetting the appropriation of the products of international popular culture to be found in other countries. Therefore, this paper examines the transnational circulation of Fantômas films and, in particular, the creative processes engendered outside of France their origin country. As a controversial character and a central player in the relationship between cinema and literature in the crucial years when the feature and serial film boosted and legitimized the film industry, Fantômas represents an exemplary case study to discuss the cross-cultural and cross-media dynamics engendered by popular fiction.

An allelic series reveals essential roles for FY in plant development in addition to flowering-time control.

The autonomous pathway functions to promote flowering in Arabidopsis by limiting the accumulation of the floral repressor FLOWERING LOCUS C (FLC). Within this pathway FCA is a plant-specific, nuclear RNA-binding protein, which interacts with FY, a highly conserved eukaryotic polyadenylation factor. FCA and FY function to control polyadenylation site choice during processing of the FCA transcript. Null mutations in the yeast FY homologue Pfs2p are lethal. This raises the question as to whether these essential RNA processing functions are conserved in plants. Characterisation of an allelic series of fy mutations reveals that null alleles are embryo lethal. Furthermore, silencing of FY, but not FCA, is deleterious to growth in Nicotiana. The late-flowering fy alleles are hypomorphic and indicate a requirement for both intact FY WD repeats and the C-terminal domain in repression of FLC. The FY C-terminal domain binds FCA and in vitro assays demonstrate a requirement for both C-terminal FY-PPLPP repeats during this interaction. The expression domain of FY supports its roles in essential and flowering-time functions. Hence, FY may mediate both regulated and constitutive RNA 3'-end processing.

Stonehenge:Digging in the Past Series.

Malone, C. and N. Bernard, Stonehenge. 2004, New York, Oxford University Press.

Transnational connections in European crime film series (1908–1914)

This article addresses the issue of ‘European popular cinema’ by discussing a very specific phenomenon, i.e. the crime series produced in the years immediately preceding World War I (e.g. Victorin Jasset’s Nick Carter, Viggo Larsen’s Arsène Lupin contra Sherlock, Ubaldo Maria del Colle’s Raffles, il ladro misterioso, Louis Feuillade’s Fantômas, George Pearson’s Ultus). On the one hand, the transnational circulation of these films is seen as the result of the development of the European cultural industries since the late nineteenth century; on the other hand, the rapid decline of this genre testifies of the historical peculiarity of this production. In particular, the popular heroic figure of the ‘gentleman thief’ seems to express at the same time the liberating, anti-hierarchial ethos of modernization and the dream of a quiet conciliation of the new and the traditional values: as a consequence, it might be regarded as a telling example of the economical, social and ideological transformations of that crucial phase in European history, when the development of the second industrial revolution and the first phase of ‘globalization’ pointed at the birth of a supranational sphere before the outbreak of World War I, which would temporarily stop this process.