Gold(I)-Catalysed Direct Thioetherifications Using Allylic Alcohols: an Experimental and Computational Study

A gold(I)-catalysed direct thioetherification reaction between allylic alcohols and thiols is presented. The reaction is generally highly regioselective (S(N)2′). This dehydrative allylation procedure is very mild and atom economical, producing only water as the by-product and avoiding any unnecessary waste/steps associated with installing a leaving or activating group on the substrate. Computational studies are presented to gain insight into the mechanism of the reaction. Calculations indicate that the regioselectivity is under equilibrium control and is ultimately dictated by the thermodynamic stability of the products

Analysis of Clumps in Molecular Cloud Models: Mass Spectrum, Shapes, Alignment and Rotation

Observations reveal concentrations of molecular line emission on the sky, called ``clumps,'' in dense, star-forming molecular clouds. These clumps are believed to be the eventual sites of star formation. We study the three-dimensional analogs of clumps using a set of self-consistent, time-dependent numerical models of molecular clouds. The models follow the decay of initially supersonic turbulence in an isothermal, self-gravitating, magnetized fluid. We find the following. (1) Clumps are intrinsically triaxial. This explains the observed deficit of clumps with a projected axis ratio near unity, and the apparent prolateness of clumps. (2) Simulated clump axes are not strongly aligned with the mean magnetic field within clumps, nor with the large-scale mean fields. This is in agreement with observations. (3) The clump mass spectrum has a high-mass slope that is consistent with the Salpeter value. There is a low-mass break in the slope at \sim 0.5 \msun, although this may depend on model parameters including numerical resolution. (4) The typical specific spin angular momentum of clumps is $4 \times 10^{22} {\rm cm^2 s^{-1}}$. This is larger than the median specific angular momentum of binary stars. Scaling arguments suggest that higher resolution simulations may soon be able to resolve the scales at which the angular momentum of binary stars is determined.Comment: 14 pages, 13 figures, to appear in 2003 July 20 Ap

Huntingtin-lowering strategies for Huntington's disease.

INTRODUCTION: Huntington's disease (HD) is an incurable, autosomal dominant neurodegenerative disease caused by an abnormally long polyglutamine tract in the huntingtin protein. Because this mutation causes disease via gain-of-function, lowering huntingtin levels represents a rational therapeutic strategy. AREAS COVERED: We searched MEDLINE, CENTRAL, and other trial databases, and relevant company and HD funding websites for press releases until April 2020 to review strategies for huntingtin lowering, including autophagy and PROTACs, which have been studied in preclinical models. We focussed our analyses on oligonucleotide (ASOs) and miRNA approaches, which have entered or are about to enter clinical trials. EXPERT OPINION: ASO and mRNA approaches for lowering mutant huntingtin protein production and strategies for increasing mutant huntingtin clearance are attractive because they target the cause of disease. However, questions concerning the optimal mode of delivery and associated safety issues remain. It is unclear if the human CNS coverage with intrathecal or intraparenchymal delivery will be sufficient for efficacy. The extent that one must lower mutant huntingtin levels for it to be therapeutic is uncertain and the extent to which CNS lowering of wild-type huntingtin is safe is unclear. Polypharmacy may be an effective approach for ameliorating signs and symptoms and for preventing/delaying onset and progression

Chirality Transfer in Gold(I)-Catalysed Direct Allylic Etherifications of Unactivated Alcohols:Experimental and Computational Study

Gold(I)-catalysed direct allylic etherifications have been successfully carried out with chirality transfer to yield enantioenriched, γ-substituted secondary allylic ethers. Our investigations include a full substrate-scope screen to ascertain substituent effects on the regioselectivity, stereoselectivity and efficiency of chirality transfer, as well as control experiments to elucidate the mechanistic subtleties of the chirality-transfer process. Crucially, addition of molecular sieves was found to be necessary to ensure efficient and general chirality transfer. Computational studies suggest that the efficiency of chirality transfer is linked to the aggregation of the alcohol nucleophile around the reactive π-bound Au–allylic ether complex. With a single alcohol nucleophile, a high degree of chirality transfer is predicted. However, if three alcohols are present, alternative proton transfer chain mechanisms that erode the efficiency of chirality transfer become competitive

Habitual Behavior Is Mediated by a Shift in Response-Outcome Encoding by Infralimbic Cortex

The ability to flexibly switch between goal-directed actions and habits is critical for adaptive behavior. The infralimbic prefrontal cortex (IfL-C) has been consistently identified as a crucial structure for the regulation of response strategies. To investigate the role of the IfL-C, the present study employed two validated reinforcement schedules that either promote habits or goal-directed actions in mice. The results reveal that information about action-outcome relationships is differentially encoded in the IfL-C during actions and habits as evidenced by encoding of behavioral outcomes during goal-directed actions that is lost during habits. Optogenetic inhibition of the IfL-C selectively at press during habitual behavior (when firing rates are reduced during unreinforced goal-directed actions) resulted in restoration of sensitivity to change of action-outcome contingency. These results reveal a novel functional mechanism by which IfL-C promotes habitual behavior, and provide insight into strategies for the treatment and prevention of pathological, inflexible behavior common in neuropsychiatric illness

Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension

BACKGROUND: Inflammation is a feature of pulmonary arterial hypertension (PAH), and increased circulating levels of cytokines are reported in patients with PAH. However, to date, no information exists on the significance of elevated cytokines or their potential as biomarkers. We sought to determine the levels of a range of cytokines in PAH and to examine their impact on survival and relationship to hemodynamic indexes. METHODS AND RESULTS: We measured levels of serum cytokines (tumor necrosis factor-alpha, interferon-gamma and interleukin-1beta, -2, -4, -5, -6, -8, -10, -12p70, and -13) using ELISAs in idiopathic and heritable PAH patients (n=60). Concurrent clinical data included hemodynamics, 6-minute walk distance, and survival time from sampling to death or transplantation. Healthy volunteers served as control subjects (n=21). PAH patients had significantly higher levels of interleukin-1beta, -2, -4, -6, -8, -10, and -12p70 and tumor necrosis factor-alpha compared with healthy control subjects. Kaplan-Meier analysis showed that levels of interleukin-6, 8, 10, and 12p70 predicted survival in patients. For example, 5-year survival with interleukin-6 levels of >9 pg/mL was 30% compared with 63% for patients with levels < or = 9 pg/mL (P=0.008). In this PAH cohort, cytokine levels were superior to traditional markers of prognosis such as 6-minute walk distance and hemodynamics. CONCLUSIONS: This study illustrates dysregulation of a broad range of inflammatory mediators in idiopathic and familial PAH and demonstrates that cytokine levels have a previously unrecognized impact on patient survival. They may prove to be useful biomarkers and provide insight into the contribution of inflammation in PAH

SNPServer: a real-time SNP discovery tool

SNPServer is a real-time flexible tool for the discovery of SNPs (single nucleotide polymorphisms) within DNA sequence data. The program uses BLAST, to identify related sequences, and CAP3, to cluster and align these sequences. The alignments are parsed to the SNP discovery software autoSNP, a program that detects SNPs and insertion/deletion polymorphisms (indels). Alternatively, lists of related sequences or pre-assembled sequences may be entered for SNP discovery. SNPServer and autoSNP use redundancy to differentiate between candidate SNPs and sequence errors. For each candidate SNP, two measures of confidence are calculated, the redundancy of the polymorphism at a SNP locus and the co-segregation of the candidate SNP with other SNPs in the alignment. SNPServer is available at

Religion as practices of attachment and materiality: the making of Buddhism in contemporary London

This article aims to explore Buddhism’s often-overlooked presence on London’s urban landscape, showing how its quietness and subtlety of approach has allowed the faith to grow largely beneath the radar. It argues that Buddhism makes claims to urban space in much the same way as it produces its faith, being as much about the practices performed and the spaces where they are enacted as it is about faith or beliefs. The research across a number of Buddhist sites in London reveals that number of people declaring themselves as Buddhists has indeed risen in recent years, following the rise of other non-traditional religions in the UK; however, this research suggests that Buddhism differs from these in several ways. Drawing on Baumann’s (2002) distinction between traditionalist and modernist approaches to Buddhism, our research reveals a growth in each of these. Nevertheless, Buddhism remains largely invisible in the urban and suburban landscape of London, adapting buildings that are already in place, with little material impact on the built environment, and has thus been less subject to contestation than other religious movements and traditions. This research contributes to a growing literature which foregrounds the importance of religion in making contemporary urban and social worlds