Mechanistic studies of azolium ions and their role in organocatalysis

Azolium ion precursors to N-heterocyclic carbenes (NHCs) have risen to prominence as versatile organocatalysts for a broad range of synthetic transformations. In recent years, methodologies have been developed for the generation and exploitation of azolium homoenolates, azolium enolates, and acyl azolium intermediates, leading to a diverse range of asymmetric products. It is common in many synthetic procedures to generate the active NHC in situ by deprotonation of the parent azolium ion. Knowledge of the kinetic and thermodynamic acidities of these species is therefore an essential first step in understanding their catalytic behaviour. We have used a kinetic method to determine kinetic acidities and aqueous pKa values for a set of triazolium, thiazolium and imidazolium ions at the C(3)-H or C(2)-H positions. Using 1H NMR spectroscopy to follow deuterium exchange, pseudo-first-order rate constants for exchange, kex (s-1), were determined at a range of pDs in D2O at 25 °C and I = 1.0 (KCl), from which second-order rate constants for deprotonation by deuteroxide ion, kDO (M-1 s-1) could be obtained. By application of a secondary solvent isotope effect (kDO/kHO = 2.4), corresponding values of kHO were calculated. General base catalysis experiments support the conclusion that the rate constant for carbene protonation by solvent water is limited by solvent reorganisation, and occurs with a rate constant of kHOH = kreorg = 1011 s-1. These values of kHO and kHOH permitted the calculation of carbon acid pKa values for ionisation of the azolium ion in water. For a homologous series of catalytically-relevant triazolium salts, the effect of the N-aryl substituent on values of kDO and pKa was probed, and comparisons between azolium ion families will be made. The pD-rate profile of an N-C6F5 substituted triazolium ion indicates that in acidic media, protonation at the N(1) position may occur to give a dicationic triazolium ion. Using this methodology, the kinetic acidities of the conjugate acids of ‘mesoionic’ or ‘abnormal’ carbenes were also investigated. For a series of 1,2,3-triazolium ions and C(2)-alkylated 1,3-imidazolium ions, rate constants for exchange at the C(4)-H and C(5)-H positions were determined. Our results suggest that these sites are 105-fold less acidic than the C(3)-H and C(2)-H positions of ‘classical’ triazolium and imidazolium ions. To explain the deviation from a first-order dependence on deuteroxide ion for the imidazolium ions in strong KOD solution, we have proposed a number of exchange pathways that proceed via a hydrate. The effects of N-aryl substituent and counterion on kDO and pKa are also discussed. We have also conducted mechanistic studies of the triazol-3-ylidene-catalysed benzoin condensation. In situ 1H NMR spectroscopic studies of the reaction in triethylamine-buffered methanol-d4 at 25 °C show that the 3-(hydroxyaryl)triazolium adduct, generated from addition of the NHC to the aldehyde, is the only intermediate observed over the course of the reaction. Evidence is presented to show that the formation of these intermediates under these conditions is reversible, and reliable equilibrium and rate constants for the formation of these species have been determined using independent approaches. Our results suggest that N-mesityl substituents on the catalyst, and ortho-alkoxyl groups on the aromatic aldehyde result in significantly enhanced equilibrium concentrations of this intermediate. Slow deprotonation of these intermediates results in the benzoin product. Rate constants for the deprotonation step suggest that electron-deficient adducts result in the fastest rates of deprotonation. Finally, an initial rates study of the benzoin condensation at catalytic concentrations of azolium ion precatalyst has also been undertaken. An HPLC analysis method was used to determine the concentrations of benzoin and benzaldehyde over the course of the reaction in triethylamine-buffered methanol at 50 °C. Our results suggest that the thiazolium-catalysed reaction is first-order with respect to aldehyde over the full range of benzaldehyde concentrations studied (0.32 – 1.60 M). In contrast, the triazolium-catalysed reaction displays a first-order dependence at low aldehyde concentrations, before changing to a zero-order dependence at higher benzaldehyde concentrations. From the maximum rate of catalysis in this zero-order region, the effect of N-aryl substituent on rate of turnover was investigated for a homologous series of triazolium precatalysts

Second-order phase transition at the phase boundary through the FeRh first-order metamagnetic phase transition

The phase coexistence present through first-order phase transitions implies the presence of phase boundary walls, which can be of finite size. Better understanding of the phase boundary wall properties will provide an insight into the dynamics of first-order phase transitions. Here, by combining x-ray photon correlation spectroscopy investigations with magnetometry measurements of magnetic relaxation through the thermally activated first-order metamagnetic phase transition present in the B2-ordered FeRh alloy, we are able to isolate the dynamic behaviour of the phase boundary wall present in this system. These investigations reveal a change in the nature of the dynamic behaviour and critical scaling of the relaxation time centred around the point of maximum phase coexistence within the phase transition. All of this behaviour can be attributed to the introduction of exchange coupling across the phase boundary wall and raises questions about the role of latent heat in dynamic behaviour of this region

X-ray and Radio Variability of M31*, The Andromeda Galaxy Nuclear Supermassive Black Hole

We confirm our earlier tentative detection of M31* in X-rays and measure its light-curve and spectrum. Observations in 2004-2005 find M31* rather quiescent in the X-ray and radio. However, X-ray observations in 2006-2007 and radio observations in 2002 show M31* to be highly variable at times. A separate variable X-ray source is found near P1, the brighter of the two optical nuclei. The apparent angular Bondi radius of M31* is the largest of any black hole, and large enough to be well resolved with Chandra. The diffuse emission within this Bondi radius is found to have an X-ray temperature ~0.3 keV and density 0.1 cm-3, indistinguishable from the hot gas in the surrounding regions of the bulge given the statistics allowed by the current observations. The X-ray source at the location of M31* is consistent with a point source and a power law spectrum with energy slope 0.9+/-0.2. Our identification of this X-ray source with M31* is based solely on positional coincidence.Comment: 25 pages, 8 figures, submitted to Ap

Environmentalism, performance and applications: uncertainties and emancipations

This introductory article for a themed edition on environmentalism provides a particular context for those articles that follow, each of which engages with different aspects of environmentalism and performance in community-related settings. Responding to the proposition that there is a lacuna in the field of applied drama and environmentalism (Bottoms, 2010), we suggest that the more significant lack is that of ecocriticism. As the articles in this journal testify, there are many examples of applied theatre practice; what is required is sustained and rigorous critical engagement. It is to the gap of ecocriticism that we address this issue, signalling what we hope is the emergence of a critical field. One response to the multiple challenges of climate change is to more transparently locate the human animal within the environment, as one agent amongst many. Here, we seek to transparently locate the critic, intertwining the personal – ourselves, human actants – with global environmental concerns. This tactic mirrors much contemporary writing on climate change and its education, privileging personal engagement – a shift we interrogate as much as we perform. The key trope we anchor is that of uncertainty: the uncertainties that accompany stepping into a new research environment; the uncertainties arising from multiple relations (human and non-human); the uncertainties of scientific fact; the uncertainties of forecasting the future; and the uncertainties of outcomes – including those of performance practices. Having analysed a particular turn in environmental education (towards social learning) and the failure to successfully combine ‘art and reality’ in recent UK mainstream theatre events, such uncertainties lead to our suggestion for an ‘emancipated’ environmentalism. In support of this proposal, we offer up a reflection on a key weekend of performance practice that brought us to attend to the small – but not insignificant – and to consider first hand the complex relationships between environmental ‘grand narratives’ and personal experiential encounters. Locating ourselves within the field and mapping out some of the many conceptual challenges attached to it serves to introduce the territories which the following journal articles expand upon

The Third Gravitational Lensing Accuracy Testing (GREAT3) Challenge Handbook

The GRavitational lEnsing Accuracy Testing 3 (GREAT3) challenge is the third in a series of image analysis challenges, with a goal of testing and facilitating the development of methods for analyzing astronomical images that will be used to measure weak gravitational lensing. This measurement requires extremely precise estimation of very small galaxy shape distortions, in the presence of far larger intrinsic galaxy shapes and distortions due to the blurring kernel caused by the atmosphere, telescope optics, and instrumental effects. The GREAT3 challenge is posed to the astronomy, machine learning, and statistics communities, and includes tests of three specific effects that are of immediate relevance to upcoming weak lensing surveys, two of which have never been tested in a community challenge before. These effects include realistically complex galaxy models based on high-resolution imaging from space; spatially varying, physically-motivated blurring kernel; and combination of multiple different exposures. To facilitate entry by people new to the field, and for use as a diagnostic tool, the simulation software for the challenge is publicly available, though the exact parameters used for the challenge are blinded. Sample scripts to analyze the challenge data using existing methods will also be provided. See http://great3challenge.info and http://great3.projects.phys.ucl.ac.uk/leaderboard/ for more information.Comment: 30 pages, 13 figures, submitted for publication, with minor edits (v2) to address comments from the anonymous referee. Simulated data are available for download and participants can find more information at http://great3.projects.phys.ucl.ac.uk/leaderboard

Photoactivation of the BLUF protein PixD Probed by the Site-Specific Incorporation of Fluorotyrosine Residues

The flavin chromophore in blue light using FAD (BLUF) photoreceptors is surrounded by a hydrogen bond network that senses and responds to changes in the electronic structure of the flavin on the ultrafast time scale. The hydrogen bond network includes a strictly conserved Tyr residue, and previously we explored the role of this residue, Y21, in the photoactivation mechanism of the BLUF protein AppA by the introduction of fluorotyrosine (F-Tyr) analogs that modulated the pKa and reduction potential of Y21 by 3.5 pH units and 200 mV, respectively. Although little impact on the forward (dark to light adapted form) photoreaction was observed, the change in Y21 pKa led to a 4,000-fold increase in the rate of dark state recovery. In the present work we have extended these studies to the BLUF protein PixD, where, in contrast to AppA, modulation in the Tyr (Y8) pKa has a profound impact on the forward photoreaction. In particular, a decrease in Y8 pKa by 2 or more pH units prevents formation of a stable light state, consistent with a photoactivation mechanism that involves proton transfer or proton coupled electron transfer from Y8 to the electronically excited FAD. Conversely, the effect of pKa on the rate of dark recovery is markedly reduced in PixD. These observations highlight very significant differences between the photocycles of PixD and AppA, despite their sharing highly conserved FAD binding architectures

Asymmetric magnetic relaxation behavior of domains and domain walls observed through the FeRh first-order metamagnetic phase transition

The phase coexistence present through a first-order phase transition means there will be finite regions between the two phases where the structure of the system will vary from one phase to the other, known as a phase boundary wall. This region is said to play an important but unknown role in the dynamics of the first-order phase transitions. Here, by using both x-ray photon correlation spectroscopy and magnetometry techniques to measure the temporal isothermal development at various points through the thermally activated first-order metamagnetic phase transition present in the near-equiatomic FeRh alloy, we are able to isolate the dynamic behavior of the domain walls in this system. These investigations reveal that relaxation behavior of the domain walls changes when phase coexistence is introduced into the system and that the domain-wall dynamics is different to the macroscale behavior. We attribute this to the effect of the exchange coupling between regions of either magnetic phase changing the dynamic properties of domain walls relative to bulk regions of either phase. We also believe this behavior comes from the influence of the phase boundary wall on other magnetic objects in the system

'To live and die [for] Dixie': Irish civilians and the Confederate States of America

Around 20,000 Irishmen served in the Confederate army in the Civil War. As a result, they left behind, in various Southern towns and cities, large numbers of friends, family, and community leaders. As with native-born Confederates, Irish civilian support was crucial to Irish participation in the Confederate military effort. Also, Irish civilians served in various supporting roles: in factories and hospitals, on railroads and diplomatic missions, and as boosters for the cause. They also, however, suffered in bombardments, sieges, and the blockade. Usually poorer than their native neighbours, they could not afford to become 'refugees' and move away from the centres of conflict. This essay, based on research from manuscript collections, contemporary newspapers, British Consular records, and Federal military records, will examine the role of Irish civilians in the Confederacy, and assess the role this activity had on their integration into Southern communities. It will also look at Irish civilians in the defeat of the Confederacy, particularly when they came under Union occupation. Initial research shows that Irish civilians were not as upset as other whites in the South about Union victory. They welcomed a return to normalcy, and often 'collaborated' with Union authorities. Also, Irish desertion rates in the Confederate army were particularly high, and I will attempt to gauge whether Irish civilians played a role in this. All of the research in this paper will thus be put in the context of the Drew Gilpin Faust/Gary Gallagher debate on the influence of the Confederate homefront on military performance. By studying the Irish civilian experience one can assess how strong the Confederate national experiment was. Was it a nation without a nationalism

Hsp72 is targeted to the mitotic spindle by Nek6 to promote K-fiber assembly and mitotic progression

Hsp70 proteins represent a family of chaperones that regulate cellular homeostasis and are required for cancer cell survival. However, their function and regulation in mitosis remain unknown. In this paper, we show that the major inducible cytoplasmic Hsp70 isoform, Hsp72, is required for assembly of a robust bipolar spindle capable of efficient chromosome congression. Mechanistically, Hsp72 associates with the K-fiber-stabilizing proteins, ch-TOG and TACC3, and promotes their interaction with each other and recruitment to spindle microtubules (MTs). Targeting of Hsp72 to the mitotic spindle is dependent on phosphorylation at Thr-66 within its nucleotide-binding domain by the Nek6 kinase. Phosphorylated Hsp72 concentrates on spindle poles and sites of MT-kinetochore attachment. A phosphomimetic Hsp72 mutant rescued defects in K-fiber assembly, ch-TOG/TACC3 recruitment and mitotic progression that also resulted from Nek6 depletion. We therefore propose that Nek6 facilitates association of Hsp72 with the mitotic spindle, where it promotes stable K-fiber assembly through recruitment of the ch-TOG-TACC3 complex

Evolution and Global Transmission of a Multidrug-Resistant, Community-Associated Methicillin-Resistant Staphylococcus aureus Lineage from the Indian Subcontinent

The evolution and global transmission of antimicrobial resistance have been well documented for Gram-negative bacteria and health care-associated epidemic pathogens, often emerging from regions with heavy antimicrobial use. However, the degree to which similar processes occur with Gram-positive bacteria in the community setting is less well understood. In this study, we traced the recent origins and global spread of a multidrug-resistant, community-associated Staphylococcus aureus lineage from the Indian subcontinent, the Bengal Bay clone (ST772). We generated whole-genome sequence data of 340 isolates from 14 countries, including the first isolates from Bangladesh and India, to reconstruct the evolutionary history and genomic epidemiology of the lineage. Our data show that the clone emerged on the Indian subcontinent in the early 1960s and disseminated rapidly in the 1990s. Short-term outbreaks in community and health care settings occurred following intercontinental transmission, typically associated with travel and family contacts on the subcontinent, but ongoing endemic transmission was uncommon. Acquisition of a multidrug resistance integrated plasmid was instrumental in the emergence of a single dominant and globally disseminated clade in the early 1990s. Phenotypic data on biofilm, growth, and toxicity point to antimicrobial resistance as the driving force in the evolution of ST772. The Bengal Bay clone therefore combines the multidrug resistance of traditional health care-associated clones with the epidemiological transmission of community-associated methicillin-resistant S. aureus (MRSA). Our study demonstrates the importance of whole-genome sequencing for tracking the evolution of emerging and resistant pathogens. It provides a critical framework for ongoing surveillance of the clone on the Indian subcontinent and elsewhere