Asymmetric triplex metallohelices with high and selective activity against cancer cells

Small cationic amphiphilic α-helical peptides are emerging as agents for the treatment of cancer and infection, but they are costly and display unfavourable pharmacokinetics. Helical coordination complexes may offer a three-dimensional scaffold for the synthesis of mimetic architectures. However, the high symmetry and modest functionality of current systems offer little scope to tailor the structure to interact with specific biomolecular targets, or to create libraries for phenotypic screens. Here, we report the highly stereoselective asymmetric self-assembly of very stable, functionalized metallohelices. Their anti-parallel head-to-head-to-tail ‘triplex’ strand arrangement creates an amphipathic functional topology akin to that of the active sub-units of, for example, host-defence peptides and ​p53. The metallohelices display high, structure-dependent toxicity to the human colon carcinoma cell-line HCT116 ​p53++, causing dramatic changes in the cell cycle without DNA damage. They have lower toxicity to human breast adenocarcinoma cells (MDA-MB-468) and, most remarkably, they show no significant toxicity to the bacteria methicillin-resistant Staphylococcus aureus and Escherichia coli. At a glanc

Computations in non-commutative Iwasawa theory

We study special values of L-functions of elliptic curves over Q twisted by Artin representations that factor through a false Tate curve extension $Q(\mu_p^\infty,\sqrt[p^\infty]{m})/Q$. In this setting, we explain how to compute L-functions and the corresponding Iwasawa-theoretic invariants of non-abelian twists of elliptic curves. Our results provide both theoretical and computational evidence for the main conjecture of non-commutative Iwasawa theory.Comment: 60 pages; with appendix by John Coates and Ramdorai Sujath

Evaluation of two lyophilized molecular assays to rapidly detect foot-and-mouth disease virus directly from clinical samples in field settings

Accurate, timely diagnosis is essential for the control, monitoring and eradication of foot‐and‐mouth disease (FMD). Clinical samples from suspect cases are normally tested at reference laboratories. However, transport of samples to these centralized facilities can be a lengthy process that can impose delays on critical decision making. These concerns have motivated work to evaluate simple‐to‐use technologies, including molecular‐based diagnostic platforms, that can be deployed closer to suspect cases of FMD. In this context, FMD virus (FMDV)‐specific reverse transcription loop‐mediated isothermal amplification (RT‐LAMP) and real‐time RT‐PCR (rRT‐PCR) assays, compatible with simple sample preparation methods and in situ visualization, have been developed which share equivalent analytical sensitivity with laboratory‐based rRT‐PCR. However, the lack of robust ‘ready‐to‐use kits’ that utilize stabilized reagents limits the deployment of these tests into field settings. To address this gap, this study describes the performance of lyophilized rRT‐PCR and RT‐LAMP assays to detect FMDV. Both of these assays are compatible with the use of fluorescence to monitor amplification in real‐time, and for the RT‐LAMP assays end point detection could also be achieved using molecular lateral flow devices. Lyophilization of reagents did not adversely affect the performance of the assays. Importantly, when these assays were deployed into challenging laboratory and field settings within East Africa they proved to be reliable in their ability to detect FMDV in a range of clinical samples from acutely infected as well as convalescent cattle. These data support the use of highly sensitive molecular assays into field settings for simple and rapid detection of FMDV

Direct detection and characterization of foot-and-mouth disease virus in East Africa using a field-ready real-time PCR platform

Effective control and monitoring of foot-and-mouth disease (FMD) relies upon rapid and accurate disease confirmation. Currently, clinical samples are usually tested in reference laboratories using standardized assays recommended by The World Organisation for Animal Health (OIE). However, the requirements for prompt and serotype-specific diagnosis during FMD outbreaks, and the need to establish robust laboratory testing capacity in FMD-endemic countries have motivated the development of simple diagnostic platforms to support local decision-making. Using a portable thermocycler, the T-COR™ 8, this study describes the laboratory and field evaluation of a commercially available, lyophilized pan-serotype-specific real-time RT-PCR (rRT-PCR) assay and a newly available FMD virus (FMDV) typing assay (East Africa-specific for serotypes: O, A, Southern African Territories [SAT] 1 and 2). Analytical sensitivity, diagnostic sensitivity and specificity of the pan-serotype-specific lyophilized assay were comparable to that of an OIE-recommended laboratory-based rRT-PCR (determined using a panel of 57 FMDV-positive samples and six non-FMDV vesicular disease samples for differential diagnosis). The FMDV-typing assay was able to correctly identify the serotype of 33/36 FMDV-positive samples (no cross-reactivity between serotypes was evident). Furthermore, the assays were able to accurately detect and type FMDV RNA in multiple sample types, including epithelial tissue suspensions, serum, oesophageal–pharyngeal (OP) fluid and oral swabs, both with and without the use of nucleic acid extraction. When deployed in laboratory and field settings in Tanzania, Kenya and Ethiopia, both assays reliably detected and serotyped FMDV RNA in samples (n = 144) collected from pre-clinical, clinical and clinically recovered cattle. These data support the use of field-ready rRT-PCR platforms in endemic settings for simple, highly sensitive and rapid detection and/or characterization of FMDV

Race and sex: teachers' views on who gets ahead in schools?

The research reported here was part of a large study of the impact of age, disability, race and sex on the teaching profession in England. The basic question asked in this research was how do these factors interact with career aspirations and achievements of classteachers, promoted teachers and headteachers? There were three different data sources: a large postal survey drawn from diverse geographic regions across England with over 2000 respondents; face‐to‐face individual interviews with over 100 teachers in 18 case study schools from across all of the main regions of England; discussions with special interest groups of teachers. Not surprisingly, the answer to the above question was complex. Nonetheless, the paper's conclusion highlights some of the noteworthy themes across this broad sample of teachers from primary, secondary and special schools

A probabilistic analysis of argument cogency

This paper offers a probabilistic treatment of the conditions for argument cogency as endorsed in informal logic: acceptability, relevance, and sufficiency. Treating a natural language argument as a reason-claim-complex, our analysis identifies content features of defeasible argument on which the RSA conditions depend, namely: change in the commitment to the reason, the reason’s sensitivity and selectivity to the claim, one’s prior commitment to the claim, and the contextually determined thresholds of acceptability for reasons and for claims. Results contrast with, and may indeed serve to correct, the informal understanding and applications of the RSA criteria concerning their conceptual dependence, their function as update-thresholds, and their status as obligatory rather than permissive norms, but also show how these formal and informal normative approachs can in fact align

Baseline ecological data collection from the marine area around Filfla (Malta, Central Mediterranean Sea)

Acoustic and limited video sampling were carried out in a 1.1 nautical mile-radius area around Filfla, an islet 4.4 to the south-west of Malta, to characterize the benthos and the habitat type distribution. In addition, identified priority areas were sampled during SCUBA diving surveys. A total of 173 species were recorded during the current survey. Rhodophytes were the most represented (29 species), followed by molluscs (25 species). The biotic assemblages recorded from the marine area around Filfla are generally representative of those found in Maltese inshore waters.peer-reviewe

Critical Dynamics of a Vortex Loop Model for the Superconducting Transition

We calculate analytically the dynamic critical exponent $z_{MC}$ measured in Monte Carlo simulations for a vortex loop model of the superconducting transition, and account for the simulation results. In the weak screening limit, where magnetic fluctuations are neglected, the dynamic exponent is found to be $z_{MC} = 3/2$. In the perfect screening limit, $z_{MC} = 5/2$. We relate $z_{MC}$ to the actual value of $z$ observable in experiments and find that $z \sim 2$, consistent with some experimental results

Magnetic phases and reorientation transitions in antiferromagnetically coupled multilayers

In antiferromagnetically coupled superlattices grown on (001) faces of cubic substrates, e.g. based on materials combinations as Co/Cu, Fe/Si, Co/Cr, or Fe/Cr, the magnetic states evolve under competing influence of bilinear and biquadratic exchange interactions, surface-enhanced four-fold in-plane anisotropy, and specific finite-size effects. Using phenomenological (micromagnetic) theory, a comprehensive survey of the magnetic states and reorientation transitions has been carried out for multilayer systems with even number of ferromagnetic sub-layers and magnetizations in the plane. In two-layer systems (N=2) the phase diagrams in dependence on components of the applied field in the plane include ``swallow-tail'' type regions of (metastable) multistate co-existence and a number of continuous and discontinuous reorientation transitions induced by radial and transversal components of the applied field. In multilayers (N \ge 4) noncollinear states are spatially inhomogeneous with magnetization varying across the multilayer stack. For weak four-fold anisotropy the magnetic states under influence of an applied field evolve by a complex continuous reorientation into the saturated state. At higher anisotropy they transform into various inhomogeneous and asymmetric structures. The discontinuous transitions between the magnetic states in these two-layers and multilayers are characterized by broad ranges of multi-phase coexistence of the (metastable) states and give rise to specific transitional domain structures.Comment: Manuscript 34 pages, 14 figures; submitted for publicatio

Nature of the Low Field Transition in the Mixed State of High Temperature Superconductors

We have numerically studied the statics and dynamics of a model three-dimensional vortex lattice at low magnetic fields. For the statics we use a frustrated 3D XY model on a stacked triangular lattice. We model the dynamics as a coupled network of overdamped resistively-shunted Josephson junctions with Langevin noise. At low fields, there is a weakly first-order phase transition, at which the vortex lattice melts into a line liquid. Phase coherence parallel to the field persists until a sharp crossover, conceivably a phase transition, near $T_{\ell} > T_m$ which develops at the same temperature as an infinite vortex tangle. The calculated flux flow resistivity in various geometries near $T=T_{\ell}$ closely resembles experiment. The local density of field induced vortices increases sharply near $T_\ell$, corresponding to the experimentally observed magnetization jump. We discuss the nature of a possible transition or crossover at $T_\ell$(B) which is distinct from flux lattice melting.Comment: Updated references. 46 pages including low quality 25 eps figures. Contact [email protected] or visit http://www.physics.ohio-state.edu:80/~ryu/ for better figures and additional movie files from simulations. To be published in Physical Review B1 01Jun9