Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 1.

The alarming reduction in drug effectiveness against bacterial infections has created an urgent need for the development of new antibacterial agents that circumvent bacterial resistance mechanisms. We report here a series of DNA gyrase and topoisomerase IV inhibitors that demonstrate potent activity against a range of Gram-positive and selected Gram-negative organisms, including clinically-relevant and drug-resistant strains. In part 1, we present a detailed structure activity relationship (SAR) analysis that led to the discovery of our previously disclosed compound, REDX05931, which has a minimum inhibitory concentration (MIC) of 0.06 µg mL-1 against fluoroquinolone-resistant Staphylococcus aureus. Although in vitro hERG and CYP inhibition precluded further development, it validates a rational design approach to address this urgent unmet medical need and provides a scaffold for further optimisation, which is presented in part 2.

Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 2.

Building on our previously-reported novel tricyclic topoisomerase inhibitors (NTTIs), we disclose the discovery of REDX07965, which has an MIC90 of 0.5 µg mL-1 against Staphylococcus aureus, favourable in vitro pharmacokinetic properties, selectivity versus human topoisomerase II and an acceptable toxicity profile. The results herein validate a rational design approach to address the urgent unmet medical need for novel antibiotics.

Piston cylinder cell for high pressure ultrasonic pulse echo measurements.

Ultrasonic techniques such as pulse echo, vibrating reed, or resonant ultrasound spectroscopy are powerful probes not only for studying elasticity but also for investigating electronic and magnetic properties. Here, we report on the design of a high pressure ultrasonic pulse echo apparatus, based on a piston cylinder cell, with a simplified electronic setup that operates with a single coaxial cable and requires sample lengths of mm only. The design allows simultaneous measurements of ultrasonic velocities and attenuation coefficients up to a pressure of 1.5 GPa. We illustrate the performance of the cell by probing the phase diagram of a single crystal of the ferromagnetic superconductor UGe2.

Composition-tuning in a solid-state electrotransport furnace with active thermal expansion compensation.

A new solid-state electrotransport (SSE) apparatus for refining ultra-pure single crystals of metallic compounds under ultra-high vacuum is described. The setup employs a novel thermal expansion compensation mechanism to minimize mechanical stress on the sample during refinement with cold clamps for contamination-less purification at elevated temperatures. The apparatus is designed to tune the composition of initially slightly off-stoichiometric samples. The expansion compensation and stress-free operation were tested by recording the thermal expansion of elemental cerium in a treatment up to 655 °C. SSE refinement was then performed on a high-quality single crystal of U6Fe resulting in a 50% increase of its residual resistivity ratio to the highest value obtained for a single crystal to date.

Anisotropic critical magnetic fluctuations in the ferromagnetic superconductor UCoGe.

We report neutron scattering measurements of critical magnetic excitations in the weakly ferromagnetic superconductor UCoGe. The strong non-Landau damping of the excitations we observe, although unusual, has been found in another related ferromagnet, UGe(2) at zero pressure. However, we also find that there is a significant anisotropy of the magnetic correlation length in UCoGe that contrasts with an almost isotropic length for UGe(2). The values of the magnetic correlation length and damping are found to be compatible with superconductivity on small Fermi-surface pockets. The anisotropy may be important to explain why UCoGe is a superconductor at zero pressure while UGe(2) is not.

Large volume high-pressure cell for inelastic neutron scattering.

Inelastic neutron scattering measurements typically require two orders of magnitude longer data collection times and larger sample sizes than neutron diffraction studies. Inelastic neutron scattering measurements on pressurised samples are particularly challenging since standard high-pressure apparatus restricts sample volume, attenuates the incident and scattered beams, and contributes background scattering. Here, we present the design of a large volume two-layered piston-cylinder pressure cell with optimised transmission for inelastic neutron scattering experiments. The design and the materials selected for the construction of the cell enable its safe use to a pressure of 1.8 GPa with a sample volume in excess of 400 mm(3). The design of the piston seal eliminates the need for a sample container, thus providing a larger sample volume and reduced absorption. The integrated electrical plug with a manganin pressure gauge offers an accurate measurement of pressure over the whole range of operational temperatures. The performance of the cell is demonstrated by an inelastic neutron scattering study of UGe(2).

Coexistence and interplay of superconductivity and ferromagnetism in URhGe.

As ferromagnetism and superconductivity are usually considered to be antagonistic, the discovery of their coexistence in UGe(2), URhGe, UIr and UCoGe has attracted a lot of interest. The mechanism to explain such a state has, however, not yet been fully elucidated. In these compounds superconductivity may be unconventional: Cooper pairs could be formed by electrons with parallel spins and magnetic fluctuations might be involved in the pairing mechanism. URhGe becomes ferromagnetic below a Curie temperature of 9.5 K, with a spontaneous moment aligned to the c-axis. For temperatures below 260 mK and fields lower than 2 T, superconductivity was first observed in 2001. Recently, we discovered a second pocket of superconductivity. This new pocket of superconductivity appears at higher fields applied close to the b-axis, enveloping a sudden magnetic moment rotation transition at H(R) = 12 T. Detailed studies of the field induced metamagnetic transition and superconductivity are presented. The possibility that magnetic fluctuations emerging from a quantum critical point provide the pairing mechanism for superconductivity is discussed.

Superconductivity in doped cubic silicon.

Although the local resistivity of semiconducting silicon in its standard crystalline form can be changed by many orders of magnitude by doping with elements, superconductivity has so far never been achieved. Hybrid devices combining silicon's semiconducting properties and superconductivity have therefore remained largely underdeveloped. Here we report that superconductivity can be induced when boron is locally introduced into silicon at concentrations above its equilibrium solubility. For sufficiently high boron doping (typically 100 p.p.m.) silicon becomes metallic. We find that at a higher boron concentration of several per cent, achieved by gas immersion laser doping, silicon becomes superconducting. Electrical resistivity and magnetic susceptibility measurements show that boron-doped silicon (Si:B) made in this way is a superconductor below a transition temperature T(c) approximately 0.35 K, with a critical field of about 0.4 T. Ab initio calculations, corroborated by Raman measurements, strongly suggest that doping is substitutional. The calculated electron-phonon coupling strength is found to be consistent with a conventional phonon-mediated coupling mechanism. Our findings will facilitate the fabrication of new silicon-based superconducting nanostructures and mesoscopic devices with high-quality interfaces.

Magnetic field-induced superconductivity in the ferromagnet URhGe.

In several metals, including URhGe, superconductivity has recently been observed to appear and coexist with ferromagnetism at temperatures well below that at which the ferromagnetic state forms. However, the material characteristics leading to such a state of coexistence have not yet been fully elucidated. We report that in URhGe there is a magnetic transition where the direction of the spin axis changes when a magnetic field of 12 tesla is applied parallel to the crystal b axis. We also report that a second pocket of superconductivity occurs at low temperature for a range of fields enveloping this magnetic transition, well above the field of 2 tesla at which superconductivity is first destroyed. Our findings strongly suggest that excitations in which the spins rotate stimulate superconductivity in the neighborhood of a quantum phase transition under high magnetic field.

Flux-line lattice distortion in PrOs4Sb12.

We report that the flux-line lattice in the cubic superconductor Pr(Os4Sb12 is strongly distorted from an ideal hexagonal lattice at very low temperatures in a small applied field. We attribute this to the presence of gap nodes in the superconducting state on at least some Fermi-surface sheets.

Magnetic excitations in the ferromagnetic superconductor UGe2.

We report that the uniform magnetization is not conserved in the magnetic excitation spectrum of UGe2. The measured spectrum is therefore different from that in d-electron ferromagnetic metals in a way that would facilitate magnetically mediated superconductivity.

Pressure dependence of the magnetization in the ferromagnetic superconductor UGe2.

We report measurements of the pressure dependence of the low-temperature magnetization that show that the two pressure induced magnetic transitions in UGe2 are of first order. Further, the pressure dependence of the uniform susceptibility relative to the superconducting transition is not as expected if the latter is driven by the proximity to a ferromagnetic quantum critical point. Our data instead suggest that the superconducting pairing could be associated with a sharp spike in the electronic density of states that is also responsible for the lower pressure magnetic transition.

Hodgkin and the action potential 1935-1952.

It is naturally very gratifying that the Editors of The Journal of Physiology have decided to make available online a paper that Alan Hodgkin and I published 50 years ago (Hodgkin & Huxley, 1952). This was the final paper in the series on the voltage clamp experiments by us and Bernard Katz. In this note, I will set out the background against which this work was done.

Coexistence of superconductivity and ferromagnetism in URhGe.

The discovery of superconductivity at high pressure (albeit over a restricted range) in the ferromagnetic material UGe2 raised the possibility that bulk superconductivity might be found in other ferromagnets. The exact symmetry of the paired state and the dominant mechanism responsible for the pairing, however, remain unidentified. Meanwhile, the conjecture that superconductivity could occur more generally in ferromagnets has been fuelled by the recent observation of a low-temperature transition that suggests an onset of superconductivity in high-quality crystals of the itinerant-ferromagnet ZrZn2 (ref. 2), although the thermodynamic signature of this transition could not be detected. Here we show that the ferromagnet URhGe is superconducting at ambient pressure. In this case, we find the thermodynamic signature of the transition-its form is consistent with a superconducting pairing of a spin-triplet type, although further testing with cleaner samples is needed to confirm this. The combination of superconductivity and ferromagnetism may thus be more common and consequently more important than hitherto realized.

Strangulation of pregnant woman leads to one first-degree murder indictment for the death of the mother: a medicolegal reconsideration of maternal/fetal/homicide.

A Hispanic woman, 7 1/4, to 7 1/2 lunar months pregnant, was strangled to death by her common-law husband. After receiving information from an informant, a reporter uncovered the remains of the woman and fetus in a grave in a river bank near Eloy, Arizona. The remains were submitted by local law enforcement officials to the forensic pathologist for medicolegal examination. After this analysis, they were turned over to the consulting forensic anthropologist for positive identification of the mother and for fetal age determination to assess possible viability. During the 1970s and 1980s, viability for a fetus of this age was thought possible, although not probable. Prosecution of the common-law husband on the charge of first-degree murder of his wife was successful, whereas a comparable charge for the fetus was not sought. Many issues are raised, including gestational age estimation in relation to fetal viability. Fetal age is reassessed by means of measurements from diaphyseal lengths. These measurements allowed for comparability of fetal age estimations between published studies, with discussion of changing dates of fetal viability made possible through technologic advances. Because fetal viability changes with these advances, it is necessary to establish and update the guidelines for medicolegal practice.

Evidence for a two component magnetic response in UPt3

The magnetic response of the heavy fermion superconductor UPt3 has been investigated on a microscopic scale by muon Knight shift studies. Two distinct and isotropic Knight shifts have been found for the field in the basal plane. While the volume fractions associated with the two Knight shifts are approximately equal at low and high temperatures, they show a dramatic and opposite temperature dependence around T(N). Our results are independent on the precise muon localization site. We conclude that UPt3 is characterized by a two component magnetic response.