Ground state search, hysteretic behaviour, and reversal mechanism of skyrmionic textures in confined helimagnetic nanostructures

Magnetic skyrmions have the potential to provide solutions for low-power, high-density data storage and processing. One of the major challenges in developing skyrmion-based devices is the skyrmions' magnetic stability in confined helimagnetic nanostructures. Through a systematic study of equilibrium states, using a full three-dimensional micromagnetic model including demagnetisation effects, we demonstrate that skyrmionic textures are the lowest energy states in helimagnetic thin film nanostructures at zero external magnetic field and in absence of magnetocrystalline anisotropy. We also report the regions of metastability for non-ground state equilibrium configurations. We show that bistable skyrmionic textures undergo hysteretic behaviour between two energetically equivalent skyrmionic states with different core orientation, even in absence of both magnetocrystalline and demagnetisation-based shape anisotropies, suggesting the existence of Dzyaloshinskii-Moriya-based shape anisotropy. Finally, we show that the skyrmionic texture core reversal dynamics is facilitated by the Bloch point occurrence and propagation.Comment: manuscript: 14 pages, 7 figures; supplementary information: 8 pages, 7 figure

A hardware/application overlay model for large-scale neuromorphic simulation

Neuromorphic computing is gaining momentum as an alternative hardware platform for large-scale neural simulation. However, with several major devices and systems available and planned, often with very different characteristics, it is not always clear which platform is suitable for which application. Simulating the platform on conventional computers is typically too slow to be of use, but an alternative approach is to implement an ‘emulation’ of the hardware in FPGAs which can execute at near-hardware speeds but does not commit to a specific hardware architecture. We present an overlay model - a method which superimposes bespoke features on top of a standard template - in both hardware and software to implement neuromorphic architectures using the POETS (Partially Ordered Event Triggered Systems) system. This combination of overlays permits very large-scale simulations to be performed in real time for hardware exploration or application verification, while retaining the flexibility to redefine either the hardware or software layer, if results indicate potential to improve performance, or significant design problems. Using this system we simulate up to 500,000 neurons on a single-box system, that can be scaled to ∼4,000,000 neurons in an 8-box configuration. Results indicate the crucial constraint for real-time simulation: peak input spike rate per neuron; and help to optimise both hardware and software around neural application requirements. The preliminary architecture demonstrates the feasibility of an overlay model, while indicating directions for future neuromorphic systems. With POETS, we introduce a platform that can help to shape and investigate the neuromorphic architectures of the future

Dynamics of skyrmionic states in confined helimagnetic nanostructures

In confined helimagnetic nanostructures, skyrmionic states in the form of incomplete and isolated skyrmion states can emerge as the ground state in absence of both external magnetic field and magnetocrystalline anisotropy. In this work, we study the dynamic properties (resonance frequencies and corresponding eigenmodes) of skyrmionic states in thin film FeGe disk samples. We employ two different methods in finite-element based micromagnetic simulation: eigenvalue and ringdown method. The eigenvalue method allows us to identify all resonance frequencies and corresponding eigenmodes that can exist in the simulated system. However, using a particular experimentally feasible excitation can excite only a limited set of eigenmodes. Because of that, we perform ringdown simulations that resemble the experimental setup using both in-plane and out-of-plane excitations. In addition, we report the nonlinear dependence of resonance frequencies on the external magnetic bias field and disk sample diameter and discuss the possible reversal mode of skyrmionic states. We compare the power spectral densities of incomplete skyrmion and isolated skyrmion states and observe several key differences that can contribute to the experimental identification of the state present in the sample. We measure the FeGe Gilbert damping, and using its value we determine what eigenmodes can be expected to be observed in experiments. Finally, we show that neglecting the demagnetization energy contribution or ignoring the magnetization variation in the out-of-film direction—although not changing the eigenmode's magnetization dynamics significantly—changes their resonance frequencies substantially. Apart from contributing to the understanding of skyrmionic states physics, this systematic work can be used as a guide for the experimental identification of skyrmionic states in confined helimagnetic nanostructures

Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells

e Glasgow and Manchester Experimental Cancer Medicine Centres (ECMC), which are funded by CR-UK and the Chief Scientist’s Office (Scotland). We acknowledge the funders who have contributed to this work: MRC stratified medicine infrastructure award (A.D.W.), CR-UK C11074/A11008 (F.P., L.E.M.H., T.L.H., A.D.W.); LLR08071 (S.A.A., E.C.); LLR11017 (M.C.); SCD/04 (M.C.); LLR13035 (S.A.A., K.D., A.D.W., and A.P.); LLR14005 (M.T.S., D.V.); KKL690 (L.E.P.); KKL698 (P.B.); LLR08004 (A.D.W., A.P. and A.J.W.); MRC CiC (M.E.D.); The Howat Foundation (FACS support); Friends of Paul O’Gorman (K.D. and FACS support); ELF 67954 (S.A.A.); BSH start up fund (S.A.A.); MR/K014854/1 (K.D.)

Mevalonate Cascade Regulation of Airway Mesenchymal Cell Autophagy and Apoptosis: A Dual Role for p53

Statins inhibit the proximal steps of cholesterol biosynthesis, and are linked to health benefits in various conditions, including cancer and lung disease. We have previously investigated apoptotic pathways triggered by statins in airway mesenchymal cells, and identified reduced prenylation of small GTPases as a primary effector mechanism leading to p53-mediated cell death. Here, we extend our studies of statin-induced cell death by assessing endpoints of both apoptosis and autophagy, and investigating their interplay and coincident regulation. Using primary cultured human airway smooth muscle (HASM) and human airway fibroblasts (HAF), autophagy, and autophagosome formation and flux were assessed by transmission electron microscopy, cytochemistry (lysosome number and co-localization with LC3) and immunoblotting (LC3 lipidation and Atg12-5 complex formation). Chemical inhibition of autophagy increased simvastatin-induced caspase activation and cell death. Similarly, Atg5 silencing with shRNA, thus preventing Atg5-12 complex formation, increased pro-apoptotic effects of simvastatin. Simvastatin concomitantly increased p53-dependent expression of p53 up-regulated modulator of apoptosis (PUMA), NOXA, and damage-regulated autophagy modulator (DRAM). Notably both mevalonate cascade inhibition-induced autophagy and apoptosis were p53 dependent: simvastatin increased nuclear p53 accumulation, and both cyclic pifithrin-α and p53 shRNAi partially inhibited NOXA, PUMA expression and caspase-3/7 cleavage (apoptosis) and DRAM expression, Atg5-12 complex formation, LC3 lipidation, and autophagosome formation (autophagy). Furthermore, the autophagy response is induced rapidly, significantly delaying apoptosis, suggesting the existence of a temporally coordinated p53 regulation network. These findings are relevant for the development of statin-based therapeutic approaches in obstructive airway disease

Constraints on cosmic strings using data from the first Advanced LIGO observing run

Cosmic strings are topological defects which can be formed in grand unified theory scale phase transitions in the early universe. They are also predicted to form in the context of string theory. The main mechanism for a network of Nambu-Goto cosmic strings to lose energy is through the production of loops and the subsequent emission of gravitational waves, thus offering an experimental signature for the existence of cosmic strings. Here we report on the analysis conducted to specifically search for gravitational-wave bursts from cosmic string loops in the data of Advanced LIGO 2015-2016 observing run (O1). No evidence of such signals was found in the data, and as a result we set upper limits on the cosmic string parameters for three recent loop distribution models. In this paper, we initially derive constraints on the string tension Gμ and the intercommutation probability, using not only the burst analysis performed on the O1 data set but also results from the previously published LIGO stochastic O1 analysis, pulsar timing arrays, cosmic microwave background and big-bang nucleosynthesis experiments. We show that these data sets are complementary in that they probe gravitational waves produced by cosmic string loops during very different epochs. Finally, we show that the data sets exclude large parts of the parameter space of the three loop distribution models we consider

A hardware/application overlay model for large-scale neuromorphic simulation

Neuromorphic computing is gaining momentum as an alternative hardware platform for large-scale neural simulation. However, with several major devices and systems available and planned, often with very different characteristics, it is not always clear which platform is suitable for which application. Simulating the platform on conventional computers is typically too slow to be of use, but an alternative approach is to implement an `emulation' of the hardware in FPGAs which can execute at near-hardware speeds but does not commit to a specific hardware architecture. We present an overlay model - a method which superimposes bespoke features on top of a standard template - in both hardware and software to implement neuromorphic architectures using the POETS (Partially Ordered Event Triggered Systems) system. This combination of overlays permits very large-scale simulations to be performed in real time for hardware exploration or application verification, while retaining the flexibility to redefine either the hardware or software layer, if results indicate potential to improve performance, or significant design problems. Using this system we simulate up to 500,000 neurons on a single-box system, that can be scaled to ~4,000,000 neurons in an 8-box configuration. Results indicate the crucial constraint for real-time simulation: peak input spike rate per neuron; and help to optimise both hardware and software around neural application requirements. The preliminary architecture demonstrates the feasibility of an overlay model, while indicating directions for future neuromorphic systems. With POETS, we introduce a platform that can help to shape and investigate the neuromorphic architectures of the future

Evaluation of chlorofusin, its seven chromophore diastereomers, and key analogues

Chlorofusin, its seven chromophore diastereomers, and key analogues were comparatively examined for inhibition of MDM2–p53 binding revealing that the chromophore, but not simple replacements, contributes significantly to the natural products properties, and that this contribution is independent of its relative and absolute stereochemistry

The isolation, total synthesis and structure elucidation of chlorofusin, a natural product inhibitor of the p53–MDM2 protein–protein interaction

Inhibitors of key protein-protein interactions are emerging as exciting therapeutic targets for the treatment of cancer. One such interaction between MDM2 (HDM2) and p53, that silences the tumour suppression activities of p53, was found to be inhibited by the recently isolated natural product chlorofusin. Synthetic studies on this complex natural product summarized herein have served to reassign its chromophore relative stereochemistry, assign its absolute stereochemistry, and provided access to a series of key analogues and partial structures for biological evaluation