The importance of the weak: Interaction modifiers in artificial spin ices

The modification of geometry and interactions in two-dimensional magnetic nanosystems has enabled a range of studies addressing the magnetic order, collective low-energy dynamics, and emergent magnetic properties, in e.g. artificial spin ice structures. The common denominator of all these investigations is the use of Ising-like mesospins as building blocks, in the form of elongated magnetic islands. Here we introduce a new approach: single interaction modifiers, using slave-mesospins in the form of discs, within which the mesospin is free to rotate in the disc plane. We show that by placing these on the vertices of square artificial spin ice arrays and varying their diameter, it is possible to tailor the strength and the ratio of the interaction energies. We demonstrate the existence of degenerate ice-rule obeying states in square artificial spin ice structures, enabling the exploration of thermal dynamics in a spin liquid manifold. Furthermore, we even observe the emergence of flux lattices on larger length-scales, when the energy landscape of the vertices is reversed. The work highlights the potential of a design strategy for two-dimensional magnetic nano-architectures, through which mixed dimensionality of mesospins can be used to promote thermally emergent mesoscale magnetic states.Comment: 17 pages, including methods, 4 figures. Supplementary information contains 16 pages and 15 figure

Lifshitz spacetimes from AdS null and cosmological solutions

We describe solutions of 10-dimensional supergravity comprising null deformations of $AdS_5\times S^5$ with a scalar field, which have $z=2$ Lifshitz symmetries. The bulk Lifshitz geometry in 3+1-dimensions arises by dimensional reduction of these solutions. The dual field theory in this case is a deformation of the N=4 super Yang-Mills theory. We discuss the holographic 2-point function of operators dual to bulk scalars. We further describe time-dependent (cosmological) solutions which have anisotropic Lifshitz scaling symmetries. We also discuss deformations of $AdS\times X$ in 11-dimensional supergravity, which are somewhat similar to the solutions above. In some cases here, we expect the field theory duals to be deformations of the Chern-Simons theories on M2-branes stacked at singularities.Comment: Latex, 29pgs, v3. references, minor clarifications (subsection on Lifshitz geometry seen by scalar probes) added, to appear in JHE

Topology by Design in Magnetic nano-Materials: Artificial Spin Ice

Artificial Spin Ices are two dimensional arrays of magnetic, interacting nano-structures whose geometry can be chosen at will, and whose elementary degrees of freedom can be characterized directly. They were introduced at first to study frustration in a controllable setting, to mimic the behavior of spin ice rare earth pyrochlores, but at more useful temperature and field ranges and with direct characterization, and to provide practical implementation to celebrated, exactly solvable models of statistical mechanics previously devised to gain an understanding of degenerate ensembles with residual entropy. With the evolution of nano--fabrication and of experimental protocols it is now possible to characterize the material in real-time, real-space, and to realize virtually any geometry, for direct control over the collective dynamics. This has recently opened a path toward the deliberate design of novel, exotic states, not found in natural materials, and often characterized by topological properties. Without any pretense of exhaustiveness, we will provide an introduction to the material, the early works, and then, by reporting on more recent results, we will proceed to describe the new direction, which includes the design of desired topological states and their implications to kinetics.Comment: 29 pages, 13 figures, 116 references, Book Chapte

The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eµ-MYC driven B-cell lymphoma.

CCT245737 is the first orally active, clinical development candidate CHK1 inhibitor to be described. The IC50 was 1.4 nM against CHK1 enzyme and it exhibited>1,000-fold selectivity against CHK2 and CDK1. CCT245737 potently inhibited cellular CHK1 activity (IC50 30-220 nM) and enhanced gemcitabine and SN38 cytotoxicity in multiple human tumor cell lines and human tumor xenograft models. Mouse oral bioavailability was complete (100%) with extensive tumor exposure. Genotoxic-induced CHK1 activity (pS296 CHK1) and cell cycle arrest (pY15 CDK1) were inhibited both in vitro and in human tumor xenografts by CCT245737, causing increased DNA damage and apoptosis. Uniquely, we show CCT245737 enhanced gemcitabine antitumor activity to a greater degree than for higher doses of either agent alone, without increasing toxicity, indicating a true therapeutic advantage for this combination. Furthermore, development of a novel ELISA assay for pS296 CHK1 autophosphorylation, allowed the quantitative measurement of target inhibition in a RAS mutant human tumor xenograft of NSCLC at efficacious doses of CCT245737. Finally, CCT245737 also showed significant single-agent activity against a MYC-driven mouse model of B-cell lymphoma. In conclusion, CCT245737 is a new CHK1 inhibitor clinical development candidate scheduled for a first in man Phase I clinical trial, that will use the novel pS296 CHK1 ELISA to monitor target inhibition

Changes in microphytobenthos fluorescence over a tidal cycle: implications for sampling designs

Intertidal microphytobenthos (MPB) are important primary producers and provide food for herbivores in soft sediments and on rocky shores. Methods of measuring MPB biomass that do not depend on the time of collection relative to the time of day or tidal conditions are important in any studies that need to compare temporal or spatial variation, effects of abiotic factors or activity of grazers. Pulse amplitude modulated (PAM) fluorometry is often used to estimate biomass of MPB because it is a rapid, non-destructive method, but it is not known how measures of fluorescence are altered by changing conditions during a period of low tide. We investigated this experimentally using in situ changes in minimal fluorescence (F) on a rocky shore and on an estuarine mudflat around Sydney (Australia), during low tides. On rocky shores, the time when samples are taken during low tide had little direct influence on measures of fluorescence as long as the substratum is dry. Wetness from wave-splash, seepage from rock pools, run-off, rainfall, etc., had large consequences for any comparisons. On soft sediments, fluorescence was decreased if the sediment dried out, as happens during low-spring tides on particularly hot and dry days. Surface water affected the response of PAM and therefore measurements used to estimate MPB, emphasising the need for care to ensure that representative sampling is done during low tide

Eta Carinae -- Physics of the Inner Ejecta

Eta Carinae's inner ejecta are dominated observationally by the bright Weigelt blobs and their famously rich spectra of nebular emission and absorption lines. They are dense (n_e ~ 10^7 to 10^8 cm^-3), warm (T_e ~ 6000 to 7000 K) and slow moving (~40 km/s) condensations of mostly neutral (H^0) gas. Located within 1000 AU of the central star, they contain heavily CNO-processed material that was ejected from the star about a century ago. Outside the blobs, the inner ejecta include absorption-line clouds with similar conditions, plus emission-line gas that has generally lower densities and a wider range of speeds (reaching a few hundred km/s) compared to the blobs. The blobs appear to contain a negligible amount of dust and have a nearly dust-free view of the central source, but our view across the inner ejecta is severely affected by uncertain amounts of dust having a patchy distribution in the foreground. Emission lines from the inner ejecta are powered by photoionization and fluorescent processes. The variable nature of this emission, occurring in a 5.54 yr event cycle, requires specific changes to the incident flux that hold important clues to the nature of the central object.Comment: This is Chapter 5 in a book entitled: Eta Carinae and the Supernova Impostors, Kris Davidson and Roberta M. Humphreys, editors Springe

Rapid Discovery of Pyrido[3,4- d ]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach

Monopolar spindle 1 (MPS1) plays a central role in the transition of cells from metaphase to anaphase and is one of the main components of the spindle assembly checkpoint. Chromosomally unstable cancer cells rely heavily on MPS1 to cope with the stress arising from abnormal numbers of chromosomes and centrosomes and are thus more sensitive to MPS1 inhibition than normal cells. We report the discovery and optimization of a series of new pyrido[3,4-d]pyrimidine based inhibitors via a structure-based hybridization approach from our previously reported inhibitor CCT251455 and a modestly potent screening hit. Compounds in this novel series display excellent potency and selectivity for MPS1, which translates into biomarker modulation in an in vivo human tumor xenograft mode

X-Ray Spectroscopy of Stars

(abridged) Non-degenerate stars of essentially all spectral classes are soft X-ray sources. Low-mass stars on the cooler part of the main sequence and their pre-main sequence predecessors define the dominant stellar population in the galaxy by number. Their X-ray spectra are reminiscent, in the broadest sense, of X-ray spectra from the solar corona. X-ray emission from cool stars is indeed ascribed to magnetically trapped hot gas analogous to the solar coronal plasma. Coronal structure, its thermal stratification and geometric extent can be interpreted based on various spectral diagnostics. New features have been identified in pre-main sequence stars; some of these may be related to accretion shocks on the stellar surface, fluorescence on circumstellar disks due to X-ray irradiation, or shock heating in stellar outflows. Massive, hot stars clearly dominate the interaction with the galactic interstellar medium: they are the main sources of ionizing radiation, mechanical energy and chemical enrichment in galaxies. High-energy emission permits to probe some of the most important processes at work in these stars, and put constraints on their most peculiar feature: the stellar wind. Here, we review recent advances in our understanding of cool and hot stars through the study of X-ray spectra, in particular high-resolution spectra now available from XMM-Newton and Chandra. We address issues related to coronal structure, flares, the composition of coronal plasma, X-ray production in accretion streams and outflows, X-rays from single OB-type stars, massive binaries, magnetic hot objects and evolved WR stars.Comment: accepted for Astron. Astrophys. Rev., 98 journal pages, 30 figures (partly multiple); some corrections made after proof stag

Spatiotemporal scaling of North American continental interior wetlands: implications for shorebird conservation

Within interior North America, erratic weather patterns and heterogeneous wetland complexes cause wide spatio-temporal variation in the resources available to migrating shorebirds. Identifying the pattern-generating components of landscape-level resources and the scales at which shorebirds respond to these patterns will better facilitate conservation efforts for these species. We constructed descriptive models that identified weather variables associated with creating the spatio-temporal patterns of shorebird habitat in ten landscapes in north-central Oklahoma. We developed a metric capable of measuring the dynamic composition and configuration of shorebird habitat in the region and used field data to empirically estimate the spatial scale at which shorebirds respond to the amount and configuration of habitat. Precipitation, temperature, solar radiation and wind speed best explained the incidence of wetland habitat, but relationships varied among wetland types. Shorebird occurrence patterns were best explained by habitat density estimates at a 1.5 km scale. This model correctly classified 86 % of shorebird observations. At this scale, when habitat density was low, shorebirds occurred in 5 % of surveyed habitat patches but occurrence reached 60 % when habitat density was high. Our results suggest scale dependence in the habitat-use patterns of migratory shorebirds. We discuss potential implications of our results and how integrating this information into conservation efforts may improve conservation strategies and management practices

Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation.

PI3K plays a key role in cellular metabolism and cancer. Using a mass spectrometry-based metabolomics platform, we discovered that plasma concentrations of 26 metabolites, including amino acids, acylcarnitines, and phosphatidylcholines, were decreased in mice bearing PTEN-deficient tumors compared with non-tumor-bearing controls and in addition were increased following dosing with class I PI3K inhibitor pictilisib (GDC-0941). These candidate metabolomics biomarkers were evaluated in a phase I dose-escalation clinical trial of pictilisib. Time- and dose-dependent effects were observed in patients for 22 plasma metabolites. The changes exceeded baseline variability, resolved after drug washout, and were recapitulated on continuous dosing. Our study provides a link between modulation of the PI3K pathway and changes in the plasma metabolome and demonstrates that plasma metabolomics is a feasible and promising strategy for biomarker evaluation. Also, our findings provide additional support for an association between insulin resistance, branched-chain amino acids, and related metabolites following PI3K inhibition. Mol Cancer Ther; 15(6); 1412-24. ©2016 AACR