Four-year Prostate-specific Antigen Response Rate as a Predictive Measure in Intermediate-risk Prostate Cancer Treated With Ablative Therapies: The SPRAT Analysis.

AIMS: There is a lack of early predictive measures of outcome for patients with intermediate-risk prostate cancer (PCa) treated with stereotactic body radiotherapy (SBRT). The aim of the present study was to explore 4-year prostate-specific antigen response rate (4yPSARR) as an early predictive measure. MATERIALS AND METHODS: Individual patient data from six institutions for patients with intermediate-risk PCa treated with SBRT between 2006 and 2016 with a 4-year (42-54 months) PSA available were analysed. Cumulative incidences of biochemical failure and metastasis were calculated using Nelson-Aalen estimates and overall survival was calculated using the Kaplan-Meier method. Biochemical failure-free survival was analysed according to 4yPSARR, with groups dichotomised based on PSA <0.4 ng/ml or ≥0.4 ng/ml and compared using the Log-rank test. A multivariable competing risk analysis was carried out to predict for biochemical failure and the development of metastases. RESULTS: Six hundred and thirty-seven patients were included, including 424 (67%) with favourable and 213 (33%) with unfavourable intermediate-risk disease. The median follow-up was 6.2 years (interquartile range 4.9-7.9). The cumulative incidence of biochemical failure and metastasis was 7 and 0.6%, respectively; overall survival at 6 years was 97%. The cumulative incidence of biochemical failure at 6 years if 4yPSARR <0.4 ng/ml was 1.7% compared with 27% if 4yPSARR ≥0.4 ng/ml (P < 0.0001). On multivariable competing risk analysis, 4yPSARR was a statistically significant predictor of biochemical failure-free survival (subdistribution hazard ratio 15.3, 95% confidence interval 7.5-31.3, P < 0.001) and metastasis-free survival (subdistribution hazard ratio 31.2, 95% confidence interval 3.1-311.6, P = 0.003). CONCLUSION: 4yPSARR is an encouraging early predictor of outcome in patients with intermediate-risk PCa treated with SBRT. Validation in prospective trials is warranted.

Ocean acidification effects on fish hearing.

Humans are rapidly changing the marine environment through a multitude of effects, including increased greenhouse gas emissions resulting in warmer and acidified oceans. Elevated CO2 conditions can cause sensory deficits and altered behaviours in marine organisms, either directly by affecting end organ sensitivity or due to likely alterations in brain chemistry. Previous studies show that auditory-associated behaviours of larval and juvenile fishes can be affected by elevated CO2 (1000 µatm). Here, using auditory evoked potentials (AEP) and micro-computer tomography (microCT) we show that raising juvenile snapper, Chrysophyrs auratus, under predicted future CO2 conditions resulted in significant changes to their hearing ability. Specifically, snapper raised under elevated CO2 conditions had a significant decrease in low frequency (less than 200 Hz) hearing sensitivity. MicroCT demonstrated that these elevated CO2 snapper had sacculus otolith's that were significantly larger and had fluctuating asymmetry, which likely explains the difference in hearing sensitivity. We suggest that elevated CO2 conditions have a dual effect on hearing, directly effecting the sensitivity of the hearing end organs and altering previously described hearing induced behaviours. This is the first time that predicted future CO2 conditions have been empirically linked through modification of auditory anatomy to changes in fish hearing ability. Given the widespread and well-documented impact of elevated CO2 on fish auditory anatomy, predictions of how fish life-history functions dependent on hearing may respond to climate change may need to be reassessed.

A positive, growth-based PAM screen identifies noncanonical motifs recognized by the S. pyogenes Cas9.

CRISPR technologies have overwhelmingly relied on the Streptococcus pyogenes Cas9 (SpyCas9), with its consensus NGG and less preferred NAG and NGA protospacer-adjacent motifs (PAMs). Here, we report that SpyCas9 also recognizes sequences within an N(A/C/T)GG motif. These sequences were identified on the basis of preferential enrichment in a growth-based screen in Escherichia coli. DNA binding, cleavage, and editing assays in bacteria and human cells validated recognition, with activities paralleling those for NAG(A/C/T) PAMs and dependent on the first two PAM positions. Molecular-dynamics simulations and plasmid-clearance assays with mismatch-intolerant variants supported induced-fit recognition of an extended PAM by SpyCas9 rather than recognition of NGG with a bulged R-loop. Last, the editing location for SpyCas9-derived base editors could be shifted by one nucleotide by selecting between (C/T)GG and adjacent N(C/T)GG PAMs. SpyCas9 and its enhanced variants thus recognize a larger repertoire of PAMs, with implications for precise editing, off-target predictions, and CRISPR-based immunity.

Observation of strong nonlinear interactions in parametric down-conversion of X-rays into ultraviolet radiation.

Nonlinear interactions between X-rays and long wavelength radiation can be used as a powerful atomic-scale probe for light-matter interactions and for properties of valence electrons. However, reported X-ray nonlinear effects were small and their observations required tremendous efforts. Here we report the observation of strong nonlinearities in parametric down-conversion (PDC) of X-rays to long wavelength radiation in gallium arsenide and lithium niobate crystals, with efficiencies about 4 orders of magnitude stronger than the efficiencies measured in any material studied before. Furthermore, we show that the efficiency in the ferroelectric phase of strontium barium niobite is two orders of magnitude stronger than in its paraelectric phase. This observation suggests that the lack of inversion symmetry is the origin for the strong observed nonlinearity. Additionally, we demonstrate the ability to use the effect for the investigation of the spectral response of non-centrosymmetric materials at wavelengths ranging from infrared to soft X-rays.

Selective probing of magnetic order on Tb and Ir sites in stuffed Tb2Ir2O7  using resonant x-ray scattering.

We study the magnetic structure of the 'stuffed' (Tb-rich) pyrochlore iridate Tb2+x Ir2-x O7-y  (x ∼ 0.18), using resonant elastic x-ray scattering (REXS). In order to disentangle contributions from Tb and Ir magnetic sublattices, experiments were performed at the Ir L 3 and Tb M 5 edges, which provide selective sensitivity to Ir 5d and Tb 4f  magnetic moments, respectively. At the Ir L 3 edge, we found the onset of long-range [Formula: see text] magnetic order below [Formula: see text] K, consistent with the expected signal of all-in all-out (AIAO) magnetic order. Using a single-ion model to calculate REXS cross-sections, we estimate an ordered magnetic moment of [Formula: see text] at 5 K. At the Tb M 5 edge, long-range [Formula: see text] magnetic order appeared below ∼[Formula: see text] K, also consistent with an AIAO magnetic structure on the Tb site. Additional insight into the magnetism of the Tb sublattice is gleaned from measurements at the M 5 edge in applied magnetic fields up to 6 T, which is found to completely suppress the Tb AIAO magnetic order. In zero applied field, the observed gradual onset of the Tb sublattice magnetisation with temperature suggests that it is induced by the magnetic order on the Ir site. The persistence of AIAO magnetic order, despite the greatly reduced ordering temperature and moment size compared to stoichiometric Tb2Ir2O7, for which [Formula: see text] K and [Formula: see text], indicates that stuffing could be a viable means of tuning the strength of electronic correlations, thereby potentially offering a new strategy to achieve topologically non-trivial band crossings in pyrochlore iridates.

Critical fluctuations in the spin-orbit Mott insulator Sr3Ir2O7.

X-ray magnetic critical scattering measurements and specific heat measurements were performed on the perovskite iridate [Formula: see text]. We find that the magnetic interactions close to the Néel temperature [Formula: see text] are three-dimensional. This contrasts with previous studies which suggest two-dimensional behaviour like Sr2IrO4. Violation of the Harris criterion ([Formula: see text]) means that weak disorder becomes relevant. This leads a rounding of the antiferromagnetic phase transition at [Formula: see text], and modifies the critical exponents relative to the clean system. Specifically, we determine that the critical behaviour of [Formula: see text] is representative of the diluted 3D Ising universality class.

Band Filling Control of the Dzyaloshinskii-Moriya Interaction in Weakly Ferromagnetic Insulators.

We observe and explain theoretically a dramatic evolution of the Dzyaloshinskii-Moriya interaction (DMI) in the series of isostructural weak ferromagnets, MnCO_{3}, FeBO_{3}, CoCO_{3}, and NiCO_{3}. The sign of the interaction is encoded in the phase of the x-ray magnetic diffraction amplitude, observed through interference with resonant quadrupole scattering. We find very good quantitative agreement with first-principles electronic structure calculations, reproducing both sign and magnitude through the series, and propose a simplified "toy model" to explain the change in sign with 3d shell filling. The model gives insight into the evolution of the DMI in Mott and charge transfer insulators.

Multiple Supersonic Phase Fronts Launched at a Complex-Oxide Heterointerface.

Selective optical excitation of a substrate lattice can drive phase changes across heterointerfaces. This phenomenon is a nonequilibrium analogue of static strain control in heterostructures and may lead to new applications in optically controlled phase change devices. Here, we make use of time-resolved nonresonant and resonant x-ray diffraction to clarify the underlying physics and to separate different microscopic degrees of freedom in space and time. We measure the dynamics of the lattice and that of the charge disproportionation in NdNiO_{3}, when an insulator-metal transition is driven by coherent lattice distortions in the LaAlO_{3} substrate. We find that charge redistribution propagates at supersonic speeds from the interface into the NdNiO_{3} film, followed by a sonic lattice wave. When combined with measurements of magnetic disordering and of the metal-insulator transition, these results establish a hierarchy of events for ultrafast control at complex-oxide heterointerfaces.

Parametric Down-Conversion of X Rays into the Optical Regime.

We report the observation of parametrically down-converted x-ray signal photons at photon energies that correspond to idler photons at optical wavelengths. The count-rate dependence on the angles of the input beam and of the detector and on the slit sizes agrees with theory within the experimental uncertainties. The nonlinear susceptibility, which we calculated from the measured efficiencies, is comparable to the nonlinear susceptibility evaluated from the measurements of x-ray and optical wave mixing. The results of the present Letter advance the development of a spectroscopy method for probing valence-electron charges and the microscopic optical response of crystals with atomic-scale resolution.

On the possibility of using X-ray Compton scattering to study magnetoelectrical properties of crystals.

This paper discusses the possibility of using Compton scattering--an inelastic X-ray scattering process that yields a projection of the electron momentum density--to probe magnetoelectrical properties. It is shown that an antisymmetric component of the momentum density is a unique fingerprint of such time- and parity-odd physics. It is argued that polar ferromagnets are ideal candidates to demonstrate this phenomenon and the first experimental results are shown, on a single-domain crystal of GaFeO3. The measured antisymmetric Compton profile is very small (≃ 10(-5) of the symmetric part) and of the same order of magnitude as the statistical errors. Relativistic first-principles simulations of the antisymmetric Compton profile are presented and it is shown that, while the effect is indeed predicted by theory, and scales with the size of the valence spin-orbit interaction, its magnitude is significantly overestimated. The paper outlines some important constraints on the properties of the antisymmetric Compton profile arising from the underlying crystallographic symmetry of the sample.

Diffuse multiple scattering.

A new form of diffraction lines has been identified, similar to Rutherford, Kikuchi and Kossel lines. This paper highlights some of the properties of these lines and shows how they can be used to eliminate the need for sample/source matching in Lonsdale's triple convergent line method in lattice-parameter determination.

Effects of dispersion and absorption in resonant Bragg diffraction of x-rays.

Resonant diffraction of x-rays by crystals with anisotropic optical properties is investigated theoretically, to assess how the intensity of a Bragg spot is influenced by effects related to dispersion (birefringence) and absorption (dichroism). Starting from an exact but opaque expression, simple analytic results are found to expose how intensity depends on dispersion and absorption in the primary and secondary beams and, also, the azimuthal angle (rotation of the crystal about the Bragg wavevector). If not the full story for a given application, our results are more than adequate to explore consequences of dispersion and absorption in the intensity of a Bragg spot. Results are evaluated for antiferromagnetic copper oxide, and low quartz. For CuO, one of our results reproduces all salient features of a previously published simulation of the azimuthal-angle dependence of a magnetic Bragg peak. It is transparent in our analytic result that dispersion and absorption effects alone cannot reproduce published experimental data. Available data for the azimuthal-angle dependence of space-group forbidden reflections (0,0, l), with l ≠ 3n, of low quartz depart from symmetry imposed by the triad axis of rotation symmetry. The observed asymmetry can be induced by dispersion and absorption even though absorption coefficients are constant, independent of the azimuthal angle, in this class of reflections.

Locking of iridium magnetic moments to the correlated rotation of oxygen octahedra in Sr2IrO4 revealed by x-ray resonant scattering.

Sr2IrO4 is a prototype of the class of Mott insulators in the strong spin-orbit interaction (SOI) limit described by a Jeff = 1/2 ground state. In Sr2IrO4, the strong SOI is predicted to manifest itself in the locking of the canting of the magnetic moments to the correlated rotation by 11.8(1)° of the oxygen octahedra that characterizes its distorted layered perovskite structure. Using x-ray resonant scattering at the Ir L3 edge we have measured accurately the intensities of Bragg peaks arising from different components of the magnetic structure. From a careful comparison of integrated intensities of peaks due to basal-plane antiferromagnetism, with those due to b-axis ferromagnetism, we deduce a canting of the magnetic moments of 12.2(8)°. We thus confirm that in Sr2IrO4 the magnetic moments rigidly follow the rotation of the oxygen octahedra, indicating that, even in the presence of significant non-cubic structural distortions, it is a close realization of the Jeff = 1/2 state.

Robustness of basal-plane antiferromagnetic order and the J(eff)=1/2 state in single-layer iridate spin-orbit Mott insulators.

The magnetic structure and electronic ground state of the layered perovskite Ba(2)IrO(4) have been investigated using x-ray resonant magnetic scattering. Our results are compared with those for Sr(2)IrO(4), for which we provide supplementary data on its magnetic structure. We find that the dominant, long-range antiferromagnetic order is remarkably similar in the two compounds and that the electronic ground state in Ba(2)IrO(4), deduced from an investigation of the x-ray resonant magnetic scattering L(3)/L(2) intensity ratio, is consistent with a J(eff)=1/2 description. The robustness of these two key electronic properties to the considerable structural differences between the Ba and Sr analogues is discussed in terms of the enhanced role of the spin-orbit interaction in 5d transition metal oxides.

Hybrid diamond-silicon angular-dispersive x-ray monochromator with 0.25-meV energy bandwidth and high spectral efficiency.

We report on the design, implementation, and performance of an x-ray monochromator with ultra-high energy resolution (ΔE/E ≃ 2.7 × 10(-8)) and high spectral efficiency using x rays with photon energies E ≃ 9.13 keV. The operating principle of the monochromator is based on the phenomenon of angular dispersion in Bragg back-diffraction. The optical scheme of the monochromator is a modification of a scheme reported earlier [Shvyd'ko et al., Phys. Rev. A 84, 053823 (2011)], where a collimator/wavelength selector Si crystal was replaced with a 100-µm-thick type IIa diamond crystal. This modification provides a very-small-energy bandwidth ΔE ≃ 0.25 meV, a 3-fold increase in the aperture of the accepted beam, a reduction in the cumulative angular dispersion rate of x rays emanating from the monochromator for better focusing on a sample, a sufficient angular acceptance matching the angular divergence of an undulator source (≈ 10 µrad), and an improved throughput due to low x-ray absorption in the thin diamond crystal. The measured spectral efficiency of the monochromator was ≈ 65% with an aperture of 0.3 × 1 mm(2). The performance parameters of the monochromator are suitable for inelastic x-ray spectroscopy with an absolute energy resolution ΔE < 1 meV.

On the magnetic structure of Sr3Ir2O7: an x-ray resonant scattering study.

This report presents azimuthal dependent and polarization dependent x-ray resonant magnetic scattering at the Ir L(3) edge for the bilayered iridate compound Sr(3)Ir(2)O(7). The two magnetic wave vectors, k1 = (1/2, 1/2, 0) and k2 = (1/2, -1/2, 0), result in domains of two symmetry-related G-type antiferromagnetic structures, denoted A and B, respectively. These domains are approximately 0.02 mm(2) and are independent of the thermal history. An understanding of this key aspect of the magnetism is necessary for an overall picture of the magnetic behaviour in this compound. The azimuthal and polarization dependence of the magnetic reflections, relating to both magnetic wavevectors, show that the Ir magnetic moments in the bilayer compound are oriented along the c axis. This contrasts with single layer Sr(2)IrO(4) where the moments are confined to the ab plane.

Ab initio calculations of the forbidden Bragg reflections energy spectra in wurtzites versus temperature.

Thermal-motion induced (TMI) scattering is caused by the influence of atomic displacements on electronic states in crystals and strongly depends on temperature. It corresponds to dipole-dipole resonant x-ray scattering, but is usually accompanied by dipole-quadrupole scattering. The phenomenological theory supposes the dipole-quadrupole term to be temperature independent (TI). As a result, the transformation of the energy spectra with temperature observed experimentally in ZnO and GaN corresponds to the interference between the TMI and TI terms. In the present paper the direct confirmation of this theoretical prediction is given. Ab initio molecular dynamics was used to simulate the sets of atomic sites at various temperatures followed by quantum mechanical calculation of resonant Bragg reflection energy spectra. The results of simulation are in excellent coincidence with experimental energy spectra of forbidden reflections and confirm the earlier phenomenological conjecture about the interference between the TI dipole-quadrupole and TMI dipole-dipole contributions to the resonant atomic factor.

Determination of the absolute chirality of tellurium using resonant diffraction with circularly polarized x-rays.

Many proteins, sugars and pharmaceuticals crystallize into two forms that are mirror images of each other (enantiomers) like our right and left hands. Tellurium is one enantiomer having a space group pair, P3(1)21 (right-handed screw) and P3(2)21 (left-handed screw). X-ray diffraction with dispersion correction terms has been playing an important role in determining the handedness of enantiomers for a long time. However, this approach is not applicable for an elemental crystal such as tellurium or selenium. We have demonstrated that positive and negative circularly polarized x-rays at the resonant energy of tellurium can be used to absolutely distinguish right from left tellurium. This method is applicable to chiral motifs that occur in biomolecules, liquid crystals, ferroelectrics and antiferroelectrics, multiferroics, etc.

The influence of interfacial roughness on the coherence of structure and magnetic coupling across barriers in Fe/MgO multilayers.

Single-crystal Fe/MgO multilayers are model systems in which to study magnetic tunnel junctions. We find that the interfacial roughness leads to the loss of coherence of the crystal structure. For thick MgO layers ferromagnetic (FM) ordering is found using polarized neutron reflectivity (PNR). For thin MgO layers magnetization measurements reveal the presence of antiferromagnetic (AF) interactions, but no long-range AF order is found using PNR. After cycling in a hysteresis loop, FM correlations are found at the coercive point, and this will limit the maximum tunnelling magnetoresistance.

Numerical simulation of the forbidden Bragg reflection spectra observed in ZnO.

Thermal motion induced (TMI) scattering is a unique probe of changes in electronic states with atomic displacements in crystals. We show that it provides a novel approach to extract atomic correlation functions. Using numerical calculations, we are able to reproduce the temperature-dependent energy spectrum of the 115 'forbidden' Bragg reflection in ZnO. Our previous experimental studies showed that the intensity growth of such reflections over a wide range of temperatures is accompanied by a dramatic change in the resonant spectral lineshape. This is the result of the interplay between the temperature-independent (TI) and temperature-dependent TMI contributions. Here, we confirm that the TI part of the resonant structure factor can be associated with the dipole-quadrupole contribution to the structure factor and show that the temperature-dependent part arises from the zinc and oxygen vibrations, which provide additional temperature-dependent dipole-dipole tensor components to the structure factor. By fitting the experimental data at various temperatures we have determined the temperature dependences of autocorrelation and correlation functions.