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The current trend for Magnetic Resonance Imaging points towards higher magnetic fields. Even though sensitivity and resolution are increased in stronger fields, T1 contrast is often reduced, and this represents a challenge for contrast agent design. Field-dependent measurements of relaxivity are thus important to characterize contrast agents. At present, the field-dependent curves of relaxivity are usually carried out in the field range of 0 T to 2 T, using fast field cycling relaxometers. Here, we employ a high-speed sample shuttling device to switch the magnetic fields experienced by the nuclei between virtually zero field, and the center of any commercial spectrometer. We apply this approach on rare-earth (mixed Gadolinium-Europium) vanadate nanoparticles, and obtain the dispersion curves from very low magnetic field up to 11.7 T. In contrast to the relaxivity profiles of Gd chelates, commonly used for clinical applications, which display a plateau and then a decrease for increasing magnetic fields, these nanoparticles provide maximum contrast enhancement for magnetic fields around 1–1.5 T. These field-dependent curves are fitted using the so-called Magnetic Particle (MP) model and the extracted parameters discussed as a function of particle size and composition. We finally comment on the new possibilities offered by this approach.
Spatial resolution, signal-to-noise and contrast-to-noise ratios are crucial quality factors of Magnetic Resonance Imaging (MRI). Even though clinical MRI systems are nowadays operating at 1.5 T or 3.0 T, the trend for research MRI scanners is towards increasing magnetic fields, such as 7.0 T, 9.4 T1, or more recently even 11.7 T2. The drive towards ultra-high magnetic fields is motivated by subsequent benefits in terms of ultra-high spatial resolution, signal-to-noise ratio and spectroscopic information.
One of the most common modality for clinical imaging is based on contrast due to variations of the longitudinal relaxation time T1. However, the extension of T1 contrast to high fields is not straightforward. Although the measured T1 in tissues and blood have been found to rise with increasing fields3,4, the difference in T1 for different tissues becomes less pronounced at higher magnetic fields (B0 > 2 T), leading to a reduction in imaging contrast. This points to the necessity for increasing the image contrast with appropriately designed contrast agents5,6. The T1 contrast agents currently used in clinical practice are based on Gadolinium (Gd3+) chelates which generate contrast by reducing the relaxation time of water protons 1H ref. 7. However, their efficiency as contrast agents strongly decreases above 0.2 T ref. 7.
One approach to increase imaging contrast at high magnetic field was to synthesize multinuclear Gd3+ complexes8 or Europium (Eu2+) complexes9. Other material design approaches have proposed paramagnetic nanoparticles as promising materials for contrast agents in high magnetic fields10. In particular, Gd2O311, GdS12, GdPO413 and GdVO414 nanoparticles have been proposed as efficient T1 contrast agents. In several of these refs11,12,13, doping with luminescent rare-earth ions like Eu3+ added a fluorescence imaging functionality, and, in the case of GdVO4, doping with Eu3+ ions lead to multifunctional particles allowing MRI contrast enhancement together with both optical imaging and reactive oxygen species detection14.
The physical principle of MRI contrast agents is the perturbation of relaxation mechanisms in tissues or solutions by using the paramagnetic effects to differentially alter the relaxation times in the targeted tissues. Currently, clinical usage is dominated by gadolinium-based T1-contrast agents using Gd3+ ions embedded in chelate molecules, which increase imaging contrast on T1-weighted images, shorten acquisition time and improve diagnostic confidence15,16. The performance of contrast agents is characterized by the relaxivity defined as the change in relaxation rate (R1 = 1/T1, s−1) of water protons upon addition of the contrast agent, normalized to the concentration of the contrast agent [CA] in units of mM:
The higher the relaxivity, the higher the contrast of the image, which is, as indicated by the definition of the relaxivity, dependent upon the magnetic field B0 and the corresponding Larmor frequency ω. The fluctuations of the dipolar interactions between the nuclei of the solvent and the electron spin of the contrast agent, as well as the fluctuations of the electronic spin of the contrast agent are responsible for the nuclear spin relaxation of the solvent. Because of the nonlinear magnetic field dependence of this relaxation mechanism, the field-dependent curves of relaxivity r1( ω ), the so-called "Nuclear Magnetic Relaxation Dispersion" curves (NMRD), are also nonlinear.
In common NMRD studies, T1 relaxation is measured in a range of magnetic field strengths using pulsed magnets, commonly known as fast field cycling relaxometers. Their range of magnetic fields is limited from μT up to 2 T15,16,17 (~40 Hz–80 MHz for proton MRI), because higher fields would require higher electrical power and tremendous heat dissipation17. This technique does cover several decades in frequency, however the data in the literature usually stop at about ~60 MHz. Thus, relaxivity measurements at fields higher than 1.5 T are usually done at discrete magnetic field values on different NMR spectrometers, or on different high-field MR scanners18,19. Such time consuming measurements provide information for the efficiency of the relaxation enhancement by contrast agents at discrete values of the magnetic field only, and cannot be routinely performed for the design of new contrast agents in a chemical laboratory having a single high-field NMR magnet.
An alternative approach to the use of pulsed magnetic fields for NMRD studies, is the use of rapid sample translation between positions in the stray magnetic field produced by the NMR magnet20,21,22,23. This approach offers the possibility to reach a wider range of magnetic fields, which can cover the entire span between the field values at the center of the magnet and virtually a null magnetic field. The major disadvantage lies however in the significantly longer time that the sample requires in order to travel between the locations of pre-polarization, relaxation and detection which can be of the order of several hundreds of milliseconds. Rapid sample shuttling is achieved using pneumatic21,24,25, or mechanic technologies20,22,23. Mechanical technologies are much more versatile and precise and can be easily used with standard NMR hardware as we recently demonstrated in the area of bio-molecular high-resolution fast field cycling relaxometry22,23,26.
Here we use our rapid mechanical sample-shuttling device for performing T1 relaxation measurements covering an ultra-wide range of magnetic fields in a virtually continuous fashion23,27. We demonstrate the high reliability of the measurements by observing the equilibrium magnetization of newly designed mixed Gd-Eu vanadate nanoparticles at different magnetic fields and perform a field-dependent study of T1 relaxation on three different nanoparticle compositions and sizes. In contrast to Gd chelates, the particles present a maximum contrast performance for magnetic fields between 1 and 1.5 T. We use the Magnetic Particle (MP) model28 to fit the data and discuss the extracted parameters. These results display how using ultra-wide range and continuous field dependent measurements of relaxivity should allow scientists to better understand crucial factors for relaxation, such as the nanoparticle microstructural properties, thus opening the way toward a rational design of optimized contrast agents for high filed MRI.
Materials and Methods
High-field high-resolution relaxometer
A high speed sample shuttling instrument, named field-cycler, based on the design of Chou et al.23 was installed to a 500 MHz wide-bore superconducting magnet equipped with a 5-mm broadband homebuilt radio-frequency probe-head. The sample can be shuttled from the center of the magnet (at 11.7 T) to the top of the magnet (at <0.01 T) in 80 ms. Lower values of the magnetic field can be easily achieved using a μ-metal cylindrical box around the rail of the shuttle29. The magnetic field profile along the center axis was measured precisely using a Senis 3MH3-20T Hall probe. The probe was mounted on the shuttle and a high-resolution profile was acquired prior to the experiments. The radio frequency saddle-coil of the homebuilt broadband probe-head was specially designed to accommodate a small sample volume of 5 mm in length and 5 mm in diameter, in order to minimize position-dependent relaxation in the presence of a strong stray field gradient. An option to improve this without restricting the sample volume would be the generation of multiple homogeneous sweet spots as proposed recently30, but was not performed in the present work. The magnetic field strength at a given shuttle position was determined from the stray field profile. A programmable motor controller, as depicted in Fig. 1, drives the sample shuttling device. The sample was polarized at the center of the magnet before being shuttled to the desired upper positions for spin relaxation at various lower magnetic field strengths. After a predefined but variable time period in the presence of the low magnetic field, the sample was shuttled back to the high field center for signal acquisition. In Fig. 1, Δt is the sample shuttling time, equaling the effective field switching time. This time is controlled precisely by the power applied to the motor and stays constant during the relaxivity experiments. The high speed shuttling instrument has been operated for 10 million cycles without damaging the NMR sample tube nor to the probe-head. Because of its design, it can be adapted virtually to any modern commercial high-field NMR spectrometer.
Sample preparation
The synthesis protocols and material properties of the Gd/Eu nanoparticles were previously published14. These particles are obtained by precipitation at low temperature. Two different synthesis protocols yielded 30-nm (normal route) and 5-nm nanoparticles (citrate route). The normal route synthesis consists in mixing rare earth nitrates with sodium orthovanadate at room temperature. These ions precipitate and form rare earth vanadate nanoparticles. The citrate route synthesis differs from the normal route by the addition of a citrate complexing agent that limits the particle growth. In both cases, the obtained nanoparticles were purified by centrifugation and washings, or dialysis in order to eliminate residual reactants and counter ions.
The particles were characterized with dynamic light scattering, transmission electron microscopy (TEM), X-ray diffraction and zeta potential measurements14. During all experiments, the samples were suspended homogeneously in distilled water as a colloidal dispersion. All samples were sonicated immediately prior to the measurements to disperse transiently formed aggregates. Bare 30-nm particles present a low surface charge (8.6 mV for Gd0.6Eu0.4VO4 particles) and tended to partially precipitate during the acceleration periods transporting the sample between the different magnetic field locations. We therefore used SiO2-coated nanoparticles obtained by silicate condensation at room temperature in water31. Silica-coated nanoparticles present a higher surface charge (−31 mV for Gd0.6Eu0.4VO4 particles) and thus show higher colloidal stability and do not precipitate in the experimental conditions. Note that the presence of a silica coating changes the relaxivity of the nanoparticles only slightly14. This is not surprising given the amorphous nature of the silica coating31 which allows the penetration of small molecules14,32. 5-nm nanoparticles obtained with the citrate route have a surface charge of −13 mV due to the presence of citrate ions at the particle surface and did not require any further coating.
The R1 of background water was measured in the suspension buffers after removal of the nanoparticles by centrifugation and filtration. We centrifuged the solutions containing the nanoparticles during 10 minutes at 10000 g. The supernatant was then filtered by centrifugation, 5 min at 5000 g, through a 10 kDa (equivalent to 10 kg/mol) molecular weight cut-off membrane to filter out any remaining small particles and ensure that the filtrate only contained solvent molecules.
Concentration determination
All sample concentrations were set to 0.1 mM in vanadate ions. Relatively low concentrations were chosen so that the relaxation during the 80-ms shuttling time remains negligible. The vanadate concentration was determined after nanoparticle dissolution with a mix of hydrochloric acid and hydrogen peroxide that causes the formation of orange-brown colored vanadium complexes. The detection of their specific absorption peaks at 405 nm and at 460 nm leads to the precise colorimetric quantification of vanadate ions in the colloids33. Assuming stoichiometric composition, the Gd3+-ion concentration can be determined from the vanadate ion concentration by multiplying with 0.6 for the Eu-doped particles and with 1 for GdVO4 particles. To calculate the nanoparticle concentration from the vanadate ion concentration, we used the nanoparticle volume and the volume of the Gd1−xEuxVO4 unit cell (Vu.c. = 330 × 106 pm3 for GdVO4) to determine the number of unit cells and, subsequently, the number of vanadate ions per nanoparticle for each type of nanoparticles, as explained in Casanova, D. et al. in 2006 34. Note that each unit cell contains 4 vanadate ions. To determine the nanoparticle volume, we used the nanoparticle dimensions as obtained from TEM measurements and assumed that the third dimension is equal to the smaller of the two axis dimensions (i.e. that the particles are prolate spheroids). In the case of the larger particles, their two-dimensional projection is an ellipse with the two major axes having lengths of 13.1 ± 1.1 and 26.6 ± 4.8 nm (mean ± standard deviation); in the case of the smaller ones, their two-dimensional projection is a circle with diameter 5 ± 0.2 nm14. We thus obtained from the measured values in s−1, the relaxivity values in mM−1.s−1, normalized to the nanoparticle concentration for comparison with the Magnetic-Particle model described below.
Data Validation
To demonstrate the reliability of the field-cycler on the application of relaxivity measurement, the peak intensities after a long relaxation delay time, 20 s, at different fields were extracted from the relaxation rate R1 measurements. The residual equilibrium magnetization was measured by applying a π/2 pulse immediately after the sample was shuttled back to the center of the magnet. The experimental field-dependent residual equilibrium magnetization is shown in Figs 2 and 3. According to the Langevin function35:
where B is the magnetic field, N is the total number of spins, T is the temperature, μ is the magnetic moment, M is the magnetization, and k is the Boltzmann constant. In the high temperature limit, , the correlation between magnetic moment and magnetic field is considered to be a positive linear function, which is the well-known Curie's law35. Our experiments were performed at a constant room temperature of 300 K. The measured field range covers from 11.7 T to the fringe field of 0.01 T, where is not in the limit case of , over the full range of magnetic fields. The field-dependent profiles of our experimental measurements were found to be in good agreement with hyperbolic tangent function, as shown for an example curve in Fig. 2, for a sample containing 5-nm Gd0.6Eu0.4VO4 nanoparticles (the correlation coefficient of the fit was higher than 0.97). This result demonstrated the high accuracy and high reliability of our sample shuttling device and therefore of the relaxivity measurements. Figure 3 demonstrates the inversion recovery curves for 30 nm GdVO4 nanoparticles at low fields.
Results and Discussion
Measurements of NMRD curves
The contrast agents studied here were vanadate nanoparticles having two different sizes, citrate-stabilized 5-nm and silicate-stabilized 30-nm particles, and two different compositions, GdVO4 and Gd0.6Eu0.4VO4. These nanoparticles were shown to be multifunctional combining the functionalities of luminescent labels, oxidant sensors, and MRI contrast agents14. In particular, the administration of 5-nm and 30-nm Gd0.6Eu0.4VO4 nanoparticles into a mouse lead to considerable contrast enhancement in different organs in in vivo MRI images acquired at 200 MHz (4.7 T)14. Our previous work included the measurement of NMRD profiles for frequencies up to 20 MHz (0.469 T). These data indicated an increase in relaxivity above 10 MHz but did not encompass high enough frequencies to be able to determine if there is a maximum relaxivity and the corresponding magnetic field14. The data obtained here (Fig. 4) confirm these previous data and enable the determination of the full NMRD profile up to magnetic fields of 11.7 T.
All NMRD profiles were recorded by applying an inversion recovery pulse sequence. First the sample was left to relax for 15 s at the center of the magnet. After an inversion π pulse (22.5 μs), the sample was rapidly sent to the lower magnetic field and left there for the duration of the relaxation delay. Subsequently, the sample was shuttled back to the initial position where transverse magnetization was detected following a hard π/2 pulse (11.25 μs). 8 scans were recorded for each value of the magnetic field. 25 values of the magnetic field were explored for a total acquisition time of 21 hours per sample.
The three main requirements of this sample shuttling NMRD approach are the following: First, the samples should not precipitate under acceleration during the transfer between the different magnetic field locations. This is the case for most stable colloidal solutions. In our case, nanoparticles precipitate for accelerations on the order of 5000 g for the 30-nm nanoparticles and >10 000 g for the 5-nm particles, with spinning durations of several minutes. In our measurement, the samples experience the shuttling acceleration, which is lower than 20 g and much lower than the acceleration required to precipitate the nanoparticles. Second, the relaxation times should be long compared to the shuttling time of 80 ms. This is easily achieved by lowering the concentration of the contrast agent, as mentioned above. Third, the particles should not precipitate in the presence of large field gradients. This was not the case for the paramagnetic nanoparticles described here.
There are two possible ways to present r1(ω): either normalized to the Gd3+ concentration14,15 for general medical purposes, or normalized to the nanoparticle concentration in order to investigate the molecular and hydrodynamic effects on the relaxivity. The normalization to the Gd3+-ion concentration is more relevant if we are interested in determining whether small (5 nm) or large (30 nm) nanoparticles are more efficient as contrast agents for a fixed Gd3+-ion concentration. For understanding the hydrodynamic mechanism on the nanoparticle scale, the comparison and fitting with the Magnetic-Particle (MP) model described below normalization by the nanoparticle concentration is essential and is designated in the following discussion as . The obtained NMRD profiles of colloidal nanoparticle solutions of two different sizes and two compositions are shown in Fig. 4, where the values are normalized by the concentration of Gd3+-ions. All three samples were found to have a maximum r1 value around 1–1.5 T in an asymmetric hump of the NMRD curves. The maximal values for the three NMRD profiles of Fig. 4 are: s−1mM−1 for the 30-nm Gd0.6Eu0.4VO4 colloid, 6.8 s−1mM−1 for 5-nm Gd0.6Eu0.4VO4 particles, and 0.56 s−1mM−1 for 30-nm GdVO4 particles. These measurements normalized to the Gd3+-ion concentration reveal a relaxation enhancement maximum in the following order: 5-nm Gd0.6Eu0.4VO4 > 30-nm Gd0.6Eu0.4VO4 > 30-nm GdVO4. Interestingly, the Eu-doped vanadate nanoparticles were found to have higher maximal r1 than the non-doped ones. This effect was also observed in our previous work in the low-field range14. We attribute it, at least partially, to the contribution of the Eu3+-ion magnetic moment due to non-zero total angular momentum J at room temperature, known as the Van Vleck paramagnetism of europium36,37. Indeed, the ground state of the Eu3+-ion has a zero magnetic moment. However, the excited states of Eu ions possess non-zero magnetic moment and are located close to the ground state. They are therefore partially occupied at room temperature. This magnetic contribution is not taken into account because we normalize with the Gd3+ concentration resulting in seemingly higher relaxivity values for the Eu3+-doped colloids. Another possible contribution to the enhancement of relaxation properties in Eu-doped particles may result from structural differences. Doping with different ions could potentially modify the crystallinity of the particles and might yield a greater access to water molecules.
For a same chemical composition, the dispersion curves also indicate that the smaller nanoparticles are more efficient relaxing agents. 5-nm Gd0.6Eu0.4VO4 particles displayed a distinct NMRD profile with significantly higher maximal relaxivity than 30-nm Gd0.6Eu0.4VO4 particles (Fig. 4). This effect is consistent with a higher surface-to-volume ratio for smaller particles, which implies that water molecules have direct access to a larger fraction of Gd3+ ions in smaller particles. It is also consistent with the correlation between the reduction of nanoparticle size and longitudinal relaxivity enhancement observed for MnO2 particles38. However, Gd0.6Eu0.4VO4 relaxivities are almost size-independent for field values higher than 8 T or lower than 0.55 T (r1(9.9 T;5-nm Gd0.6Eu0.4VO4) = 2.321 s−1.mM−1 and r1(9.9 T; 30–nm Gd0.6Eu0.4VO4) = 2.254 mM−1s−1).
Moreover, our previous work showed that the presence of a silicate layer on the 30-nm particles induces only a small change in their relaxivity. Indeed, we measured at 20 MHz a value of 3.47 and 3.03 mM−1.s−1 for bare and silicate-coated Gd0.6Eu0.4VO4 30-nm particles, respectively, corresponding to values of 67 300 and 58 800 mM−1.s−1, respectively. Note in particular that the magnetic field value corresponding to 20 MHz (0.47 T) lies in the range of the relaxivity increase due to the onset of the peak reaching a maximum at 1–1.5 T (see Fig. 4). This small effect of the silicate coating cannot explain the large difference observed between 5-nm and 30-nm nanoparticles, i. e. about 2 200 and 82 000 mM−1.s−1, respectively, as discussed in the following. The small influence of the silicate layer is not surprising given that i) its thickness is small according to ref.31, and ii) it is only partially condensed and permeable to small molecules. The latter point was confirmed by our previous observation that H2O2 molecules can penetrate the silicate layer and oxidize 30-nm reduced Y0.6Eu0.4VO4 particles32.
Thus, both the chemical compositions and the size of the nanoparticles contribute to the relaxivity properties. Moreover, the nanoparticle microstructure in terms of crystallinity, surface properties, and internal porosity should also influence the water accessibility to the inner part of the particles and consequently the relaxivity properties. To gain further insight into these microstructure effects, we compare our results with the Magnetic-Particle relaxation model in the following section.
Model Analysis
Amongst the relaxation models for contrast agents, the most notable and classic one is the "Solomon-Bloembergen-Morgan model" (or SBM model)39,40. This model describes far field dipolar and contact interactions between protons and contrast agents. The SBM model is suitable for analyzing the relaxation enhancement induced by paramagnetic molecules, such as Gd-chelates. The extension of its dipolar component to nanoparticles14,38,41,42,43,44,45,46, the so-called magnetic particle (MP) model, has been developed recently and applied to crystalline Fe2O3 nanoparticles28. In solutions of magnetic nanoparticles, the dipole interactions between the nuclear spin of the water protons and the electronic magnetic moment of the nanoparticle is the dominant mechanism for the nuclear spin relaxation of the protons28. The relaxation mechanisms of magnetic nanoparticles were modeled by considering two contributions due (i) to the thermal average value of the Curie spin of the nanoparticles and (ii) to the fluctuations of the nanoparticle electronic magnetic moment around its thermal average value :
Given the size of the nanoparticles, the rotational diffusion of the nanoparticles is too slow to affect the relaxation and can be neglected47,48. The particle dynamics are thus completely described by the knowledge of the translational diffusion, i.e. the relative motion of the particle and of surrounding water molecules, characterized by the diffusion correlation time τtrans. Since the diffusion of nanoparticles is several orders of magnitude slower than the diffusion of water, τtrans depends only on the effective diffusive properties of water molecules at the surface of the nanoparticles, mostly determined by the nanoparticle surface chemistry and microstructure. Hence, the spectral density function was given as48.
where N is the number of nanoparticles per unit volume, d is the closest distance between the nanoparticle electronic magnetic moment and the proton spin.
To describe the Curie spin relaxation, the classical spin factor in the SBM model is replaced by the Curie spin , where BS(B0) is the Brillouin function. Consequently, the Curie relaxation rate was written as:
The relaxation due to the fluctuations of the nanoparticle electronic magnetic moment was written as:
Here, R1e and R2e represent electron spin-lattice relaxation rates, which are assumed to be field-independent28 and have a typical magnitude of 1–10 ns−1 28,49. Constants in Equation (5) and (6) are: permeability, μ0; Boltzmann constant, k; gyromagnetic ratio of proton and paramagnetic spin, γH and γS, respectively, and the temperature T = 300 K in our measurements. The control variables here are Larmor frequencies of the proton and of the paramagnetic spin, ωH and ωS, respectively.
This model provides a physical picture of hydrodynamic (τtrans, d) factors controlling water proton spin relaxation mechanisms due to paramagnetic nanoparticles. The field dependency of and and R1 functions are presented in Fig. 5. The hydrodynamic parameters (i. e. the translational diffusion) impact mainly on the function, which has high field dependency for fields higher than 1 T. The relaxation function dominated by the electronic spin fluctuations shows less field dependency in the field range higher than 1 T and is much weaker than above 0.1 T.
This model has been successfully applied at different temperatures only within the low-field range from 10 kHz to 20 MHz for Fe2O3 nanoparticles28. This low field range could not reveal the nonlinear behavior of relaxivity caused by the hydrodynamic coupling that can induce an important relaxation enhancement at magnetic fields higher than 1 T.
Discussion of the fitting parameters
Our experimental data were fitted to the MP model using the equations presented above and programing in Mathematica. The fitting parameters were: the typical distance between the paramagnetic particles and the water proton, d; the translational correlation time, τtrans; the spin number, S; and the electron spin-lattice and spin-spin relaxation rates, R1e and R2e.
The fitting procedure was the following: (i) in order to find initial values for the fitting parameters suitable for further optimization, we fit the experimental data only with from 1.5 T to 11.75 T, (ii) the optimal parameters were determined by fitting the relaxivity data with the full function of R1MP.
We observed large tolerances with respect to the value of the electron spin relaxation rates R1e and R2e (0.1 to 10 ns−1), which indicates that any values within the ns range are compatible with our data. This is due to the fact that the contribution of the function related to the fluctuations of the electronic magnetic moment is small compared to the term and can be neglected for the field range we are interested in. Figure 5 indeed shows that the function contribution becomes important only for low fields below 0.1 T. The major contribution is thus due to the component R1C, dependent on hydrodynamic parameters. We therefore used only the R1C component to fit the data.
Figure 6 shows the overall fitting of NMRD profiles for the three different nanoparticles. The determined parameters d, τ, S are presented in Table 1 The relaxivity values were calculated per nanoparticle, i.e. the relaxation rate changes due to the nanoparticles were divided with the nanoparticle concentration [see Eq. (1)].
Let us first examine the parameters obtained for the 5-nm Gd0.6Eu0.4VO4 nanoparticles. (Table 1). The distance between the paramagnetic nanoparticle and the water proton (d = 1.9 ± 0.2 nm) is found to be close to the value expected from the nanoparticle radius, 2.5 nm. This finding is similar to the results of Kruk et al.28, who found distances d to be consistent with the nanoparticle radii. The solvent diffusion coefficient can be approximated by the square of the distance between water protons and the paramagnetic particle divided by the translational correlation time, D = d2/τ. We find 0.24 × 10−9 m2/s which is lower than the water self-diffusion coefficient (2.2 × 10−9 m2/s)50. This lower diffusion coefficient may be due to the presence of a solvation shell around the nanoparticles51.
Surprisingly, however, the parameter values found for the 30-nm Gd0.6Eu0.4VO4 and GdVO4 nanoparticles and, in particular, the particle-water proton distance d, do not correspond to the nanoparticle radius. Although the d values found are similar for Eu-doped and undoped 30-nm particles (0.80 ± 0.06 and 0.89 ± 0.07 nm, respectively), they are much smaller than the particle radius and even smaller than the distance value obtained for the smaller 5-nm particles. Moreover, the diffusion coefficients are also found to be similar for Eu-doped and undoped 30-nm particles (0.07 and 0.06 × 10−9 m2/s, respectively) but are much smaller than the diffusion coefficient obtained for the 5-nm Gd0.6Eu0.4VO4 colloid.
These striking results for the distance d and the diffusion coefficient D can possibly be explained by taking into account the 30-nm particle microstructure. Contrast fluctuations in TEM images indeed evidence the inhomogeneous microstructure of the particles14. Gas adsorption measurements on 30-nm Y0.6Eu0.4VO4 particles synthesized with the same protocol yielded a specific surface 20 times higher than the specific surface expected from the nanoparticle geometric size52, so that the particles are expected to present a significant porosity and a rugged surface texture as a result of their formation process53. In contrast, structural investigations of the 5-nm particles support a monocrystalline (dense) structure14.
The presence of significant internal porosity, or a highly rugged surface of the 30-nm particles may explain both of our findings: the small nanoparticle-water proton distance and the low diffusion coefficient. The magnetic particle model assumes a perfectly crystalline structure. However, the deviations from crystallinity present in 30-nm particles may lead to an effective diffusion coefficient affected by the altered motion of water molecules around or inside the particles determined by their surface roughness and/or internal porosity.
Concerning the spin number, one may expect the 30-nm particles to be characterized by a larger spin number than the 5-nm particles because of the larger number of Gd3+ ions that they contain. However, given the size of 30-nm particles, and despite their microstructure, it is highly probable that a large number of Gd3+ ions are located too far away from the water molecules to contribute to the spin number involved in the dipole-dipole interaction with the water protons. Indeed, as mentioned above, these nanoparticles have some porosity, which allows to some extent water molecule penetration to a typical distance lower than the particle size, via a network of interconnected free spaces with a highly reduced effective diffusion coefficient. It is however probable that water molecules do not penetrate in the totality of the particle or, even if they do, they cannot be easily exchanged. Thus, only a subset of Gd3+ ions, possibly close the surface of the particles or to the surface of crystallites inside the nanoparticles, contributes to the interaction with protons. The total effective spin number obtained from the fits would thus result only from the contribution of these surface Gd3+ ions leading to spin number values lower than those expected if every ion was interacting with water protons (Table 1).
Fitting the NMRD profiles of nanoparticles of different sizes and compositions with the Magnetic Particle model showed that, for fields above 0.1 T, the contribution of nanoparticle magnetic moment fluctuations is negligible and that the relaxivity profile and its maximum value are dominated by hydrodynamic effects. The MP model considers monocrystalline particles. However, our data demonstrate that the internal nanoparticle microstructure may have a crucial influence on the hydrodynamic factors governing the nanoparticle relaxation enhancement properties, namely the water diffusion coefficient and the nanoparticle-water proton distance. Translational diffusion and water accessibility to the paramagnetic ions inside the nanoparticles due to varying nanoparticle microstructures require further investigations with relaxivity experiments, ideally in systems where the microstructure can be controlled. A better understanding of the hydrodynamics involved should lead to the establishment of appropriate relaxation models.
We have successfully applied a novel approach to measure contrast agent relaxivities over a continuous and large range of magnetic field strengths going from potentially zero magnetic field, up to the center field of a commercial superconducting system, using our rapid sample shuttling device (the "field-cycler"). Our measurements showed a good robustness and allowed us to measure Gd and mixed Gd/Eu vanadate nanoparticle relaxivities for two different particle sizes. The Gd nanoparticles were found to significantly enhance proton relaxation (relaxivity r1 > 4 s−1mM−1) in a broad range of magnetic fields. The highest relaxivity occurred at a magnetic field of 1–1.5 T, which is in the range of the typical field used for clinical MRI. Comparing the r1 curves for these nanoparticles and fitting them with the magnetic-particle model, we demonstrated that the relaxivity efficiency correlates with both size and composition and that the relaxation enhancement was related to the water-accessible area as reflected by the size and porosity of particles. These results show that a great number of relaxation data could be routinely obtained on any commercial high-field NMR spectrometer. We can thus put them to the test and possibly improve on existing relaxation models. Our results obtained on Gd-Eu vanadate based nanoparticles are a striking illustration of how macroscopic properties such as the contrast in MRI can be controlled by the microstructure of the nanoparticles used as contrast agents. In this context, our method could be a central tool for the further MRI contrast agent rational design and optimization.
Additional Information
How to cite this article: Chou, C.-Y. et al. Ultra-wide range field-dependent measurements of the relaxivity of Gd1-xEuxVO4 nanoparticle contrast agents using a mechanical sample-shuttling relaxometer. Sci. Rep. 7, 44770; doi: 10.1038/srep44770 (2017).
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We thank the staffs at the Academia Sinica Machine Shop, Taiwan, especially Mr. Cherng-Yin Lin, for the production of high precision hardware. This research has received funding from ERC Grant 205119 (R-EvolutioN-M-R) to D.S., Grant 279519 (2F4BIODYN) to F.F., grant from the Agence Nationale de la Recherche (ANR-DYN-IDP), funding from the CNRS Mission Interdisciplinaire Défi Nano (STREAMER), and grant from the Ministry of Science and Technology, Republic of China, to T.H.H. (NSC102-2113-M-001-010).
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Authors and Affiliations
C.Y.C. Built the instrument, performed shuttling experiments, collected and analyzed data, wrote the manuscript. M.A. Synthesized the samples, performed experiments, analyzed data, wrote the manuscript. C.B. Analyzed data, wrote the manuscript. M.C. Built part of the instrument and controller. A.G. Modified and adapted the instrument. T.H.H. Conceived the shuttling instrument, wrote the manuscript. F.F. Wrote the manuscript. T.G. Designed the nanoparticles, wrote the manuscript. A.A. Designed research project, analyzed data, wrote the manuscript. D.S. Designed research project, analyzed data, wrote the manuscript.
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Chou, CY., Abdesselem, M., Bouzigues, C. et al. Ultra-wide range field-dependent measurements of the relaxivity of Gd1−xEuxVO4 nanoparticle contrast agents using a mechanical sample-shuttling relaxometer. Sci Rep 7, 44770 (2017). https://doi.org/10.1038/srep44770
DOI: https://doi.org/10.1038/srep44770
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Fuel, vol.328, 2022 (SCI-Expanded)
© 2022 Elsevier LtdThe thermal efficiency of a CI engine is better than that of an SI, which leads to increased fuel economy. However, emissions of NOx induced by diesel fuel combustion characteristics are a key source of concern. The combustion and exhaust properties of a diesel engine operating on diesel–gasoline mixtures were examined at different fuel injection advance angles. The objective of this research is to see how injection time affects the performance of common rail DICI with two cylinders and four strokes. The fuel mixtures were made by adding gasoline to diesel fuel in increments of 5 % by volume, ranging from 0 % to 10 % by volume. The experiments were carried out at 1500 rpm with a variety of injection timings and loads. The results showed that the maximum BTE was achieved in 20 Nm torque at IT of 2° BTDC for %5 gasoline addition and the peak pressure was achieved in 30 Nm torque at injection timing of 342 CA. CO and HC emissions increase while gasoline is supplied to diesel. When closing TDC by angle, firstly decrease then increase. CO2 emissions show extreme fluctuation. But NO emission decreased for all tests by adding gasoline to diesel fuel.

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Vocal Alchemy for Chakra Clearing
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25 years after Dayton: Seize the moment with Biden
November 12, 2020The 1995 Dayton agreement was only intended to end the Bosnian War and not to provide a lasting political framework. Everyone sensed, however, that none of the parties would later give up what they had won at Dayton in the name of setting up a more permanent, potentially more stable-looking arrangement.
In practice, this means that the Bosnian Serbs have agreed to nothing that subtracts from the sovereignty, as they view it, that they and the RS achieved through Dayton - even though the the Dayton agreement speaks of "entities" rather than sovereignty.
Moreover, there are now power brokers throughout Bosnia and among each of the three major ethnic groups that have profited from the present system and have no intention of giving up the wealth and power they have.
Read more: Opinion: Dayton made Bosnia and Herzegovina ungovernable
Consolidating vested interests for want of an EU perspective
In fact, in a region where mafia states are no rarity, there is no real incentive for the bosses of Banja Luka or elsewhere to give up their advantages in return for possible prosperity for their people. By effectively closing the door to new members, the EU has deprived itself of its most important tool for promoting change in the western Balkans.
Instead, the EU, international organizations, and the NGO world have wasted 25 years in repeating political slogans about the European integration of the region that have no chance of being translated into facts.
The most promising way forward is to think outside the box of ritualistic political mantras and concentrate on concrete programs to promote economic growth and regional integration, give people decent jobs, and present young people with good reasons for staying home and not emigrating.
After all, prosperity and stability often go hand in hand. Perhaps if there were more opportunities to make money, the political picture could improve as well.
Read more: Opinion: EU must join US in renewed Western Balkans talks
No capitulation in the face of authoritarianism
As they did in the 1990s, the US and the EU need to work together toward the common ends of promoting growth and democracy. President-elect Joe Biden pointed out this past summer that the European-American "partnership is as necessary today as it has ever been, and it requires all parties to work together toward our shared goal."
The EU and US share the same values and must cooperate, lest the Balkans be dominated by the influence of Russia, China, and perhaps Turkey, all of which play by rules that differ from ours. They live and think in an alternative universe.
The Western states are democracies that work toward transparent goals through partnerships and alliances, whereas the authoritarian states to the East view the world as a zero-sum game - an arena of combat - and have no allies, but only clients and satellites.
Even during the Boris Yeltsin years of the 1990s, Russia never lost its age-old interest and influence in the Balkans, and the trend has become much more pronounced under the more aggressive regime of Vladimir Putin, most notably - but not only - in Serbia.
For its part, China seeks to expand its influence through economic muscle. It has formed its own regional working group without the EU and has found willing partners for major infrastructure projects in Greece, Hungary, Serbia and elsewhere.
Building trust among partners
To offset the influence of Russia and China, the US and EU must work together in mutual trust once again toward our common ends. The outgoing Trump administration took the initiative to develop economic ties between Serbia and Kosovo, and there is no reason to think that the Biden administration will let up on these efforts.
Our European friends should not feel put out by such moves, but rather should support them. Similarly, Washington is likely to continue its backing for the Three Seas Initiative - in which 12 central and eastern European states cooperate to develop major infrastructure projects and promote growth.
Read more: Opinion: Redrawing borders in the Balkans is a recurring, bad idea
Representatives of the EU and Germany attend the group's summits, as do the Americans. An important element of those infrastructure projects is to reduce energy dependence on Russia, which is in the interest of the West as a whole.
New beginning, new opportunity
There is a new administration in Washington for the Europeans to work with over the next four years. It is committed to multilateralism and will surely offer a return to more established and predictable ways of conducting international relations, including in the Balkans.
Biden himself is no stranger to the region. In 1993, he visited Sarajevo during the siege and afterwards wrote a long report condemning Serbian aggression and expressing support for its victims. His late son Beau Biden worked in Kosovo in 1998-99, training judges and prosecutors.
During the recent US presidential election campaign, Biden outlined his vision for America's future relationship with Bosnia-Herzegovina, Albania and Kosovo, which have rarely figured in US campaigns before. Biden has repeatedly stated his commitment to multilateralism and NATO.
There never was and probably never will be complete harmony between Washington and its European partners, just as those partners often have huge differences among themselves. But the new administration will offer a more serious and transparent way of doing business with its allies than has been the case over the past four years. Biden has already signaled a willingness to engage with Europe. Our European friends should seize the moment and join with him.
Patrick Moore was Senior Balkan Analyst for Radio Free Europe Research in Munich and Prague from 1977 to 2008.


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Featured Image Photo credit: Joey Martinez
April 5, 2023—Today, Nashville vocalist and songwriter Nikki Lane unveils the video for her current single, "Denim & Diamonds," which premiered exclusively via People
Directed by Wade Crescent and Chase Manhattan of L.A.'s honky tonk Desert 5 Spot and featuring close friends of Lane's, the "Denim & Diamonds" video was filmed in L.A. using a DIY approach to highlight the song's overarching message of female empowerment. The video features set design and styling by Lane herself, including custom western wear and one-of-a-kind pieces from her own Nashville vintage store, High Class Hillbilly, as well as a Catherine D'Lish gown, a custom hat by Ben Kennimer, diamonds and jewelry by Esteemable Objects and floral arrangements by Black Leaf Flowers.
Later this month, Lane will return to Stagecoach with her highly curated Stage Stop Marketplace, where festival goers can peruse Lane's own High Class Hillbilly shop alongside more than two dozen vintage clothing vendors hand-picked by Lane. Across the way at the Horseshoe Stage, up and coming artists from all over the country curated by Lane will showcase their rising talent, all under the shade of the Yeehaw Tent from noon until 9pm PT daily.
"Denim & Diamonds" is the title track from Lane's critically acclaimed album—released last year on New West Records (stream/purchase here). Lane is currently on the second leg of her Denim & Diamonds Tour with headline shows in San Francisco, Seattle, Denver and more as well as festival appearances at Stagecoach and Two Step Inn and a handful of dates supporting
Chris Stapleton—see below for full routing and get tickets here.
Denim & Diamonds received widespread critical praise upon release…
"Lane is sharpest when she leans all the way into irreverence. She sings with the authority and weariness of someone who's been through the wringer, the cool insistence of her voice giving her an air of earned wisdom."—Pitchfork
"The result has the rock-country grit of Tanya Tucker and some harder-edged guitars while still keeping Lane's signature sound fully intact."—SPIN
"It shows Nikki Lane at her best, stepping towards a darker direction while keeping one foot planted in the country and roots music of her past."—American Songwriter
"Her brash kiss-offs, lovelorn pleas, and plenty of that good old-fashioned American grit come out to play with producer Homme's thrashing rock and roll sensibility — a deliciously satisfying combo."—No Depression
"Nikki Lane spent the last five years since the release of her breakthrough album, Highway Queen, searching for the right combination of confidants to help her realize the vision of the paradigm-spinning outlaw country songs on Denim & Diamonds. And it's paid off."—SanFrancisco Chronicle
Additionally, Lane was featured on CBS Saturday Morning last year as part of their "Saturday Sessions" series, performing three songs from Denim & Diamonds: "First High," "Try Harder" and the title track.
Denim & Diamonds was born out of a moment of careful consideration in Lane's career—when several years of touring behind her last album came to an end and the early days of the pandemic forced everyone inside, Lane knew it was time to find inspiration somewhere new. Lane enlisted Queens of the Stone Age frontman Joshua Homme to help her bring Denim & Diamonds to life, with whom she assembled a studio band of big-budget talent consisting of his Queens of the Stone Age collaborators Alain Johannes on guitar, Dean Fertita on organ and Michael Shuman on bass, as well as drummers Matt Helders of Arctic Monkeys and Carla Azar of Autolux. With Homme's help, Lane transformed the seeds of ideas she had for years into an album that nods to her wide-ranging influences, from the psychedelia of The 13th Floor Elevators to traditional country stalwarts like Loretta Lynn. Denim & Diamonds was a chance for Lane to take stock of her first decade as a songwriter as she traces her origin story from South Carolina to Nashville mainstay.
Born and raised in Greenville, South Carolina, Lane discovered music as an outlet for creative expression at an early age, dropping out of school at 17 to move to Los Angeles, then New York, and then Nashville to launch her songwriting career. She has released three albums—her 2011 debut Walk of Shame, 2014's All or Nothin' and Highway Queen from 2017. Aside from steadily releasing new music of her own and touring the world, she was featured on "Breaking Up Slowly" on Lana Del Rey's 2021 album Chemtrails Over the Country Club and contributed to Spiritualized's Everything Was Beautiful.
April 14—Houston, TX—Last Concert Café
April 15—Georgetown, TX—Two Step Inn
April 17—Denver, CO—Bluebird Theater
April 19 —Bozeman, MT—The Rialto
April 21—Vancouver, BC—Hollywood Theatre
April 22—Seattle, WA—Tractor Tavern
April 23—Portland, OR—Aladdin Theater
April 24—San Francisco, CA—The Chapel
April 26—El Paso, TX—Don Haskins Center*
April 27—Albuquerque, NM—Isleta Amphitheater*
April 29—Indio, CA—Stagecoach
May 5—Decatur, AL—Princess Theatre
May 6—Maryville, TN—The Shed
May 19—Hurricane Mills, TN—Tennessee Motorcycle and Music Revival 2023
June 22—Valencia, ES—Loco Club
June 23—Zaragoza, ES—Casa Del Loco
June 24—Bilbao, ES—BBK Legends
June 25—Madrid, ES—Noches de Botánico
June 30—Roskilde, DK—Roskilde Festival
July 14—Whitefish, MT—Under the Big Sky Festival
July 26—Floyd, VA—Floydfest
August 26—Sant Louis Palace, MO—Evolution Festival
October 5—Charlottesville, VA—John Paul Jones Arena*
October 6—University Park, PA—Bryce Jordan Center*
October 7—Belmont Park, NY—UBS Arena*
October 12—Corpus Christi, TX—American Bank Center Selena Auditorium*
October 19—San Antonio, TX—AT&T Center*
October 20—Austin, TX—Moody Center*
October 21—Austin, TX—Moody Center*
October 26—Tulsa, OK—BOK Center*
October 27—Dallas, TX—Dos Equis Pavilion*
October 28—Dallas, TX—Dos Equis Pavilion*
- 1. First High
2. Denim & Diamonds
3. Faded
4. Born Tough
5. Try Harder
6. Good Enough
7. Live/Love
8. Black Widow
9. Pass It Down
10. Chimayo
Photographer and Editor/Founder of AllMusicMagazine.com. My love of live music has taken me to incredible experiences with the top bands of all time in stadium shows to the smallest venues with equally inspiring musicians. Using the medium of photography and my publication, these memories will last forever.


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SCHOOL ROADSHOWS – FREE VISITS to Primary & Secondary classes!
The Young Tassie Scientists Roadshows visit all over Tasmania during August in celebration of National Science Week. Prepare to be amazed and inspired as they share their stories about what they do and why they do it!
Applications open in Term 2, 2019.
Southern Tasmania:
6 – 13 August 2019
North West Tasmania
30 July – 2 August 2019
North & North Eastern Tasmania
20 – 22 August 2019
Central Tasmania & Midlands
Availability on Tuesday 30 July, Friday 2 August, Tuesday 20 August and Thursday 22 August 2019
Other Areas
Not listed? Please apply and we will be in touch to arrange a suitable date!
COMMUNITY EVENTS – Invite us to your Science Festival or Event!
The Young Tassie Scientists will also be appearing at numerous community science fairs and other National Science Week events. Come along and find out what real scientists do, meet some of the amazing young people working in science in Tasmania right now and find out about their research!
Interested in having the Young Tassie Scientists at your event? We can provide short engaging talks or hands-on science stalls with activities for all ages.
YTS at TastroFest in Ulverstone (1 – 3 August 2019)
Huge Astronomy and Aurora Photography Festival – for schools and for the public – includes FREE live science shows with real life scientists, exhibitions, Virtual Reality, ROCKETRY workshops and a PLANETARIUM! Come ask the Young Tassie Scientists all your science questions!
Ulverstone Schweppes Stadium,
Flora St, West Ulverstone
YTS at BeakerStreet@TMAG in Hobart
BeakerStreet@TMAG, a pop-up science bar at the Tasmanian Museum and Art Gallery, is a stunning two-night festival of science and art for adults. Stop in for fascinating talks by world-leading scientists, hands-on workshops, live music, the Antarctic bar, Tassie food and drink, and much more!
Tasmanian Museum and Art Gallery
Dunn Place, Hobart
YTS at the Festival of Bright Ideas in Hobart
Celebrate Science Week in Tasmania at the Festival of Bright Ideas! Come mingle with scientists and science communicators with a diverse program of hands-on activities, science entertainment, and celebrity speakers. Come see some real-life science with the Young Tassie Scientists!
Friday 9 August 2019 (Schools day – bookings required – note this books out very quickly!)
Saturday 10 August 2019 (Public day – all welcome!); 9:00am – 4:00pm
Princes Wharf 1,
Castray Esplanade, Hobart
YTS at Huon Valley Science Expo
The Huon Valley knows how to Science – local schools will converge at Huonville Primary for an afternoon of Science, Engineering & Robotics! See local student's Science Invetigatios on display, watch student's robots competing, try your hand at some engineering, and of course, see interactive presentations from the Young Tassie Scientists – with bonus fun hands-on science activities too!
2019 dates TBC
YTS at RoboCup Junior Tasmanian Finals
Primary & secondary students across Tasmania design, build & program robots to compete in one of three categories – Rescue, Dance and Soccer. Open for spectators – come see robots in action! Young Tassie Scientists will be judging the various competitions, and are available to answer all your science questions!
2019 dates TBC


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Stranger Things, a show so continually obsessed over that it's become a game of find that reference, is still fascinating fans.
The thriller pays tribute to a ton of iconic shows and movies, sometimes in ways that make the audience feel rewarded and cool, and other times in ways that make people feel like conspiracy theorists tumbling down an endless rabbit hole filled with mystery waffles.
Of all the roughly 8,362 different influences in the canon of influences that the creators confirmed inspired the series, the PlayStation game Beyond Two Souls starring Ellen Page isn't one of them. But the interactive drama adventure game and the Netflix series do share some common elements. It's not that the show is directly referencing this game. It's that in the summer of Stranger Things-mania, diehard fans might find some of the coincidental parallels a solid excuse to dive back into the rabbit hole.
Released at the Tribeca Film Festival in 2013, the David Cage-directed Quantic Dream cinematic game is about Jodie (Ellen Page) who shows up out of nowhere with a shaved head and reveals she can totally do telepathy. There's more. She's linked to the supernatural ghost guy, Aiden. (Like Stranger Things, it's alternate reality-themed, and the young woman's the key to the creature.)
"Ever since I was born, I've been linked to an entity," she confesses to a cop after shattering a perfectly innocent coffee cup with her mind. Like Eleven, Jodie has an all-access pass to the otherworld, but unlike Eleven, Jodie joins the military.
So the game doesn't have what SNL's Stefon might call "everything." But in the storyline, Jodie's the only one who knows how to "deal with what lies beyond the rift," and she accidentally opens a passage to "Aiden's world." Plenty of this is somewhat like the strangest people and things you'll ever meet in 1980s Hawkins, Ind. Eleven also opened the portal to the otherworld, letting a flower-faced creepy creep of a monster loose, who Eleven goes up against. (This was particularly unfortunate because Mike just asked her to be his date to the Snow Ball right before she exploded into a million pieces.) Jodie can't get the romance thing down either. She's a young woman so sadly tortured by her knowledge of the otherworld that you know instantly she'll never even come close to "having it all."
Speaking of things that run parallel to the things in Stranger Things, in Beyond Two Souls, Willem Dafoe plays the overbearing surrogate dad researcher, Nathan Dawkins over at the Department of Paranormal Activity. The guy totally loses his crackers like Dr. Brenner a.k.a. "Papa" (Matthew Modine) in Stranger Things. Like Eleven on the Netflix show, Jodie wears sensors on her head when she's being studied, Firestarter-style.
So to recap: Young girl with shaved head. Check. Totally appropriate relationship with the father figure studying young girl. Check. Sensors to keep tabs of young girl's powerful mind. Check. Otherworld that only the young girl is really good at going to. Check. Passage to that world dangerously open. Check. Linking up with a creature other people are obsessed with. Check.
This game may not fill the Stranger Things-sized holes in everyone's hearts, and it may never bring Barb back, but it has so many shades of summer's biggest hit show including a tough young women with the power to break teacups, people and stuff without moving. So it just proves that everything anyone's ever done or will ever do will closely resemble some aspect of Stranger Things.
Both the Stranger Things creators and the creators of Beyond Two Souls declined to comment on this story. For more things to watch that have Stranger Things vibes, see TIME's list here.
More Must-Reads From TIME
- Meet the 2024 Women of the Year
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- East Palestine, One Year After Train Derailment
- In the Belly of MrBeast
- The Closers: 18 People Working to End the Racial Wealth Gap
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- The Best Romantic Comedies to Watch on Netflix
- Want Weekly Recs on What to Watch, Read, and More? Sign Up for Worth Your Time
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Research Report
Boyle K (2021) Academic Advisory Panel Briefing Paper Access to Remedy – Systemic Issues and Structural Orders 30 November 2020. National Task Force on Human Rights Leadership. The Scottish Government.
This briefing paper provides an introduction to the concept of structural orders as a form of remedy to address systemic issues. It is intended to inform discussions for the National Task Force Access to Remedy Roundtable on 7 December 2020 and to be read alongside the Access to Justice Briefing Paper dated 1 September 2020 that explains how access to justice can be framed as a journey from initial advice through to effective remedy using principles of adjudication.
Structural orders may help ensure effective remedies are available for violations of human rights. They are one tool of many and so should be viewed within the context of a range or remedies across a spectrum (deferential to interventionist) that should be available to the judiciary. The more flexible the remedial framework is the better placed the judiciary will be to respond appropriately to ensure the remedy deployed is effective according to international human rights law. Structural orders are one of many different ways of ensuring access to justice depending on the circumstances of each case.
Status | Published |
Publication date | 01/02/2021 |
Publication date online | 30/11/2020 |
URL | http://hdl.handle.net/1893/32268 |
Place of publication | The Scottish Government |


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Journal of the North Coasts longest serving covert.
The acacias are ringbarked for a hundred metres around the feral hippy camp I've been enjoying myself in for the last month. From this eagles nest mountain retreat they are first to see the choppers, but don't notice their kids chewing the wattle bark.
I've never met kids like this before. Born in the forest and reared in the campfire smoke, they are sharp as cockspur and tough as bracken. Some mothers go down the mountain and attempt to join the mainstream but they seem to return quickly. The kids can't handle class rooms but they are all expert on their solar powered laptops.
The wattle chewing should never have been mentioned in Unda reports because now the Feds want to ban acacias, along with any cactus which may give you a spiritual experience.
I asked the Boss if he liked Walt Disney's characters and cartoons.
"Of course", he gave me a trying look.
"You know he got them from peyote visions," I started to tell him. "On a mescaline trip he saw all these cartoon characters and came back and started drawing them. Soon…..", but he was walking away, stopped listening. Waste of breath on my part. This is why I know how alienated you hippies feel.
"Unless you've been there….", is a favourite Unda saying we comfort each other with when the Boss just doesn't believe our tales of life beyond the blue line.
But in Canberra they believe everything, just in case of insurance! They believed the dmt and mescal stories and in their inimitable method of control they want all plants that may help you get a bit of living magic, simply banned. No matter it's the Nations emblem!
Pipe, one of the older hippies in the tribe spent years with the desert blackfellas who mixed pituri and acacia. "Every plant has a purpose", he says at least once a day, as he stuffs the little wooden pipe he's named after full of the days mix.
I've seen him pinch leaves and collect bark and seeds from countless trees and he often says every day needs it's own special mix. Four of us walked for two days to meet an old aboriginal fellow from Mount Lindsay way who Pipe had befriended. The two of them talked plants the whole time we trekked through the bush and it looked true that every plant had uses we know little about.
The old fellow thought it was hysterically funny about outlawing the acacias. "That should keep the chopper crew busy. They'll need teams with chainsaws. At flowering season they should be easy to find." More mad laughter around the campfire.
He reckoned when the whitefellas first arrived there are stories of the locals offering them what was probably a dmt mix. Of course the foreigners were never going to eat from the handful of what to them looked like dirt and ash. If only they had said yes, taken the risk, the land of Oz would have gone in a whole other direction!
While Pipe and his small band of dedicated apprentices research the hidden secrets of the bush the women have been weaving their giant mull plants into the trees. I've never seen plants so tall, up to twenty feet and more, wound around branches and on upward they're trained like vines. And every few feet is a tiny cluster of blue or yellow flowers, carefully sewn around branches and the stalk. Now I can see them they're everywhere, but for two whole days I didn't notice a single bud despite being surrounded. Never ever have I seen such cleverness. As for the buds these vines grow? I'll have a lot of trouble leaving this piece of paradise.
Feb 2011: HipiLeaks exclusive from CCC (Canberra Control Centre) to All Commanders. The flux of natural disasters has savagely depleted our police numbers as they are dispatched interstate or overseas. Assaults and robberies may have to wait but the annual cannabis eradication raids must not be reduced in any way.


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Fortify Supplements recently shared a list of factors that contribute to a weakened immune system. The brand has formulated an immune system booster with elderberry, zinc and vitamins C and D to support immunity and health. Continue reading
Aliso Viejo, California, Jul 29, 2020 /prREACH/ -- Fortify Supplements is using scientifically researched ingredients in a non-proprietary formula for its immune system booster to help people counteract the many factors contributing to a weakened immune system. The brand's advanced formula contains a powerhouse of antioxidants to support immunity and health with elderberry, zinc and vitamins C and D.
Learn more about best immune system booster at amazon.com/best-immune-system-booster/dp/B086XL2MQ9.
In an article published by WebMD, a trusted online source for in-depth medical news, many things suppress your immune system¹. WebMD lists the following:
- Lack of sleep: The body releases specific proteins that help the immune system, called cytokines, only during sleep.
- Anxiety: Just having anxious thoughts can weaken the immune response in as little as 30 minutes.
- Low vitamin D: Required for strong bones and healthy blood cells, vitamin D also helps boost the immune system.
- Certain medications: They include drugs to treat allergies, arthritis, lupus, IBS and organ transplant. For example, corticosteroids, TNF inhibitors and chemotherapy.
- Too few fruits and vegetables: These foods may help the body make more of the white blood cells needed to fight off infections.
- Smoking and marijuana: Smoke from pot and cigarettes can inflame lungs, lead to breathing problems and increase the chances of lung infections, while nicotine can weaken the body's ability to fight germs.
- High-fat diet: Oils can hinder germ-fighting white blood cells and, over time, can upset the balance of bacteria in the gut that can help immune response.
- Too little time outdoors: Sunlight may energize specialized cells in the immune system called T-cells that help fight infection.
- Alcohol: Not only does it slow the body's ability to fight germs for up to 24 hours, over time, drinking too much blunts the body's self-repair function.
- Grief: There is some evidence that sorrow, especially if it lasts a long time, can depress the body's immunity.
- Lack of exercise: Exercise helps the blood get around the body more efficiently, which means germ-fighting substances get where they need to go.
Those interested in the benefits of Fortify Supplements' immune system booster vitamins can visit the official company website or Amazon storefront.
1: https://www.webmd.com/cold-and-flu/ss/slideshow-how-you-suppress-immune-system


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One of the benefits of working for yourself is having the freedom to do what you want to do, when you want to do it. But I found that does not lead to running a successful business. It just leads to running a stressful business. And I found that out the hard way!
So I plan my week in advance. No, I rarely (ok never) stick to that plan but it helps enormously to decide my priorities for the week, and make sure I do get more done.
This episode is all about how I plan my week.
[00:24] Introduction
[02:44] Make the list
[04:14] Leads
[06:28] Bespoke website building client work
[08.26] Other Client Work
[10:25] Marketing
[12:37] Business Development
[14:53] Other
[15:34] Adding to my schedule
[19:23] What About...
[19:52] Don't want to do something
[21:18] Something takes longer
[23:00] Something Urgent pops up
[24:24] Recap
Free PDF download: https://beyondthekitchentable.co.uk/downloads/
Episode blog post https://beyondthekitchentable.co.uk/
Find us at https://beyondthekitchentable.co.uk
Follow us at https://www.instagram.com/beyondthekt


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You might be a juvenile or coordinated player yet you truly need a few snippets of data and deludes to get the victorious gorge. It is workable for you to get truly empowered anyway then you truly need to audit that you should have what's going on.
In this manner, expecting you are contemplating how to succeed at the gambling club, you should review the going with tips
You ought to know when to say when:
It's clearly a reality that the house assessments 5% edge in roulette. That proposes you have a fair open door winning in the first, second and third bend. Genuinely make an effort not to rehearse it consistently of playing everlastingly since, tolerating that you do consequently, then, the house will take every one of your chips all over.
End up gaining ground or lose everything:
The commonplace betting machines are generally around costlier than table games. It could go up to twice whatever amount of what could the table cost you. You should avoid those, in all honesty. In case at all you are in a perspective to play this game, you should zero in on $5 bet. The chances are mind blowing that between 15 to 20 percent.
Do whatever it takes not to play Keno.
If you are attempting to play Keno, basically don't. Your potential outcomes are marvelous and rather terrible. At express gambling clubs, the house could have 35% edge. It is uncommon to find a card shark who has at whatever point matched all of the 20 numbers on a 20-spot ticket. Its possibilities happening ceaselessly would be 1 in 3,535,316,142,212,170,330.
You need practice.
In the video poker, the house has actually a 0.46 percent advantage while two or three if the assortments might just get in card sharks favor. The remuneration table is a monster piece of the times posted right on the high and the outcome would be high. Gambling clubs overall make gets on the video poker considering the way that a huge piece of the players essentially aren't sufficiently talented to put everything in order flawlessly, consequently, guarantee that you figure out more.
Stay back from the light.
In overabundance of 90% people who get into a gambling club have no insightful examined the possible results stacked against them. Club, when in doubt, make the games with the lousiest possible results and a short period of time later make them charming by fortifying them up with impacting mind blowing mixes and lights. Expecting you see any kind of mind blowing numbers, guarantee that you keep away from it.
Get an unequaled watch:
Gambling clubs recognize that you, as a rule, ought to lose the track of the time. You are more hesitant to see any wall tickers on the floors. Suitably, guarantee that you screen the time. This could isn't the best tip to how to succeed at a gambling club yet a fundamental one.
Expecting you are looking for tips in how to succeed at the gambling club, then, at that point, you just have dissected the best tips that have worked for some, accepting it has worked for some, it would work for you as well. Subsequently, guarantee that you follow these tips and bewilders while at the club.


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MACRA: New Directions for Medicare Physician Payment
Friday, May 20, 2016
The Medicare Access and CHIP Reauthorization Act of 2015 (MACRA) repealed the Sustainable Growth Rate formula (SGR) and set out a blueprint for reforming physician payment under Medicare with an eye towards better aligning Medicare payments with the cost and quality of patient care. On April 27, 2016, the Department of Health and Human Services (HHS) issued a proposed rule to implement the law. While the proposed rule provides more clarity on how to move the health care system from volume to value, questions about implementing the law remain among policymakers, providers, and patients.
This briefing provided an overview of the MACRA legislation; examined the newly-released proposed rule; and highlighted key issues for implementation.
Elizabeth Mitchell, president and CEO, Network for Regional Healthcare Improvement
Kate Goodrich, director, Center for Clinical Standards and Quality, Centers for Medicare & Medicaid Services
Timothy Ferris, senior vice president, Population Health Management, Partners HealthCare
Ashley Thompson, senior vice president, Public Policy Analysis and Development, American Hospital Association
Sarah Dash, Alliance for Health Reform, and Rachel Nuzum, The Commonwealth Fund, co-moderated.