Revealing Site Occupancy in a Complex Oxide: Terbium Iron Garnet.

Complex oxide films stabilized by epitaxial growth can exhibit large populations of point defects which have important effects on their properties. The site occupancy of pulsed laser-deposited epitaxial terbium iron garnet (TbIG) films with excess terbium (Tb) is analyzed, in which the terbium:iron (Tb:Fe)ratio is 0.86 compared to the stoichiometric value of 0.6. The magnetic properties of the TbIG are sensitive to site occupancy, exhibiting a higher compensation temperature (by 90 K) and a lower Curie temperature (by 40 K) than the bulk Tb3 Fe5 O12 garnet. Data derived from X-ray core-level spectroscopy, magnetometry, and molecular field coefficient modeling are consistent with occupancy of the dodecahedral sites by Tb3+ , the octahedral sites by Fe3+ , Tb3+ and vacancies, and the tetrahedral sites by Fe3+ and vacancies. Energy dispersive X-ray spectroscopy in a scanning transmission electron microscope provides direct evidence of TbFe antisites. A small fraction of Fe2+ is present, and oxygen vacancies are inferred to be present to maintain charge neutrality. Variation of the site occupancies provides a path to considerable manipulation of the magnetic properties of epitaxial iron garnet films and other complex oxides, which readily accommodate stoichiometries not found in their bulk counterparts.

Many-Body Physics of Single and Double Spin-Flip Excitations in NiO.

Understanding many-body physics of elementary excitations has advanced our control over material properties. Here, we study spin-flip excitations in NiO using Ni L_{3}-edge resonant inelastic x-ray scattering (RIXS) and present a strikingly different resonant energy behavior between single and double spin-flip excitations. Comparing our results with single-site full-multiplet ligand field theory calculations we find that the spectral weight of the double-magnon excitations originates primarily from the double spin-flip transition of the quadrupolar RIXS process within a single magnetic site. Quadrupolar spin-flip processes are among the least studied excitations, despite being important for multiferroic or spin-nematic materials due to their difficult detection. We identify intermediate state multiplets and intra-atomic core-valence exchange interactions as the key many-body factors determining the fate of such excitations. RIXS resonant energy dependence can act as a convincing proof of existence of nondipolar higher-ranked magnetic orders in systems for which, only theoretical predictions are available.

Noncollinear Ordering of the Orbital Magnetic Moments in Magnetite.

The magnitude of the orbital magnetic moment and its role as a trigger of the Verwey transition in the prototypical Mott insulator, magnetite, remain contentious. Using 1s2p resonant inelastic x-ray scattering angle distribution (RIXS-AD), we prove the existence of noncollinear orbital magnetic ordering and infer the presence of dynamical distortion creating a polaronic precursor for the metal to insulator transition. These conclusions are based on a subtle angular shift of the RIXS-AD spectral intensity as a function of the magnetic field orientation. Theoretical simulations show that these results are only consistent with noncollinear magnetic orbital ordering. To further support these claims we perform Fe K-edge x-ray magnetic circular dichroism in order to quantify the Fe average orbital magnetic moment.

Unconventional Charge Density Wave Order in the Pnictide Superconductor Ba(Ni_{1-x}Co_{x})_{2}As_{2}.

Ba(Ni_{1-x}Co_{x})_{2}As_{2} is a structural homologue of the pnictide high temperature superconductor, Ba(Fe_{1-x}Co_{x})_{2}As_{2}, in which the Fe atoms are replaced by Ni. Superconductivity is highly suppressed in this system, reaching a maximum T_{c}=2.3 K, compared to 24 K in its iron-based cousin, and the origin of this T_{c} suppression is not known. Using x-ray scattering, we show that Ba(Ni_{1-x}Co_{x})_{2}As_{2} exhibits a unidirectional charge density wave (CDW) at its triclinic phase transition. The CDW is incommensurate, exhibits a sizable lattice distortion, and is accompanied by the appearance of α Fermi surface pockets in photoemission [B. Zhou et al., Phys. Rev. B 83, 035110 (2011)PRBMDO1098-012110.1103/PhysRevB.83.035110], suggesting it forms by an unconventional mechanism. Co doping suppresses the CDW, paralleling the behavior of antiferromagnetism in iron-based superconductors. Our study demonstrates that pnictide superconductors can exhibit competing CDW order, which may be the origin of T_{c} suppression in this system.

Coulomb Correlations Intertwined with Spin and Orbital Excitations in LaCoO_{3}.

We carried out temperature-dependent (20-550 K) measurements of resonant inelastic x-ray scattering on LaCoO_{3} to investigate the evolution of its electronic structure across the spin-state crossover. In combination with charge-transfer multiplet calculations, we accurately quantified the renomalized crystal-field excitation energies and spin-state populations. We show that the screening of the effective on-site Coulomb interaction of 3d electrons is orbital selective and coupled to the spin-state crossover in LaCoO_{3}. The results establish that the gradual spin-state crossover is associated with a relative change of Coulomb energy versus bandwidth, leading to a Mott-type insulator-to-metal transition.

Jahn-Teller distortion driven magnetic polarons in magnetite.

The first known magnetic mineral, magnetite, has unusual properties, which have fascinated mankind for centuries; it undergoes the Verwey transition around 120 K with an abrupt change in structure and electrical conductivity. The mechanism of the Verwey transition, however, remains contentious. Here we use resonant inelastic X-ray scattering over a wide temperature range across the Verwey transition to identify and separate out the magnetic excitations derived from nominal Fe2+ and Fe3+ states. Comparison of the experimental results with crystal-field multiplet calculations shows that the spin-orbital dd excitons of the Fe2+ sites arise from a tetragonal Jahn-Teller active polaronic distortion of the Fe2+O6 octahedra. These low-energy excitations, which get weakened for temperatures above 350 K but persist at least up to 550 K, are distinct from optical excitations and are best explained as magnetic polarons.

Identification of the dominant photochemical pathways and mechanistic insights to the ultrafast ligand exchange of Fe(CO)5 to Fe(CO)4EtOH.

We utilized femtosecond time-resolved resonant inelastic X-ray scattering and ab initio theory to study the transient electronic structure and the photoinduced molecular dynamics of a model metal carbonyl photocatalyst Fe(CO)5 in ethanol solution. We propose mechanistic explanation for the parallel ultrafast intra-molecular spin crossover and ligation of the Fe(CO)4 which are observed following a charge transfer photoexcitation of Fe(CO)5 as reported in our previous study [Wernet et al., Nature 520, 78 (2015)]. We find that branching of the reaction pathway likely happens in the (1)A1 state of Fe(CO)4. A sub-picosecond time constant of the spin crossover from (1)B2 to (3)B2 is rationalized by the proposed (1)B2 → (1)A1 → (3)B2 mechanism. Ultrafast ligation of the (1)B2 Fe(CO)4 state is significantly faster than the spin-forbidden and diffusion limited ligation process occurring from the (3)B2 Fe(CO)4 ground state that has been observed in the previous studies. We propose that the ultrafast ligation occurs via (1)B2 → (1)A1 → (1)A' Fe(CO)4EtOH pathway and the time scale of the (1)A1 Fe(CO)4 state ligation is governed by the solute-solvent collision frequency. Our study emphasizes the importance of understanding the interaction of molecular excited states with the surrounding environment to explain the relaxation pathways of photoexcited metal carbonyls in solution.

Orbital-specific mapping of the ligand exchange dynamics of Fe(CO)5 in solution.

Transition-metal complexes have long attracted interest for fundamental chemical reactivity studies and possible use in solar energy conversion. Electronic excitation, ligand loss from the metal centre, or a combination of both, creates changes in charge and spin density at the metal site that need to be controlled to optimize complexes for photocatalytic hydrogen production and selective carbon-hydrogen bond activation. An understanding at the molecular level of how transition-metal complexes catalyse reactions, and in particular of the role of the short-lived and reactive intermediate states involved, will be critical for such optimization. However, suitable methods for detailed characterization of electronic excited states have been lacking. Here we show, with the use of X-ray laser-based femtosecond-resolution spectroscopy and advanced quantum chemical theory to probe the reaction dynamics of the benchmark transition-metal complex Fe(CO)5 in solution, that the photo-induced removal of CO generates the 16-electron Fe(CO)4 species, a homogeneous catalyst with an electron deficiency at the Fe centre, in a hitherto unreported excited singlet state that either converts to the triplet ground state or combines with a CO or solvent molecule to regenerate a penta-coordinated Fe species on a sub-picosecond timescale. This finding, which resolves the debate about the relative importance of different spin channels in the photochemistry of Fe(CO)5 (refs 4, 16 - 20), was made possible by the ability of femtosecond X-ray spectroscopy to probe frontier-orbital interactions with atom specificity. We expect the method to be broadly applicable in the chemical sciences, and to complement approaches that probe structural dynamics in ultrafast processes.

A Dutch regional trauma registry: quality check of the registered data.

BACKGROUND: Quality indicators have become increasingly important in the healthcare sector. Data from a trauma registry (TR) should be accurate and reliable as they are used to describe and evaluate (the quality of) trauma care. OBJECTIVE: To investigate the reliability of injury coding, injury severity scoring and survival status in a regional TR. The feasibility of the format that was developed for this study was also investigated. METHODS: A random sample, without replacement, was taken from the TR of a Dutch regional trauma care network. All 343 patients in the sample were then recoded by another trauma registrar (rater). Reliability was expressed in the percentage agreement between the raters. RESULTS: In the total study sample of 333 patients, the reliability of the number of Abbreviated Injury Scale (AIS) codes was substantial (intraclass correlation coefficient (ICC)=0.70); and the reliability of the Injury Severity Score (ISS) (ICC=0.84) and survival status were 'almost perfect' (Cohen's κ=0.82). Both raters had given 129 patients one AIS code. The reliability of the body region of the AIS was 'almost perfect' (Cohen's κ=0.91); and the reliability of the severity of the injury and the ISS were 'almost perfect' (weighted κ=0.88 and ICC=0.90). The reliability of the ISS in the patients who were assigned at least two AIS codes (n=128) was 'almost perfect' (ICC=0.86). The reliability of the number of AIS codes and the number of body regions was 'moderate' (ICC=0.56 and Cohen's κ=0.52). CONCLUSIONS: The reliability of injury coding in a regional trauma registry was 'substantial' and the reliability of the ISS and survival status was 'almost perfect'. The format and design of this study were feasible and could be used to investigate the quality of (trauma) registries.

The x-ray magnetic circular dichroism spin sum rule for 3d4 systems: Mn3+ ions in colossal magnetoresistance manganites.

The colossal magnetoresistance manganites La(0.87±0.02)Sr(0.12±0.02)MnO(3+δ), La(0.78±0.02)Sr(0.17±0.02)MnO(3+δ), and La(0.66±0.02)Sr(0.36±0.02)MnO(3+δ) (δ close to 0) were investigated by using soft x-ray magnetic circular dichroism (XMCD) and magnetometry. Very good agreement between the values for the average Mn magnetic moments determined with these two methods was achieved by correcting the XMCD spin sum rule results by means of charge transfer multiplet calculations, which also suggest a charge transfer of ~50% for Mn(4+) and approximately equal to 30% for Mn(3+). The magnetic moment was found to be localized at the Mn ions for x = 0.17 and 0.36 at 80 K and for x = 0.12 in the temperature range from 80 to 300 K. We discuss our findings in the light of previously published data, confirming the validity of our approach.

First principles multiplet calculations of the calcium L2,3 x-ray absorption spectra of CaO and CaF2.

First principles calculations are performed for the interpretation of the L2,3 x-ray absorption spectrum of calcium oxide and calcium fluoride. The first principles calculations are based on configuration interaction (CI) calculations using fully relativistic molecular spinors. The first principles results are compared to experimental data and also to calculations based on a semi-empirical crystal field multiplet model and also on a multichannel multiple scattering method. We show that the CI calculations show good agreement with experiment, both for bulk and for surface experiments. The remaining differences with experiment and between the theoretical models are discussed in detail.

Spin-orbit mediated interference in the radiative and nonradiative channels of the La 4d core resonances.

Symmetrical fluorescence yield profiles and asymmetrical electron yield profiles of the preresonances at the La N_{IV,V} x-ray absorption edge are experimentally observed in LaPO_{4} nanoparticles. Theoretical studies show that they are caused by interference effects. The spin-orbit interaction and the giant resonance produce symmetry entangled intermediate states that activate coherent scattering and alter the spectral distribution of the oscillator strength. The scattering amplitudes of the electron and fluorescence decays are further modified by the spin-orbit coupling in the final 5p;{5}epsilonl and 5p;{5}4f;{1} states.

The interpretation of sulfur K-edge XANES spectra: a case study on thiophenic and aliphatic sulfur compounds.

Sulfur K-edge XANES has been measured for three sulfur model compounds, dibenzothiophene, dibenzothiophene sulfone, and aliphatic sulfur (DL-methionine). The spectra have been simulated with Density Functional Theory (DFT) by using a number of methods, including the half-core-hole approximation. Dipole transition elements were calculated and the transitions were convoluted with linearly increasing Gaussian functions in the first 20 eV of the near-edge region. In the case of dibenzothiophene, relaxation of the first excited states in the presence of the core-hole gave a further improvement. The theoretical results reproduce well the features of the spectra and give insight in the relation between geometric structure and molecular orbitals. Though DL-methionine and dibenzothiophene show a similar sharp rise of the white line, their molecular levels are quite different, pointing out the difficulties in finding useful "fingerprints" in the spectra for specific compounds.

Phase segregation in cerium-lanthanum solid solutions.

Electron energy-loss spectroscopy (EELS) in combination with scanning transmission electron microscopy (STEM) reveals that the La enrichment at the surface of cerium-lanthanum solid solutions is an averaged effect and that segregation occurs in a mixed oxide phase. This separation occurs within a crystalline particle, where the dopant-rich phase is located at the surface of the dopant-deficient phase. The limiting structure appears to be a solid solution with a La fraction of x = 0.6 in the bulk and x = 0.75 at the surface. Up to a La fraction of 0.6, this phase will coexist with a lanthanum-type structure in different proportions depending on the dopant amount. STEM-EELS appears to be a powerful technique to clarify the existence of a multiphase system, and it shows that XRF, XPS, and XRD measure averaged results and do not show the phase complexity of the solids.

Elongated multiple electronic cascade and cyclization spacer systems in activatible anticancer prodrugs for enhanced drug release.

The design and synthesis of several novel elongated self-elimination spacer systems for application in prodrugs is described. These elongated spacer systems can be incorporated between a cleavable specifier and the parent drug. Naphthalene- and biphenyl-containing spacers were synthesized but did not eliminate. Prodrugs of the anticancer agents doxorubicin and paclitaxel are reported that contain two or three electronic cascade spacers. A novel catalytic application of HOBt was found for the synthesis of N-aryl carbamates through reacting a 4-nitrophenyl carbonate with an aniline derivative, to connect the 1,6-elimination spacers via a carbamate linkage. In addition, a double spacer-containing paclitaxel prodrug was synthesized, comprising a 1,6-elimination spacer and a bis-amine linker connected to paclitaxel via a 2'-carbamate linkage. Prodrugs in which the novel spacer systems were incorporated between a specific tripeptide specifier and the parent drug doxorubicin or paclitaxel proved to be significantly faster activated by plasmin in comparison with prodrugs containing conventional spacer systems. It is expected that the generally applicable novel spacer systems reported herein will contribute to future development of improved enzymatically activated prodrugs.

Anticancer prodrugs for application in monotherapy: targeting hypoxia, tumor-associated enzymes, and receptors.

In order to improve current chemotherapeutic treatment and diminish severe side effects, several prodrug strategies have evolved to achieve site-specific delivery of cytotoxic anticancer agents. This review concentrates on recent developments of antitumor prodrug monotherapy with prodrugs that are designed for direct recognition of tumor-associated factors, such as hypoxia, tumor-associated enzymes and receptors. Firstly, oxygen deficiency in the core of solid tumors leads to enhanced activity of reducing enzymes, like for example nitroreductases, which can be used for site- specific conversion of prodrug to drug. Secondly, some enzymes are present in elevated levels in tumor tissue: beta-glucuronidase leaks from necrotic areas within tumors, while tumor cells for invasive and metastatic activities need several tumor-associated proteases, like plasmin. These enzymes form an attractive target for designing selective prodrugs. Finally, tumor-selective expression of receptors can be exploited for the delivery of antitumor agents. Low molecular weight binding motifs for these receptors can be coupled to cytotoxic drugs in order to obtain tumor-homing conjugates. At present, receptor-binding motifs for a number of receptors that are required for angiogenesis are used for prodrug monotherapy. There exists an increasing body of literature, which describes the complex interplay not only between tumor-associated enzymes, but also between these enzymes and tumor-associated receptors in the process of tumor invasion and metastasis, indicating the feasibility of targeting cytotoxic drugs to these key players in tumor growth. This paper reviews the development and evaluation of anticancer prodrugs, and their application in the various prodrug monotherapy approaches.

Synthesis and biological evaluation of 2'-carbamate-linked and 2'-carbonate-linked prodrugs of paclitaxel: selective activation by the tumor-associated protease plasmin.

The nontoxic paclitaxel-2'-carbamate prodrugs 2-5 and paclitaxel-2'-carbonate prodrug 6 were synthesized and tested for activation by the tumor-associated enzyme plasmin. A generally applicable method for the synthesis of paclitaxel-2'-carbamates was developed. In buffer solution, prodrug 2, which contained an unsubstituted ethylenediamine spacer, was not stable, whereas prodrugs 3-6 were highly stable. Prodrugs 3-6 showed on average a decrease in cytotoxicity of more than 8000-fold in comparison with the parent drug in seven human tumor cell lines. Prodrugs 5 and 6 are the most nontoxic prodrugs of paclitaxel that yield the free parent drug upon selective activation currently reported. Enzyme hydrolysis and spacer elimination rates were determined by incubation of prodrugs 5 and 6 in the presence of human plasmin. From these results, prodrug 6 was selected as the promising prodrug for further in vivo studies.

Synthesis and biological evaluation of novel prodrugs of anthracyclines for selective activation by the tumor-associated protease plasmin.

New prodrugs of daunorubicin and doxorubicin designed for selective activation by the serine protease plasmin are described. The low toxic prodrugs 3, 4, and 5 are converted to the corresponding cytotoxic drugs upon proteolysis by the tumor-associated protease plasmin. Application of a self-eliminating spacer was essential for enzyme activation. A prodrug containing a chloro-substituted spacer was synthesized with the aim of enhancing the rate of conversion by plasmin. All prodrugs were highly stable in buffer solution and in serum and on the average 15-fold less cytotoxic than the parent drugs in seven human tumor cell lines. A marked in vitro selectivity was demonstrated by incubation of the doxorubicin prodrugs with a plasmin generating MCF-7 breast cancer cell line transfected with urokinase-type plasminogen activator (u-PA) in comparison with the nontransfected nonplasmin generating cell line. Prodrugs 4 and 5 showed the same cytotoxic effect as the free parent drug doxorubicin in the u-PA transfected cells, indicating complete conversion of the prodrug by plasmin. Addition of the plasmin inhibitor Trasylol drastically increased the ID(50) values in the u-PA transfected MCF-7 cells for both prodrugs 4 and 5.