Lithium confinement and dynamics in hexagonal and monoclinic tungsten oxide nanocrystals: a 7Li solid state NMR study.

Mixed-valence tungsten bronzes AxWO3 (A = alkali metal, NH4+, etc.) are a series of compounds with adaptive structural and compositional features that make them a hot research topic in thermoelectrics, electrochromics, catalysis or energy applications in battery electrodes. The mixed hexagonal lithium ammonium bronze Lix(NH4)yWO3 is a new member of this structural family whose properties are compared to those of the pure hexagonal tungsten bronze (NH4)xWO3. Surface and structural (nanoconfined) Li+ cations were characterized by 7Li single pulse excitation and 1H-7Li cross-polarization (CP) NMR experiments. CP build-up curves and two-dimensional heteronuclear correlation solid-state NMR techniques provide information about the spatial connectivity between different proton and Li+ species. At 500 °C the bronze structurally transforms from the hexagonal to a monoclinic phase, and defects are formed that are characterized through the Li+ environment. 7Li exchange spectroscopy (EXSY) NMR experiments provide information about the chemical exchange between the lithium species. The measured 7Li T1 and T2 relaxation time constants and the T1/T2 ratio allow characterizing the local strength of Li+ binding.

Nature of Cations Critically Affects Water at the Negatively Charged Silica Interface.

Understanding the collective behavior of ions at charged surfaces is of paramount importance for geological and electrochemical processes. Ions screen the surface charge, and interfacial fields break the centro-symmetry near the surface, which can be probed using second-order nonlinear spectroscopies. The effect of electrolyte concentration on the nonlinear optical response has been semi-quantitatively explained by mean-field models based on the Poisson-Boltzmann equation. Yet, to explain previously reported ion-specific effects on the spectroscopic response, drastic ion-specific changes in the interfacial properties, including surface acidities and dielectric permittivities, or strong ion adsorption/desorption had to be invoked. Here, we use sum-frequency generation (SFG) spectroscopy to probe the symmetry-breaking of water molecules at a charged silica surface in contact with alkaline metal chloride solutions (LiCl, NaCl, KCl, and CsCl) at various concentrations. We find that the water response varies with the cation: the SFG response is markedly enhanced for LiCl compared to CsCl. We show that within mean-field models, neither specific ion-surface interactions nor a reduced dielectric constant of water near the interface can account for the variation of spectral intensities with cation nature. Molecular dynamics simulations confirm that the decay of the electrochemical potential only weakly depends on the salt type. Instead, the effect of different salts on the optical response is indirect, through the reorganization of the interfacial water: the salt-type-dependent alignment of water directly at the interface can explain the observations.

Generalized synthesis of NaCrO2 particles for high-rate sodium ion batteries prepared by microfluidic synthesis in segmented flow.

NaCrO2 particles for high-rate sodium ion batteries were prepared on a multigram scale in segmented flow from chromium nitrate and sodium nitrate using a segregated flow water-in-oil emulsion drying process. Microfluidic processing is an environmentally friendly and rapid synthetic method, which can produce large-scale industrial implementation for the production of materials with superior properties. The reaction time for NaCrO2 particles was reduced by almost one order of magnitude compared to a normal flask synthesis and by several orders of magntitude compared to a conventional solid-state reaction. In addition, it allows for an easy upscaling and was generalized for the synthesis of other layered oxides NaMO2 (M = Cr, Fe, Co, Al). The automated water-in-oil emulsion approach circumvents the diffusion limits of solid-state reactions by allowing a rapid intermixing of the components at a molecular level in submicrometer-sized micelles. A combination of Raman and nuclear magnetic resonance spectroscopy (1H, 23Na), thermal analysis, X-ray diffraction and high resolution transmission electron microscopy provided insight into the formation mechanism of NaCrO2 particles. The new synthesis method allows cathode materials of different types to be produced in a large scale, constant quality and in short reaction times in an automated manner.

High-speed solid state fluorination of Nb2O5 yields NbO2F and Nb3O7F with photocatalytic activity for oxygen evolution from water.

Solid state reactions are slow because the diffusion of atoms or ions through the reactant, intermediate and crystalline product phases is the rate-limiting step. This requires days or even weeks of high temperature treatment, and consumption of large amounts of energy. We employed spark-plasma sintering, an engineering technique that is used for high-speed consolidation of powders with a pulsed electric current passing through the sample to carry out the fluorination of niobium oxide in minute intervals. The approach saves time and large amounts of waste energy. Moreover, it allows the preparation of fluorinated niobium oxides on a gram scale using poly(tetrafluoroethylene) (®Teflon) scrap and without toxic chemicals. The synthesis can be upscaled easily to the kg range with appropriate sintering equipment. Finally, NbO2F and Nb3O7F prepared by spark plasma sintering show significant photoelectrocatalytic (PEC) oxygen evolution from water in terms of photocurrent density and incident photon-to-current efficiency (% IPCE), whereas NbO2F and Nb3O7F prepared by conventional high temperature chemistry show little to no PEC response. Our study is a proof of concept for the quick, clean and energy saving production of valuable photocatalysts from plastic waste.

A Generalized Method for High-Speed Fluorination of Metal Oxides by Spark Plasma Sintering Yields Ta3 O7 F and TaO2 F with High Photocatalytic Activity for Oxygen Evolution from Water.

A general method to carry out the fluorination of metal oxides with poly(tetrafluoroethylene) (PTFE, Teflon) waste by spark plasma sintering (SPS) on a minute scale with Teflon is reported. The potential of this new approach is highlighted by the following results. i) The tantalum oxyfluorides Ta3 O7 F and TaO2 F are obtained from plastic scrap without using toxic or caustic chemicals for fluorination. ii) Short reaction times (minutes rather than days) reduce the process time the energy costs by almost three orders of magnitude. iii) The oxyfluorides Ta3 O7 F and TaO2 F are produced in gram amounts of nanoparticles. Their synthesis can be upscaled to the kg range with industrial sintering equipment. iv) SPS processing changes the catalytic properties: while conventionally prepared Ta3 O7 F and TaO2 F show little catalytic activity, SPS-prepared Ta3 O7 F and TaO2 F exhibit high activity for photocatalytic oxygen evolution, reaching photoconversion efficiencies up to 24.7% and applied bias to photoconversion values of 0.86%. This study shows that the materials properties are dictated by the processing which poses new challenges to understand and predict the underlying factors.

Gram-scale selective synthesis of WO3-x nanorods and (NH4)xWO3 ammonium tungsten bronzes with tunable plasmonic properties.

Localized surface plasmon resonance properties in unconventional materials like metal oxides or chalcogenide semiconductors have been studied for use in signal detection and analysis in biomedicine and photocatalysis. We devised a selective synthesis of the tungsten oxides WO3-x and (NH4)xWO3 with tunable plasmonic properties. We selectively synthesized WO3-x nanorods with different aspect ratios and hexagonal tungsten bronzes (NH4)xWO3 as truncated nanocubes starting from ammonium metatungstate (NH4)6H2W12O40·xH2O. Both particles form from the same nuclei at temperatures >200 °C; monomer concentration and surfactant ratio are essential variables for phase selection. (NH4)xWO3 was the preferred reaction product only for fast heating rates (25 K min-1), slow stirring speeds (∼150 rpm) and high precursor concentrations. A proton nuclear magnetic resonance (1H-NMR) spectroscopic study of the reaction mechanism revealed that oleyl oleamide, formed from oleic acid and oleylamine upon heating, is a key factor for the selective formation of WO3-x nanorods. Since oleic acid and oleylamine are standard surfactants for the wet chemical synthesis of many metal and oxide nanoparticles, the finding that oleyl oleamide acts as a chemically active reagent above 250 °C may have implications for many nanoparticle syntheses. Oriented attachment of polyoxotungstate anions is proposed as a model to rationalize phase selectivity. Magic angle spinning (MAS) 1H-NMR and powder X-ray diffraction (PXRD) studies of the bronze after annealing under (non)inert conditions revealed an oxidative phase transition. WO3-x and (NH4)xWO3 show a strong plasmon absorption for near infra-red light between 800 and 3300 nm. The maxima of the plasmon bands shift systematically with the nanocrystal aspect ratio.

Association Equilibria of Organo-Phosphoric Acids with Imines from a Combined Dielectric and Nuclear Magnetic Resonance Spectroscopy Approach.

Aggregates formed between organo-phosphoric acids and imine bases in aprotic solvents are the reactive intermediates in Brønsted acid organo-catalysis. Due to the strong hydrogen-bonding interaction of the acids in solution, multiple homo- and heteroaggregates are formed with profound effects on catalytic activity. Yet, due to the similar binding motifs-hydrogen-bonds-it is challenging to experimentally quantify the abundance of these aggregates in solution. Here we demonstrate that a combination of nuclear magnetic resonance (NMR) and dielectric relaxation spectroscopy (DRS) allows for accurate speciation of these aggregates in solution. We show that only by using the observables of both experiments heteroaggregates can be discriminated with simultaneously taking homoaggregation into account. Comparison of the association of diphenyl phosphoric acid and quinaldine or phenylquinaline in chloroform, dichloromethane, or tetrahydrofuran suggests that the basicity of the base largely determines the association of one acid and one base molecule to form an ion-pair. We find the ion-pair formation constants to be highest in chloroform, slightly lower in dichloromethane and lowest in tetrahydrofuran, which indicates that the hydrogen-bonding ability of the solvent also alters ion-pairing equilibria. We find evidence for the formation of multimers, consisting of one imine base and multiple diphenyl phosphoric acid molecules for both bases in all three solvents. This subsequent association of an acid to an ion-pair is however little affected by the nature of the base or the solvent. As such our findings provide routes to enhance the overall fraction of these multimers in solution, which have been reported to open new catalytic pathways.

Identification of tumor-associated macrophage subsets that are associated with breast cancer prognosis.

BACKGROUND: Breast cancer is the leading cause of cancer-related deaths in women, demanding new treatment options. With the advent of immune checkpoint blockade, immunotherapy emerged as a treatment option. In addition to lymphocytes, tumor-associated macrophages exert a significant, albeit controversial, impact on tumor development. Pro-inflammatory macrophages are thought to hinder, whereas anti-inflammatory macrophages promote tumor growth. However, molecular markers to identify prognostic macrophage populations remain elusive. METHODS: We isolated two macrophage subsets, from 48 primary human breast tumors, distinguished by the expression of CD206. Their transcriptomes were analyzed via RNA-Seq, and potential prognostic macrophage markers were validated by PhenOptics in tissue microarrays of patients with invasive breast cancer. RESULTS: Normal human breast tissue contained mainly CD206+ macrophages, while increased relative amounts of CD206- macrophages were observed in tumors. The presence of CD206+ macrophages correlated with a pronounced lymphocyte infiltrate and subsets of CD206+ macrophages, expressing SERPINH1 and collagen 1, or MORC4, were unexpectedly associated with improved survival of breast cancer patients. In contrast, MHCIIhi CD206- macrophages were linked with a poor survival prognosis. CONCLUSION: Our data highlight the heterogeneity of tumor-infiltrating macrophages and suggest the use of multiple phenotypic markers to predict the impact of macrophage subpopulations on cancer prognosis. We identified novel macrophage markers that correlate with the survival of patients with invasive mammary carcinoma.

Composition-Dependent Hydrogen-Bonding Motifs and Dynamics in Brønsted Acid-Base Mixtures.

In recent years the interaction of organophosphates and imines, which is at the core of Brønsted acid organocatalysis, has been established to be based on strong ionic hydrogen bonds. Yet, besides the formation of homodimers consisting of two acid molecules and heterodimers consisting of one acid and one base, also multimeric molecular aggregates are formed in solution. These multimeric aggregates consist of one base and several acid molecules. The details of the intermolecular bonding in such aggregates, however, have remained elusive. To characterize composition-dependent bonding and bonding dynamics in these aggregates, we use linear and nonlinear infrared (IR) spectroscopy at varying molar ratios of diphenyl phosphoric acid and quinaldine. We identify the individual aggregate species, giving rise to the structured, strong, and very broad infrared absorptions, which span more than 1000 cm-1. Linear infrared spectra and density functional theory calculations of the proton transfer potential show that doubly ionic intermolecular hydrogen bonds between the acid and the base lead to absorptions which peak at ∼2040 cm-1. The contribution of singly ionic hydrogen bonds between an acid anion and an acid molecule is observed at higher frequencies. As common to such strong hydrogen bonds, ultrafast IR spectroscopy reveals rapid, ∼ 100 fs, dissipation of energy from the proton transfer coordinate. Yet, the full dissipation of the excess energy occurs on a ∼0.8-1.1 ps time scale, which becomes longer when multimers dominate. Our results thus demonstrate the coupling and collectivity of the hydrogen bonds within these complexes, which enable efficient energy transfer.

Effects of IL-10 and Th 2 cytokines on human Mφ phenotype and response to CSF1R inhibitor.

Tumor-associated Mφs display a plastic phenotype that is regulated by the local tumor milieu. Gene expression analysis and functional characterization of Mφs exposed in vitro to individual cytokines aids to delineate the cross-talk between defined cytokines shaping the complex Mφ phenotype. Human monocyte-derived Mφs can be differentiated in vitro with the T helper cell type 2 response cytokines IL-4 and IL-13 or the immunosuppressive IL-10. Notably, only the latter subset undergoes apoptosis when treated with the CSF 1 receptor (CSF1R) blocking antibody emactuzumab. However, under physiologic conditions, the Mφ phenotype is regulated by cytokine combination. Hence, in this study, we characterized the plasticity of IL-4 or IL-13-differentiated Mφs upon exposure to the immunosuppressive IL-10. Although IL-4-differentiated Mφs sustained their molecular phenotype in the presence of IL-10, IL-13-differentiated Mφs were skewed towards the IL-10 phenotype. Gene expression profiling revealed unique IL-4+IL-10 and IL-13+IL-10 Mφ signatures associated with up-regulation of canonical NF-κB or Wnt/ß-catenin signaling pathways, respectively. Although IL-10 was able to alter the surface marker and gene expression profile of IL-13-differentiated Mφs, addition of IL-10 did not restore emactuzumab susceptibility. Combining NF-κB and Wnt/ß-catenin signaling inhibitors with emactuzumab had no effect on viability. On average 3-5% of cancer patients overexpressed IL-4, IL-13, or IL-10 mRNA in silico. Although a small patient subset overexpressed IL-10+IL-13, IL-4+IL-10 lacked co-expression. In vitro characterization of CSF1R inhibitor-refractory Mφ phenotypes can support novel pharmacological approaches to specifically target these cells.

Macrophage Susceptibility to Emactuzumab (RG7155) Treatment.

Blockade of colony-stimulating factor-1 receptor (CSF-1R) enables the therapeutic targeting of tumor-associated macrophages (TAM) in cancer patients. Various CSF-1R inhibitors, mAbs, and tyrosine kinase inhibitors are currently evaluated in early clinical trials. Presence of an alternative survival signal, such as GM-CSF, rescues human monocyte-derived macrophages from CSF-1R inhibitor-induced apoptosis. In this study, we sought to identify additional factors that mediate resistance to CSF-1R-blocking antibody RG7155 (emactuzumab). We investigated the impact of hypoxia, macrophage-polarizing cytokines IL4 and IL10, and genetic alterations within the CSF1R locus and mitochondrial DNA. Among all investigated factors, only IL4 completely rescued viability of RG7155-treated macrophages in vitro This RG7155-resistant population was characterized by a substantially increased mannose receptor-1 (CD206) expression. Analysis of CD206 and the hemoglobin scavenger receptor CD163 expression on normal tissue allowed for discrimination of distinct macrophage populations according to localization and frequency. In emactuzumab-treated cancer patients, we found a significant reduction of CSF-1R, CD204, and CD163 mRNA levels in contrast to a less pronounced decrease of CD206 expression by transcriptome analysis of tumor biopsies. However, we detected in normal skin tissue, which shows lower IL4 mRNA expression compared with melanoma tissue, significant reduction of CD206+ dermal macrophages in RG7155-treated skin biopsies. These results suggest that in cancers where the cytokines IL4 and GM-CSF are sufficiently expressed to induce very high CD206 expression on macrophages, CSF-1R inhibition may not deplete CD206hi TAM. This observation can help to identify those patients most likely to benefit from CSF-1R-targeting agents. Mol Cancer Ther; 15(12); 3077-86. ©2016 AACR.

Fibroblasts Influence Survival and Therapeutic Response in a 3D Co-Culture Model.

In recent years, evidence has indicated that the tumor microenvironment (TME) plays a significant role in tumor progression. Fibroblasts represent an abundant cell population in the TME and produce several growth factors and cytokines. Fibroblasts generate a suitable niche for tumor cell survival and metastasis under the influence of interactions between fibroblasts and tumor cells. Investigating these interactions requires suitable experimental systems to understand the cross-talk involved. Most in vitro experimental systems use 2D cell culture and trans-well assays to study these interactions even though these paradigms poorly represent the tumor, in which direct cell-cell contacts in 3D spaces naturally occur. Investigating these interactions in vivo is of limited value due to problems regarding the challenges caused by the species-specificity of many molecules. Thus, it is essential to use in vitro models in which human fibroblasts are co-cultured with tumor cells to understand their interactions. Here, we developed a 3D co-culture model that enables direct cell-cell contacts between pancreatic, breast and or lung tumor cells and human fibroblasts/ or tumor-associated fibroblasts (TAFs). We found that co-culturing with fibroblasts/TAFs increases the proliferation in of several types of cancer cells. We also observed that co-culture induces differential expression of soluble factors in a cancer type-specific manner. Treatment with blocking antibodies against selected factors or their receptors resulted in the inhibition of cancer cell proliferation in the co-cultures. Using our co-culture model, we further revealed that TAFs can influence the response to therapeutic agents in vitro. We suggest that this model can be reliably used as a tool to investigate the interactions between a tumor and the TME.

Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy.

Macrophage infiltration has been identified as an independent poor prognostic factor in several cancer types. The major survival factor for these macrophages is macrophage colony-stimulating factor 1 (CSF-1). We generated a monoclonal antibody (RG7155) that inhibits CSF-1 receptor (CSF-1R) activation. In vitro RG7155 treatment results in cell death of CSF-1-differentiated macrophages. In animal models, CSF-1R inhibition strongly reduces F4/80(+) tumor-associated macrophages accompanied by an increase of the CD8(+)/CD4(+) T cell ratio. Administration of RG7155 to patients led to striking reductions of CSF-1R(+)CD163(+) macrophages in tumor tissues, which translated into clinical objective responses in diffuse-type giant cell tumor (Dt-GCT) patients.