Improving the mesomorphism in bispyrazolate Pd(II) metallomesogens: an efficient platform for ionic conduction.

The introduction of structural asymmetry in metallomesogens is an established strategy to improve their mesomorphic behaviour in terms of lower melting temperatures and higher stability ranges of the mesophase, which is particularly important for metallomesogens that have potential application as electrolytes that require wide operational temperature ranges. Here in this work, a novel series of unsymmetrical bis(isoquinolinylpyrazolate)palladium(II) compounds bearing four alkyl side-chains with different lengths are described. Rectangular and hexagonal columnar mesophases were formed with low melting temperatures of 42-45 °C in most cases, whereas the clearing temperatures reached values up to 412 °C. The charge transport properties have been studied by complex impedance spectroscopy, showing that the mesophase favours proton conduction in the absence of water or humidity. The exceptional thermal stability of these species makes them promising candidates to act as a platform for ionic conduction via the nanochannels originated in the columnar mesophases. The results presented confirm that introducing structural asymmetry in the Pd(II) metallomesogens studied is a valid strategy to enhance the liquid crystalline properties, which opens new ways to develop water-free electrolytes based on unsymmetrical bis(isoquinolinylpyrazolate) Pd(II) compounds for potential applications such as proton exchange membranes (PEMs).

Viability of Glioblastoma Cells and Fibroblasts in the Presence of Imidazole-Containing Compounds.

The naturally occurring dipeptide carnosine (ß-alanyl-L-histidine) specifically attenuates tumor growth. Here, we ask whether other small imidazole-containing compounds also affect the viability of tumor cells without affecting non-malignant cells and whether the formation of histamine is involved. Patient-derived fibroblasts and glioblastoma cells were treated with carnosine, L-alanyl-L-histidine (LA-LH), ß-alanyl-L-alanine, L-histidine, histamine, imidazole, ß-alanine, and L-alanine. Cell viability was assessed by cell-based assays and microscopy. The intracellular release of L-histidine and formation of histamine was investigated by high-performance liquid chromatography coupled to mass spectrometry. Carnosine and LA-LH inhibited tumor cell growth with minor effects on fibroblasts, and L-histidine, histamine, and imidazole affected viability in both cell types. Compounds without the imidazole moiety did not diminish viability. In the presence of LA-LH but not in the presence of carnosine, a significant rise in intracellular amounts of histidine was detected in all cells. The formation of histamine was not detectable in the presence of carnosine, LA-LH, or histidine. In conclusion, the imidazole moiety of carnosine contributes to its anti-neoplastic effect, which is also seen in the presence of histidine and LA-LH. Despite the fact that histamine has a strong effect on cell viability, the formation of histamine is not responsible for the effects on the cell viability of carnosine, LA-LH, and histidine.

Impedance Spectroscopy of Encapsulated Single Graphene Layers.

In this work, we demonstrate the use of electrical impedance spectroscopy (EIS) for the disentanglement of several dielectric contributions in encapsulated single graphene layers. The dielectric data strongly vary qualitatively with the nominal graphene resistance. In the case of sufficiently low resistance of the graphene layers, the dielectric spectra are dominated by inductive contributions, which allow for disentanglement of the electrode/graphene interface resistance from the intrinsic graphene resistance by the application of an adequate equivalent circuit model. Higher resistance of the graphene layers leads to predominantly capacitive dielectric contributions, and the deconvolution is not feasible due to the experimental high frequency limit of the EIS technique.

Magnetoimpedance spectroscopy of phase-separated La0.5Ca0.5MnO3 polycrystalline manganites.

Magnetoimpedance spectroscopy was carried out on phase-separated La0.5Ca0.5MnO3 polycrystalline manganites. The La0.5Ca0.5MnO3 powder was synthesized following an adapted sol-gel route. Structural and magnetic data showed the signs of phase coexistence of ferromagnetic (FM) Pnma and charge-ordered antiferromagnetic (CO-AFM) P21/m phases. Magnetization vs. temperature (M vs. T) measurements revealed several magnetic transitions from the high temperature paramagnetic (PM) to an FM phase upon cooling (PM-FM) at ≈240 K, FM-AFM (≈170 K) and AFM-FM (≈100 K). Magnetic field (H)-dependent impedance spectroscopy data were collected from sintered pellets and fitted with an equivalent circuit model to separately analyze the different dielectric contributions from the grain boundary (GB) and the grain interior bulk areas. This allowed separating the GB and bulk magnetoresistance (MR), which was shown to amount to a maximum of ≈80% for both GB and bulk at H = 10 T near the metal-insulator transition (MIT) at ≈100 K. The GB resistance was found to be larger than the bulk resistance by a factor of ≈3, which implies that the direct current (DC) resistance and DC MR are dominated by contributions from the GBs. The magnetocapacitance (MC) effects detected were all found to be small below ≈3%, including in the presence of a CO phase.

Carnosine's inhibitory effect on glioblastoma cell growth is independent of its cleavage.

The naturally occurring dipeptide carnosine (ß-alanyl-L-histidine) inhibits the growth of tumor cells. As its component L-histidine mimics the effect, we investigated whether cleavage of carnosine is required for its antineoplastic effect. Using ten glioblastoma cell lines and cell cultures derived from 21 patients suffering from this malignant brain tumor, we determined cell viability under the influence of carnosine and L-histidine. Moreover, we determined expression of carnosinases, the intracellular release of L-histidine from carnosine, and whether inhibition of carnosine cleavage attenuates carnosine's antineoplastic effect. We observed a significantly higher response of the cells to L-histidine than to carnosine with regard to cell viability in all cultures. In addition, we detected protein and mRNA expression of carnosinases and a low but significant release of L-histidine in cells incubated in the presence of 50 mM carnosine (p < 0.05), which did not correlate with carnosine's effect on viability. Furthermore, the carnosinase 2 inhibitor bestatin did not attenuate carnosine's effect on viability. Interestingly, we measured a ~ 40-fold higher intracellular abundance of L-histidine in the presence of 25 mM extracellular L-histidine compared to the amount of L-histidine in the presence of 50 mM carnosine, both resulting in a comparable decrease in viability. In addition, we also examined the expression of pyruvate dehydrogenase kinase 4 mRNA, which was comparably influenced by L-histidine and carnosine, but did not correlate with effects on viability. In conclusion, we demonstrate that the antineoplastic effect of carnosine is independent of its cleavage.

D,L-Methadone does not improve radio- and chemotherapy in glioblastoma in vitro.

PURPOSE: Glioblastoma (GBM) is the most common malignant tumor of the central nervous system. Median survival of glioblastoma patients under standard therapy including radiotherapy and chemotherapy using temozolomide (TMZ) is 14.6 months. As cell culture experiments combining D,L-methadone with doxorubicin demonstrated an increased reduction of cell viability of glioblastoma cells, the opioid has been discussed as a drug for the treatment of GBM. Despite lack of clinical and experimental evidence that D,L-methadone in combination with standard therapy will be beneficial, an increasing number of tumor patients medicating themselves with D,L-methadone present to the hospitals in Germany. METHODS: As a first step towards understanding whether D,L-methadone may increase the efficacy of standard therapy, we used a cell culture model of primary GBM and fibroblast cell cultures derived from GBM patients. The cultures were treated with different concentrations of D,L-methadone in combination with X-irradiation, TMZ or both. Cell viability was determined by measuring ATP in cell lysates and dehydrogenase activity in living cells. RESULTS: When only treated with D,L-methadone, 1 µM of the opioid was sufficient to reduce viability of fibroblasts, whereas 10 µM was needed to significantly reduce glioblastoma cell viability. In addition, D,L-methadone did not improve the anti-neoplastic effects of X-irradiation, temozolomide or both. CONCLUSIONS: As D,L-methadone reduces glioblastoma cell viability only when concentrations are used that had been reported to be toxic to patients and as there were no interactions observable combining it with standard therapy, a recommendation for the use of D,L-methadone in glioblastoma therapy cannot be given.

In situ generation of 3D graphene-like networks from cellulose nanofibres in sintered ceramics.

Establishing a 3D electrically percolating network in an insulating matrix is key to numerous engineering and functional applications. To this end, using hydrophobic carbon nanofillers is tempting, but still results in suboptimal performance due to processing challenges. Here, we demonstrate how natural cellulose nanofibres can be in situ transformed into graphene-like sheets connected to a 3D network enhancing both the transport and the mechanical properties of sintered engineering ceramics. The network architecture also permits the decoupling of electrical and thermal conductivities, which represents a major obstacle in attaining efficient thermoelectric materials. We foresee that our transferable methodology can pave the way for the use of natural nanofibres to unravel the full potential of 3D graphene-like networks to accelerate development in fields like energy and telecommunications.

New Pyrazolium Salts as a Support for Ionic Liquid Crystals and Ionic Conductors.

Ionic liquid crystals (ILCs) are a class of materials that combine the properties of liquid crystals (LCs) and ionic liquids (ILs). This type of materials is directed towards properties such as conductivity in ordered systems at different temperatures. In this work, we synthesize five new families of ILCs containing symmetrical and unsymmetrical substituted pyrazolium cations, with different alkyl long-chains, and anions such as Cl-, BF4-, ReO4-, p-CH3-6H4SO3- (PTS) and CF3SO3- (OTf). We study their thermal behavior by polarized light optical microscopy (POM) and differential scanning calorimetry (DSC). All of them, except those with OTf as counteranion, show thermotropic mesomorphism. The observations by POM reveal textures of lamellar mesophases. Those agree with the arrangement observed in the X-ray crystal structure of [H2pzR(4),R(4)][ReO4]. The nature of the mesophases is also confirmed by variable temperature powder X-ray diffraction. On the other hand, the study of the dielectric properties at variable temperature in mesomorphic (Cl- and BF4-) and non-mesomorphic (OTf) salts indicates that the supramolecular arrangement of the mesophase favors a greater ionic mobility and therefore ionic conductivity.

Large Magnetoelectric Coupling Near Room Temperature in Synthetic Melanostibite Mn2 FeSbO6.

Multiferroic materials exhibit two or more ferroic orders and have potential applications as multifunctional materials in the electronics industry. A coupling of ferroelectricity and ferromagnetism is hereby particularly promising. We show that the synthetic melanostibite mineral Mn2 FeSbO6 (R3‾ space group) with ilmenite-type structure exhibits cation off-centering that results in alternating modulated displacements, thus allowing antiferroelectricity to occur. Massive magnetoelectric coupling (MEC) and magnetocapacitance effect of up to 4000 % was detected at a record high temperature of 260 K. The multiferroic behavior is based on the imbalance of cationic displacements caused by a magnetostrictive mechanism, which sets up an unprecedented example to pave the way for the development of highly effective MEC devices operational at or near room temperature.

Innovative approach for identifying root causes of glass defects in sterile drug product manufacturing.

In sterile drug product manufacturing, scratched and broken glass containers (i.e., vials) cause product losses, glass particles, equipment contamination and additional cleaning efforts. However, mechanical resistance and exposure of vials to mechanical stress are not sufficiently understood, and no systematic approach for reducing glass-related losses is established. Manufacturers may tackle glass-related losses more rationally if (i) frequencies for inflicting disqualifying damages to drug product containers are known for given forces, (ii) actual exposure in industrial filling lines is quantified and (iii) process enhancements are derived based on collected information. In this work, an innovative approach for exploiting these opportunities, identifying glass defect root causes and reducing glass defects is provided. Devices for quantifying (i) damaging frequencies and (ii) actual exposure are presented and then applied in an industrial case study on sterile drug product manufacturing; finally, (iii) process enhancements are derived and implemented. In the case study, frequencies for scratching vials at given forces as well as breaking forces have been determined. Peak exposure in the investigated filling line was detected at 6 N. As a result of the case study, key machine parts were identified and adjusted.

Microwave-Assisted Synthesis, Microstructure, and Magnetic Properties of Rare-Earth Cobaltites.

The series of perovskite rare-earth (RE) doped cobaltites (RE)CoO3 (RE = La-Dy) was prepared by microwave-assisted synthesis. The crystal structure undergoes a change of symmetry depending on the size of the RE cation. LaCoO3 is rhombohedral, S.G. R3̅c (No. 167), while, for the rest of the RE series (Pr-Dy), the symmetry is orthorhombic, S.G. Pnma (No. 62). The crystal structure obtained by X-ray diffraction was confirmed by high-resolution transmission electron microscopy, which yielded a good match between experimental and simulated images. It is further shown that the well-known magnetism in LaCoO3, which involves a thermally induced Co3+ (d6) low spin to intermediate or high spin state transition, is strongly modified by the RE cation, and a rich variety of magnetic order has been detected across the series.

Nanostructured discotic Pd(ii) metallomesogens as one-dimensional proton conductors.

A novel family of square-planar Pd(ii) complexes based on isoquinoline-functionalised pyrazolate ligands [Pd(pzR(n,n)iq)2] (R(n,n) = C6H3(OCnH2n+1)2, n = 4, 6, 8, 10, 12, 14, 16, 18) has been synthesised and characterised. The new complexes show mesomorphic properties and exhibit columnar mesophases that are highly-stable in exceptionally wide temperature ranges of up to 345 °C. The formation of nanochannels in the fluid liquid crystal phases generates continuous pathways for one-dimensional proton conduction on the basis of C-HN proton transfer. The complex with an intermediate chain length (n = 12) shows the highest proton conductivity of 1.34 × 10-4 S m-1 at 269 °C in the hexagonal columnar mesophase, and an activation energy of 0.84 eV. The influence of both the terminal alkyl chain length and the mesophase columnar organisation on the proton conduction mechanism is demonstrated. The series of Pd(ii) complexes investigated in this work constitutes one of the first examples of proton-conducting metallomesogens with potential applications in PEM fuel cells.

Water-Free Proton Conduction in Discotic Pyridylpyrazolate-based Pt(II) and Pd(II) Metallomesogens.

In this work we report on water-free proton conductivity in liquid-crystal pyridylpyrazolate-based Pt(II) and Pd(II) complexes [M(pz(R(n,n)py))2] (pz(R(n,n)py) = 3-(3,5-dialkyloxyphenyl)-5-(pyridin-2-yl)pyrazolate, R(n,n) = C6H3(OCnH2n+1)2; n = 4, 12, 16, M = Pd; n = 12, M = Pt) with potential application as electrolyte materials in proton exchange membrane fuel cells. The columnar ordering of the complexes in the liquid-crystalline phase opens nanochannels, which are used for fast proton exchange as detected by impedance spectroscopy and NMR. The NMR spectra indicate that the proton conduction mechanism is associated with a novel C-H···N proton transfer, which persists above the clearing point of the material. The highest conductivity of ∼0.5 µS cm(-1) at 180 °C with an activation energy of 1.2 eV is found for the Pt(II) compound in the mesophase. The Pd(II) complexes with different chain length (n = 4, 12, and 16) show lower conductivity but smaller activation energies, in the range of 0.74-0.93 eV.

Comparison of Tunable Diode Laser Absorption Spectroscopy and Isothermal Micro-calorimetry for Non-invasive Detection of Microbial Growth in Media Fills.

Two methods were investigated for non-invasive microbial growth-detection in intact glass vials as possible techniques for automated inspection of media-filled units. Tunable diode laser absorption spectroscopy (TDLAS) was used to determine microbially induced changes in O2 and CO2 concentrations within the vial headspaces. Isothermal microcalorimetry (IMC) allowed the detection of metabolic heat production. Bacillus subtilis and Streptococcus salivarius were chosen as test organisms. Parameters as robustness, sensitivity, comparability and time to detection (TtD) were evaluated to assess method adequacy. Both methods robustly detected growth of the tested microorganisms within less than 76 hours using an initial inoculum of <10CFU. TDLA turned out to be less sensitive than TDLA and IMC, as some false negative results were observed. Compared to the visual media-fill examination of spiked samples, the investigated techniques were slightly slower regarding TtD. Although IMC showed shorter TtD than TDLAS the latter is proposed for automating the media-fill inspection, as larger throughput can be achieved. For routine use either TDLA or a combination of TDLA and TDLA should be considered. IMC may be helpful for replacing the sterility assessment of commercial drug products before release.

Diketonylpyridinium Cations as a Support of New Ionic Liquid Crystals and Ion-Conductive Materials: Analysis of Counter-Ion Effects.

Ionic liquid crystals (ILCs) allow the combination of the high ionic conductivity of ionic liquids (ILs) with the supramolecular organization of liquid crystals (LCs). ILCs salts were obtained by the assembly of long-chained diketonylpyridinium cations of the type [HOOR(n)pyH]⁺ and BF4-, ReO4-, NO3-, CF3SO3-, CuCl42- counter-ions. We have studied the thermal behavior of five series of compounds by differential scanning calorimetry (DSC) and hot stage polarized light optical microscopy (POM). All materials show thermotropic mesomorphism as well as crystalline polymorphism. X-ray diffraction of the [HOOR(12)pyH][ReO4] crystal reveals a layered structure with alternating polar and apolar sublayers. The mesophases also exhibit a lamellar arrangement detected by variable temperature powder X-ray diffraction. The CuCl42- salts exhibit the best LC properties followed by the ReO4- ones due to low melting temperature and wide range of existence. The conductivity was probed for the mesophases in one species each from the ReO4-, and CuCl42- families, and for the solid phase in one of the non-mesomorphic Cl- salts. The highest ionic conductivity was found for the smectic mesophase of the ReO4- containing salt, whereas the solid phases of all salts were dominated by electronic contributions. The ionic conductivity may be favored by the mesophase lamellar structure.

Paving the way to nanoionics: atomic origin of barriers for ionic transport through interfaces.

The blocking of ion transport at interfaces strongly limits the performance of electrochemical nanodevices for energy applications. The barrier is believed to arise from space-charge regions generated by mobile ions by analogy to semiconductor junctions. Here we show that something different is at play by studying ion transport in a bicrystal of yttria (9% mol) stabilized zirconia (YSZ), an emblematic oxide ion conductor. Aberration-corrected scanning transmission electron microscopy (STEM) provides structure and composition at atomic resolution, with the sensitivity to directly reveal the oxygen ion profile. We find that Y segregates to the grain boundary at Zr sites, together with a depletion of oxygen that is confined to a small length scale of around 0.5 nm. Contrary to the main thesis of the space-charge model, there exists no evidence of a long-range O vacancy depletion layer. Combining ion transport measurements across a single grain boundary by nanoscale electrochemical strain microscopy (ESM), broadband dielectric spectroscopy measurements, and density functional calculations, we show that grain-boundary-induced electronic states act as acceptors, resulting in a negatively charged core. Besides the possible effect of the modified chemical bonding, this negative charge gives rise to an additional barrier for ion transport at the grain boundary.

The 532-nm 180-W (GreenLight®) laser vaporization of the prostate for the treatment of lower urinary tract symptoms: how durable is the new side-fire fiber with integrated cooling system?

The 532-nm side-fire laser vaporization is established for the treatment of symptomatic benign prostate hyperplasia. Meanwhile, the third generation of this system is offered by American Medical Systems, Inc. The laser power increased from 80 and 120 to 180 W from the first to the third generation. Despite good functional results, with the 80- and 120-W systems, the removal of prostate tissue is limited because of fiber degradation. To overcome this problem, the fiber was designed newly with an integrated cooling system and a sensor for decreasing the laser energy in case of overheating. We evaluate whether the new fiber still suffers from degradation with consecutive drop of power transmission during the procedure. The power output of the cooled fiber was measured in vitro and during prostate vaporization in ten patients. Laser beam power was measured at baseline and after the application each of 50 kJ during laser vaporization. Power emission of the fiber remains constant at 20, 80, and 180 W of power settings over the whole 40-kJ lifespan. During the transurethral procedure, a median total energy of 276 kJ (standard deviation 153 kJ) was applied for vaporization. Median power output from the fiber at the end of the procedure was 97% from the baseline value. There were no fiber malfunctions observed. In contrast to former generations, the third-generation laser fiber is durable without significant power loss during prostate vaporization.

Electron doping by charge transfer at LaFeO3/Sm2CuO4 epitaxial interfaces.

Using X-ray absorption spectroscopy and electron energy loss spectroscopy with atomic-scale spatial resolution, experimental evidence for charge transfer at the interface between the Mott insulators Sm2 CuO4 and LaFeO3 is obtained. As a consequence of the charge transfer, the Sm2 CuO4 is doped with electrons and thus epitaxial Sm2 CuO4 /LaFeO3 heterostructures become metallic.

Microwave-assisted synthesis, microstructure, and physical properties of rare-earth chromites.

The full rare-earth (RE) chromites series (RE)CrO(3) with an orthorhombic distorted (Pnma) perovskite structure and the isostructural compound YCrO(3) can be synthesized through a simple microwave-assisted technique, yielding high-quality materials. Magnetization measurements evidence that the Néel temperature for antiferromagnetic Cr(3+)-Cr(3+) ordering strongly depends on the RE(3+) ionic radius (IOR), and a rich variety of different magnetic spin interactions exists. Dielectric spectroscopy on sintered pellets indicates electronic inhomogeneity in all samples as manifested by the presence of at least two dielectric relaxation processes associated with grain boundary and grain interior bulk contributions. X-ray diffraction, Raman spectroscopy, and temperature-dependent dielectric permittivity data do not indicate potential noncentrosymmetry in the crystal or concomitant ferroelectricity. Strong correlations between the magnetic and dielectric properties were not encountered, and microwave-synthesized (RE)CrO(3) may not be classified as magnetoelectric or multiferroic materials.

Tissue-based Alzheimer gene expression markers-comparison of multiple machine learning approaches and investigation of redundancy in small biomarker sets.

BACKGROUND: Alzheimer's disease has been known for more than 100 years and the underlying molecular mechanisms are not yet completely understood. The identification of genes involved in the processes in Alzheimer affected brain is an important step towards such an understanding. Genes differentially expressed in diseased and healthy brains are promising candidates. RESULTS: Based on microarray data we identify potential biomarkers as well as biomarker combinations using three feature selection methods: information gain, mean decrease accuracy of random forest and a wrapper of genetic algorithm and support vector machine (GA/SVM). Information gain and random forest are two commonly used methods. We compare their output to the results obtained from GA/SVM. GA/SVM is rarely used for the analysis of microarray data, but it is able to identify genes capable of classifying tissues into different classes at least as well as the two reference methods. CONCLUSION: Compared to the other methods, GA/SVM has the advantage of finding small, less redundant sets of genes that, in combination, show superior classification characteristics. The biological significance of the genes and gene pairs is discussed.