First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure.

Diminished hepatocyte regeneration is a key feature of acute and chronic liver diseases and after extended liver resections, resulting in the inability to maintain or restore a sufficient functional liver mass. Therapies to restore hepatocyte regeneration are lacking, making liver transplantation the only curative option for end-stage liver disease. Here, we report on the structure-based development and characterization (nuclear magnetic resonance [NMR] spectroscopy) of first-in-class small molecule inhibitors of the dual-specificity kinase MKK4 (MKK4i). MKK4i increased liver regeneration upon hepatectomy in murine and porcine models, allowed for survival of pigs in a lethal 85% hepatectomy model, and showed antisteatotic and antifibrotic effects in liver disease mouse models. A first-in-human phase I trial (European Union Drug Regulating Authorities Clinical Trials [EudraCT] 2021-000193-28) with the clinical candidate HRX215 was conducted and revealed excellent safety and pharmacokinetics. Clinical trials to probe HRX215 for prevention/treatment of liver failure after extensive oncological liver resections or after transplantation of small grafts are warranted.

Investigation of Fluorine and Nitrogen as Anionic Dopants in Nickel-Rich Cathode Materials for Lithium-Ion Batteries.

Advanced lithium-ion batteries are of great interest for consumer electronics and electric vehicle applications; however, they still suffer from drawbacks stemming from cathode active material limitations (e.g., insufficient capacities and capacity fading). One approach for alleviating such limitations and stabilizing the active material structure may be anion doping. In this work, fluorine and nitrogen are investigated as potential dopants in Li1.02(Ni0.8Co0.1Mn0.1)0.98O2 (NCM) as a prototypical nickel-rich cathode active material. Nitrogen doping is achieved by ammonia treatment of NCM in the presence of oxygen, which serves as an unconventional and new approach. The crystal structure was investigated by means of Rietveld and pair distribution function analysis of X-ray diffraction data, which provide very precise information regarding both the average and local structure, respectively. Meanwhile, time-of-flight secondary-ion mass spectroscopy was used to assess the efficacy of dopant incorporation within the NCM structure. Moreover, scanning electron microscopy and scanning transmission electron microscopy were conducted to thoroughly investigate the dopant influences on the NCM morphology. Finally, the electrochemical performance was tested via galvanostatic cycling of half- and full-cells between 0.1 and 2 C. Ultimately, a dopant-dependent modulation of the NCM structure was found to enable the enhancement of the electrochemical performance, thereby opening a route to cathode active material optimization.

Formation and Structural Diversity of Organo-Functionalized Tin-Silver Selenide Clusters.

When reacting the organic functionalized tin selenide clusters [(SnR1 )3 Se4 Cl] (A, R1 =CMe2 CH2 C(O)Me) or [(SnR1 )4 Se6 ] (B) with (SiMe3 )2 Se and [Ag(PPh3 )3 Cl] at -78 °C in CH2 Cl2 , a microcrystalline intermediate (compound 1) precipitates, which was investigated by magic angle spinning (MAS) NMR spectroscopy, powder X-ray diffraction (PXRD), energy dispersive X-ray (EDX) spectroscopy, and quantum chemistry calculations, to derive information about its composition and structure. Compound 1 re-dissolves under reorganization into the organo-functionalized Ag/Sn/Se cluster compound [Ag6 (µ6 -Se)(Ag8 Se12 ){(R1 Sn)2 Se2 }6 ] (2), or the mixed-valence cluster [(AgPPh3 )2 (SnII Cl)2 Se2 {(R1 SnIV )2 Se2 }2 ] (3), depending on the presence or the exclusion of daylight, respectively. The addition of N2 H4 ⋅H2 O to a solution of 1 yields selectively [Ag7 (µ7 -Se)(Ag7 Se12 ){(R2 Sn)2 Se2 }6 ] (4, R2 =CMe2 CH2 C(N2 H2 )Me), the Ag/Sn/Se core of which is isomeric to that of 2. 2-4 were characterized by X-ray diffraction. NMR spectroscopic studies on solutions of 1 indicate the co-existence of different species.

FIB Plan View Preparation and Electron Tomography of Ga-Containing Droplets Induced by Melt-Back Etching in Si.

Melt-back etching is an effect that can occur for gallium (Ga) containing III/V semiconductors grown on Si. Since this effect influences interfaces between the two compounds and therefore the physical characteristics of the material composition, it is desirable to understand its driving forces. Therefore, we investigated Ga grown on Si (001) via metal organic chemical vapor deposition using trimethyl Ga as a precursor. As a result of the melt-back etching, Ga-containing droplets formed on the Si surface which reach into the Si wafer. The shape of these structures was analyzed by plan view investigation and cross sectional tomography in a (scanning) transmission electron microscope. For plan view preparation a focused ion beam was used to avoid damage to the Ga-containing structures, which are sensitive to the chemicals normally used during conventional plan view preparation. Combining the results of both investigation methods confirms that the Ga-containing structure within the Si exhibits a pyramid shape with facets along the Si {111} lattice planes.

Model Driven Optimization of Magnetic Anisotropy of Exchange-coupled Core-Shell Ferrite Nanoparticles for Maximal Hysteretic Loss.

This study provides a guide to maximizing hysteretic loss by matching the design and synthesis of superparamagnetic nanoparticles to the desired hyperthermia application. The maximal heat release from magnetic nanoparticles to the environment depends on intrinsic properties of magnetic nanoparticles (e.g. size, magnetization, and magnetic anisotropy), and extrinsic properties of the applied fields (e.g. frequency, field strength). Often, the biomedical hyperthermia application limits flexibility in setting of many parameters (e.g. nanoparticle size and mobility, field strength and frequency). We show that core-shell nanoparticles combining a soft (Mn ferrite) and a hard (Co ferrite) magnetic material form a system in which the effective magnetic anisotropy can be easily tuned independently of the nanoparticle size. A theoretical framework to include the crystal anisotropy contribution of the Co ferrite phase to the nanoparticles total anisotropy is developed. The experimental results confirm that this framework predicts the hysteretic heating loss correctly when including non-linear effects in an effective susceptibility. Hence, we provide a guide on how to characterize the magnetic anisotropy of core-shell magnetic nanoparticles, model the expected heat loss and therefore, synthesize tuned nanoparticles for a particular biomedical application.

Mapping nanomechanical properties of freshly grown, native, interlamellar organic sheets on flat pearl nacre.

We imaged surfaces of freshly grown flat pearl nacre (Haliotis tuberculata) in different stages of growth in seawater using an atomic force microscope (AFM). Characteristic mineral phases of nacre, such as aragonitic stacks of coins, as well as the associated organic sheets, could be detected. Apart from imaging, the acquisition of force volumes on freshly grown organic surface areas on flat pearl nacre was conducted with the AFM. The evaluation of the force volumes with the Hertz-Sneddon model resulted in Young's moduli in the MPa range. The presented values are considerably smaller than values previously determined from macroscopic tensile tests. This might reflect the anisotropy of the organic nacre layers.

Preparation of continuous gold nanowires by electrospinning of high-concentration aqueous dispersions of gold nanoparticles.

Gold nanowires are prepared by the electrospinning of highly concentrated aqueous dispersions of gold nanoparticles (AuNPs) in the presence of poly(vinyl alcohol) and subsequent annealing at higher temperatures. Continuous wires of sintered AuNPs are obtained as a result of this process. The Au wires are characterized by transmission electron microscopy, helium ion microscopy, optical microscopy, and X-ray diffractometry.

Composition mapping in InGaN by scanning transmission electron microscopy.

We suggest a method for chemical mapping that is based on scanning transmission electron microscopy (STEM) imaging with a high-angle annular dark field (HAADF) detector. The analysis method uses a comparison of intensity normalized with respect to the incident electron beam with intensity calculated employing the frozen lattice approximation. This procedure is validated with an In(0.07)Ga(0.93)N layer with homogeneous In concentration, where the STEM results were compared with energy filtered imaging, strain state analysis and energy dispersive X-ray analysis. Good agreement was obtained, if the frozen lattice simulations took into account static atomic displacements, caused by the different covalent radii of In and Ga atoms. Using a sample with higher In concentration and series of 32 images taken within 42 min scan time, we did not find any indication for formation of In rich regions due to electron beam irradiation, which is reported in literature to occur for the parallel illumination mode. Image simulation of an In(0.15)Ga(0.85)N layer that was elastically relaxed with empirical Stillinger-Weber potentials did not reveal significant impact of lattice plane bending on STEM images as well as on the evaluated In concentration profiles for specimen thicknesses of 5, 15 and 50 nm. Image simulation of an abrupt interface between GaN and In(0.15)Ga(0.85)N for specimen thicknesses up to 200 nm showed that artificial blurring of interfaces is significantly smaller than expected from a simple geometrical model that is based on the beam convergence only. As an application of the method, we give evidence for the existence of In rich regions in an InGaN layer which shows signatures of quantum dot emission in microphotoluminescence spectroscopy experiments.

Gastropod nacre: structure, properties and growth--biological, chemical and physical basics.

The biogenic polymer/mineral composite nacre is a non-brittle biological ceramic, which self-organizes in aqueous environment and under ambient conditions. It is therefore an important model for new sustainable materials. Its highly controlled structural organization of mineral and organic components at all scales down to the nano- and molecular scales is guided by organic molecules. These molecules then get incorporated into the material to be responsible for properties like fracture mechanics, beauty and corrosion resistance. We report here on structure, properties and growth of columnar (gastropod) nacre with emphasis on the genus Haliotis in contrast to sheet nacre of many bivalves.

Impact of labor on outcomes in transient tachypnea of the newborn: population-based study.

OBJECTIVE: Our aim was to assess the effect of labor on the risk and course of transient tachypnea of the newborn (TTN) in term neonates from a contemporary, population-based cohort. METHODS: We analyzed perinatal characteristics of term singleton newborns (gestational age [GA] of > or =37 completed weeks) who were born between January 2001 and December 2005 in the federal states of Hesse and Saarland (Germany). TTN was diagnosed on the basis of International Classification of Diseases, 10th Revision codes. RESULTS: Of a total of 275 459 births, 239 971 fulfilled the inclusion criteria of GA of > or =37 completed weeks and singleton live birth. Among those, 13 346 term infants were admitted for neonatal care and 1423 were diagnosed as having TTN. The overall incidence of TTN was 5.9 cases per 1000 singleton live births in our study cohort. Elective cesarean section, low GA, male gender, and low birth weight were associated with TTN. The duration of oxygen supplementation for newborns with TTN was associated inversely with the duration of labor (r = -0.151; P = .028). CONCLUSIONS: Our study indicates that TTN is strongly related to elective cesarean section and low GA. Furthermore, the absence of exposure to labor contractions is associated with increased risk and severe course of TTN at term, with longer duration of oxygen supplementation.

Measurement of specimen thickness and composition in Al(x)Ga(1-x)N/GaN using high-angle annular dark field images.

In scanning transmission electron microscopy using a high-angle annular dark field detector, image intensity strongly depends on specimen thickness and composition. In this paper we show that measurement of image intensities relative to the intensity of the incoming electron beam allows direct comparison with simulated image intensities, and thus quantitative measurement of specimen thickness and composition. Simulations were carried out with the frozen lattice and absorptive potential multislice methods. The radial inhomogeneity of the detector was measured and taken into account. Using a focused ion beam (FIB) prepared specimen we first demonstrate that specimen thicknesses obtained in this way are in very good agreement with a direct measurement of the thickness of the lamella by scanning electron microscopy in the FIB. In the second step we apply this method to evaluate the composition of Al(x)Ga(1-x)N/GaN layers. We measured ratios of image intensities obtained in regions with unknown and with known Al-concentration x, respectively. We show that estimation of the specimen thickness combined with evaluation of intensity ratios allows quantitative measurement of the composition x. In high-resolution images we find that the image intensity is well described by simulation if the simulated image is convoluted with a Gaussian with a half-width at half-maximum of 0.07 nm.

Investigations of voids in the aragonite platelets of nacre.

We studied the structure of the aragonite platelets of Haliotis laevigata nacre, using conventional transmission electron microscopy, Z-contrast, electron tomography, energy-dispersive X-ray analysis and electron energy-loss spectroscopy. We observed faceted voids several nanometers wide within the aragonite platelets. The electron tomography investigations showed that the voids are distributed more or less randomly in the studied specimen and allowed an estimation of the order of magnitude of the width and the volumetric content of the voids. Further investigations of these voids revealed that they contain an increased amount of carbon, which suggests the existence of organic material within the voids.

Correlation of the orientation of stacked aragonite platelets in nacre and their connection via mineral bridges.

In this work, we studied the correlation of the orientation of stacked aragonite platelets of Haliotis laevigata nacre, using selected area diffraction (SAD) in transmission electron microscopy (TEM). From the position of the center of Laue circle (COLC) within the diffraction patterns the tilt angles of the investigated platelets relatively to a reference platelet (oriented in zone axis) are determined. The strong correlation of the platelets supports the existence of mineral bridges, which connect the stacked platelets and enable a transfer of the platelet orientation during growth. Electron tomography and subsequent reconstruction of the obtained data yield information about the shape of the mineral bridges. The crystalline structure of the material within the mineral bridges was investigated by high resolution TEM (HRTEM).