Getting a Grip on the Undrugged: Targeting β-Catenin with Fragment-Based Methods

Aberrant WNT pathway activation, leading to nuclear accumulation of β-catenin, is a key oncogenic driver event. Mutations in the tumor suppressor gene APC lead to impaired proteasomal degradation of β-catenin and subsequent nuclear translocation. Restoring cellular degradation of β-catenin represents a potential therapeutic strategy. Here, we report the fragment-based discovery of a small molecule binder to β-catenin, including the structural elucidation of the binding mode by X-ray crystallography. The difficulty in drugging β-catenin was confirmed as the primary screening campaigns identified only few and very weak hits. Iterative virtual and NMR screening techniques were required to discover a compound with sufficient potency to be able to obtain an X-ray co-crystal structure. The binding site is located between armadillo repeats two and three, adjacent to the BCL9 and TCF4 binding sites. Genetic studies show that it is unlikely to be useful for the development of protein–protein interaction inhibitors but structural information and established assays provide a solid basis for a prospective optimization towards β-catenin proteolysis targeting chimeras (PROTACs) as alternative modality.     

Hybrid Devices by Selective and Conformal Deposition of PtSe2 at Low Temperatures

2D materials display very promising intrinsic material properties, with multiple applications in electronics, photonics, and sensing. In particular layered platinum diselenide has shown high potential due to its layer-dependent tunable bandgap, low-temperature growth, and high environmental stability. Here, the conformal and area selective (AS) low-temperature growth of layered PtSe₂ is presented defining a new paradigm for 2D material integration. The thermally-assisted conversion of platinum which is deposited by AS atomic layer deposition to PtSe₂ is demonstrated on various substrates with a distinct 3D topography. Further the viability of the approach is presented by successful on-chip integration of hybrid semiconductor devices, namely by the manufacture of a highly sensitive ammonia sensors channel with 3D topography and fully integrated infrared-photodetectors on silicon photonics waveguides. The presented methodologies of conformal and AS growth therefore lay the foundation for new design routes for the synthesis of more complex hybrid structures with 2D materials.     

Prevention of Bone Destruction by Mechanical Loading Is Not Enhanced by the Bruton’s Tyrosine Kinase Inhibitor CC-292 in Myeloma Bone Disease

Limiting bone resorption and regenerating bone tissue are treatment goals in myeloma bone disease (MMBD). Physical stimuli such as mechanical loading prevent bone destruction and enhance bone mass in the MOPC315.BM.Luc model of MMBD. It is unknown whether treatment with the Bruton’s tyrosine kinase inhibitor CC-292 (spebrutinib), which regulates osteoclast differentiation and function, augments the anabolic effect of mechanical loading. CC-292 was administered alone and in combination with axial compressive tibial loading in the MOPC315.BM.Luc model for three weeks. However, neither CC-292 alone nor its use in combination with mechanical loading was more effective in reducing osteolytic bone disease or rescuing bone mass than mechanical stimuli alone, as evidenced by microcomputed tomography (microCT) and histomorphometric analysis. Further studies are needed to investigate novel anti-myeloma and anti-resorptive strategies in combination with physical stimuli to improve treatment of MMBD.     

A computational model for molecular interactions between curved slender fibers undergoing large 3D deformations with a focus on electrostatic,van der Waals,and repulsive steric forces

This contribution proposes the first three-dimensional (3D) beam-beam interaction model for molecular interactions between curved slender fibers undergoing large deformations. While the general model is not restricted to a specific beam formulation, in the present work, it is combined with the geometrically exact beam theory and discretized via the finite element method. A direct evaluation of the total interaction potential for general 3D bodies requires the integration of contributions from molecule or charge distributions over the volumes of the interaction partners, leading to a six-dimensional integral (two nested 3D integrals) that has to be solved numerically. Here, we propose a novel strategy to formulate reduced section-section interaction laws for the resultant interaction potential between a pair of cross-sections of two slender fibers such that only two one-dimensional integrals along the fibers' length directions have to be solved numerically. This section-section interaction potential (SSIP) approach yields a significant gain in efficiency, which is essential to enable the simulation of relevant time and length scales for many practical applications. In a first step, the generic structure of SSIP laws, which is suitable for the most general interaction scenario (eg, fibers with arbitrary cross-section shape and inhomogeneous atomic/charge density within the cross-section) is presented. Assuming circular, homogeneous cross-sections, in a next step, specific analytical expressions for SSIP laws describing short-range volume interactions (eg, van der Waals (vdW) or steric interactions) and long-range surface interactions (eg, Coulomb interactions) are proposed. Besides ready-to-use expressions for the total interaction potential, also the resulting virtual work contributions, its finite element discretizations, as well as a suitable numerical regularization for the limit of zero separation are derived. The validity of the SSIP laws, as well as the accuracy and robustness of the general SSIP approach to beam-beam interactions, is thoroughly verified by means of a set of numerical examples considering steric repulsion, electrostatic, or vdW adhesion.     

ZnO-based single crystal-polycrystal structures for piezotronic applications

Electrostatic potential barriers at doped ZnO-ZnO interfaces can be modified by stress-induced polarization charges. This concept was enhanced by preparing ZnO-based single crystal-polycrystal-single crystal structures by diffusion bonding. Increasing time for epitaxial solid-state transformation results in structures with a decreasing thickness of residual polycrystalline material in between two well-oriented single crystals. Microstructural and electrical analysis quantifies the influence of high-temperature treatment during epitaxial growth on the stress sensitivity of the prepared structures. The orientation of the single crystals is defined to maximize the interaction between stress-induced polarization charges and the potential barriers at doped ZnO-ZnO interfaces. With decreasing thickness of residual polycrystalline material, the percentage of grain boundaries with favorably aligned polarization vectors is increased resulting in a higher stress sensitivity. This effect is compensated by an adverse effect of the high-temperature treatment on the initial potential barrier height. Hence, a maximum in stress sensitivity can be observed for intermediate times of epitaxial growth. The prepared structures close the gap between the varistor piezotronics based on bulk ceramics with random orientation of the polarization vector and the bicrystal piezotronics with perfect orientation of the polarization vector, demonstrating the capability of microstructural engineering for varistor-based piezotronic devices.     

Counselor Language Entry and Response (CLEAR) system: Do you hear what I hear?

The profession of counseling and psychotherapy developed its own language by borrowing from the vernacular and, in so doing, altered meanings of words in idiosyncratic ways. In the examination of the language of counseling presented here, rigorous and painstaking analysis of counselor-client interactions at different levels of counseling proficiency inspired the development of the Counselor Language Entry and Response (CLEAR) system. This system incorporates various formulas to generate counselor responses appropriate for the intent and experience level of the professional. Preliminary work with the CLEAR system reveals verbal stratagems such as core phrases and phrase enhancers concocted to amaze and stupefy both the uninitiated and experienced client-pilgrim on that inner journey toward psychological growth. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Biopebbles: DNA‐Functionalized Core–Shell Silica Nanospheres for Cellular Uptake and Cell Guidance Studies

The development of a versatile class of silica nanoparticles for cell studies is reported. The particles contain a fluorescent dye‐encoded core and a single‐stranded DNA oligonucleotide‐displaying shell. They are accessible in arbitrary size and color through robust protocols for Stöber‐based colloidal synthesis and sturdy chemical surface functionalization. Silica particles in the size range of 100 nm to 1.5 µm diameter containing fluorescein, Cy3 oder Cy5 dye‐encoded cores are synthesized and functionalized with DNA oligonucleotides. These silica biopebbles are conveniently traceable by microscopy and have a high affinity to live cells, which makes them ideal for cell uptake studies, as demonstrated for MCF7 and A431 cancer cells. The biopebbles can be utilized as building blocks for the self‐assembled formation of arbitrary surface patterns on glass substrates. With these architectures, the privileged internalization of the biopebbles can be exploited for improved adhesion and guidance of cells because the particles are no longer ingested by adhered cells due to their physical connection with the solid support. It is believed that the biopebble approach will be useful for a variety of applications, fundamental studies in cell biology and tissue engineering.     

Polyoxometalate Modified Separator for Performance Enhancement of Magnesium–Sulfur Batteries

The magnesium–sulfur (Mg-S) battery has attracted considerable attention as a candidate of post-lithium battery systems owing to its high volumetric energy density, safety, and cost effectiveness. However, the known shuttle effect of the soluble polysulfides during charge and discharge leads to a rapid capacity fade and hinders the realization of sulfur-based battery technology. Along with the approaches for cathode design and electrolyte formulation, functionalization of separators can be employed to suppress the polysulfide shuttle. In this study, a glass fiber separator coated with decavanadate-based polyoxometalate (POM) clusters/carbon composite is fabricated by electrospinning technique and its impacts on battery performance and suppression of polysulfide shuttling are investigated. Mg–S batteries with such coated separators and non-corrosive Mg[B(hfip)₄]₂ electrolyte show significantly enhanced reversible capacity and cycling stability. Functional modification of separator provides a promising approach for improving metal–sulfur batteries.     

The Cooperation Paradox

Dominant American online platforms like Amazon Alexa or Google Assistant have become Life Control Interfaces (LCIs), which facilitate consumers’ online interactions and influence what consumers do and do not see and buy. These platforms operate outside of EU regulation, and create significant costs for traditional European firms in a wide range of industries. These platforms can reduce firms’ access to customers, can charge for enabling access to customers, or can charge for access to essential data on firms’ customers. Since these platforms enjoy monopoly power there is little restraint on their charges, which indirectly increase consumers’ prices. We propose that regulators encourage the formation of a consortium to offer a single integrated EU-based Life Control Interface (EuLCI). This consortium would increase the number of EuLCIs from zero to one, and thus would actually increase consumer choice. We call cooperation that enhances rather than limits choice The Cooperation Paradox.

     

Correction to: Social Welfare Computing and the management and regulation of new online business models

Electronic Markets -