Effects of multi-media partitioning of chemicals on Junge's variability-lifetime relationship

Junge's variability-lifetime relationship describes the relation between the tropospheric residence time of a volatile trace gas and the coefficient of variation of the tropospheric mixing ratio at a remote location. However, no unique or universal quantification of this relationship exists. It can only be derived on a case-by-case basis for consistent data sets on substances with similar source and sink patterns. Using a multi-media model of the long-range transport of organic compounds, we determine variability-lifetime relationships for volatile substances. Next, we demonstrate how the variability-lifetime relationship can be obtained for semi-volatile organic compounds (SOCs) with the model and we investigate typical deviations from the Junge relationship for volatile compounds that are caused by the multi-media partitioning of SOCs. One cause of deviation from this relationship is substances undergoing significant transport in water so that their distribution in air is noticeably influenced by their distribution in water. The other, wider, deviation is caused by substances with a strong tendency for deposition and re-volatilization. Finally, we address the comparison of the model results with field data. Preliminary analyses of long-term monitoring data for polychlorinated biphenyls at remote sites have shown that the identification of Junge relationships in field data is not straightforward. We discuss possible strategies for the derivation of Junge relationships from field data on SOCs.     

Tumor Infiltration with CD20+CD73+ B Cells Correlates with Better Outcome in Colorectal Cancer

Immunotherapy has become increasingly important in the treatment of colorectal cancer (CRC). Currently, CD73, also known as ecto-5′-nucleotidase (NT5E), has gained considerable interest as a potential therapeutic target. CD73 is one of the key enzymes catalyzing the conversion of extracellular ATP into adenosine, which in turn exerts potent immune suppressive effects. However, the role of CD73 expression on various cell types within the CRC tumor microenvironment remains unresolved. The expression of CD73 on various cell types has been described recently, but the role of CD73 on B-cells in CRC remains unclear. Therefore, we analyzed CD73 on B-cells, especially on tumor-infiltrating B-cells, in paired tumor and adjacent normal tissue samples from 62 eligible CRC patients. The highest expression of CD73 on tumor-infiltrating B-cells was identified on class-switched memory B-cells, followed by naive B-cells, whereas no CD73 expression was observed on plasmablasts. Clinicopathological correlation analysis revealed that higher CD73⁺ B-cells infiltration in the CRC tumors was associated with better overall survival. Moreover, metastasized patients showed a significantly decreased number of tumor-infiltrating CD73⁺ B-cells. Finally, neoadjuvant therapy correlated with reduced CD73⁺ B-cell numbers and CD73 expression on B-cells in the CRC tumors. As promising new immune therapies are being developed, the role of CD73⁺ B-cells and their subsets in the development of colorectal cancer should be further explored to find new therapeutic options.     

Hyperinsulinemic Hypoglycemia Associated with a CaV1.2 Variant with Mixed Gain- and Loss-of-Function Effects

The voltage-dependent L-type calcium channel isoform Ca_V1.2 is critically involved in many physiological processes, e.g., in cardiac action potential formation, electromechanical coupling and regulation of insulin secretion by beta cells. Gain-of-function mutations in the calcium voltage-gated channel subunit alpha 1 C (CACNA1C) gene, encoding the Ca_V1.2 α₁-subunit, cause Timothy syndrome (TS), a multisystemic disorder that includes autism spectrum disorders and long QT (LQT) syndrome. Strikingly, TS patients frequently suffer from hypoglycemia of yet unproven origin. Using next-generation sequencing, we identified a novel heterozygous CACNA1C mutation in a patient with congenital hyperinsulinism (CHI) and associated hypoglycemic episodes. We characterized the electrophysiological phenotype of the mutated channel using voltage-clamp recordings and in silico action potential modeling experiments. The identified Ca_V1.2^L566P mutation causes a mixed electrophysiological phenotype of gain- and loss-of-function effects. In silico action potential modeling supports that this mixed electrophysiological phenotype leads to a tissue-specific impact on beta cells compared to cardiomyocytes. Thus, CACNA1C variants may be associated with non-syndromic hyperinsulinemic hypoglycemia without long-QT syndrome, explained by very specific electrophysiological properties of the mutated channel. We discuss different biochemical characteristics and clinical impacts of hypoglycemia in the context of CACNA1C variants and show that these may be associated with significant morbidity for Timothy Syndrome patients. Our findings underline that the potential of hypoglycemia warrants careful attention in patients with CACNA1C variants, and such variants should be included in the differential diagnosis of non-syndromic congenital hyperinsulinism.     

The Oncolytic Adenovirus XVir-N-31, in Combination with the Blockade of the PD-1/PD-L1 Axis,Conveys Abscopal Effects in a Humanized Glioblastoma Mouse Model

Glioblastoma (GBM) is an obligatory lethal brain tumor with a median survival, even with the best standard of care therapy, of less than 20 months. In light of this fact, the evaluation of new GBM treatment approaches such as oncolytic virotherapy (OVT) is urgently needed. Based on our preliminary preclinical data, the YB-1 dependent oncolytic adenovirus (OAV) XVir-N-31 represents a promising therapeutic agent to treat, in particular, therapy resistant GBM. Preclinical studies have shown that XVir-N-31 prolonged the survival of GBM bearing mice. Now using an immunohumanized mouse model, we examined the immunostimulatory effects of XVir-N-31 in comparison to the wildtype adenovirus (Ad-WT). Additionally, we combined OVT with the inhibition of immune checkpoint proteins by using XVir-N-31 in combination with nivolumab, or by using a derivate of XVir-N-31 that expresses a PD-L1 neutralizing antibody. Although in vitro cell killing was higher for Ad-WT, XVir-N-31 induced a much stronger immunogenic cell death that was further elevated by blocking PD-1 or PD-L1. In vivo, an intratumoral injection of XVir-N-31 increased tumor infiltrating lymphocytes (TILs) and NK cells significantly more than Ad-WT not only in the virus-injected tumors, but also in the untreated tumors growing in the contralateral hemisphere. This suggests that for an effective treatment of GBM, immune activating properties by OAVs seem to be of greater importance than their oncolytic capacity. Furthermore, the addition of immune checkpoint inhibition (ICI) to OVT further induced lymphocyte infiltration. Consequently, a significant reduction in contralateral non-virus-injected tumors was only visible if OVT was combined with ICI. This strongly indicates that for an effective eradication of GBM cells that cannot be directly targeted by an intratumoral OV injection, additional ICI therapy is required.     

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.