Overview of the PALM model system 6.0

In this paper, we describe the PALM model system 6.0. PALM (formerly an abbreviation for Parallelized Large-eddy Simulation Model and now an independent name) is a Fortran-based code and has been applied for studying a variety of atmospheric and oceanic boundary layers for about 20 years. The model is optimized for use on massively parallel computer architectures. This is a follow-up paper to the PALM 4.0 model description in Maronga et al. (2015). During the last years, PALM has been significantly improved and now offers a variety of new components. In particular, much effort was made to enhance the model with components needed for applications in urban environments, like fully interactive land surface and radiation schemes, chemistry, and an indoor model. This paper serves as an overview paper of the PALM 6.0 model system and we describe its current model core. The individual components for urban applications, case studies, validation runs, and issues with suitable input data are presented and discussed in a series of companion papers in this special issue.Peer reviewe

Thermally Activated Gold-Mediated Transition Metal Dichalcogenide Exfoliation and a Unique Gold-Mediated Transfer

Layered materials like transition metal dichalcogenides (TMDCs) enable exciting new physics in their 2D limit. Combined with successful demonstrations of 2D transistors and devices, the need for high-quality large-scale monolayers increases. In this light, scalable gold-mediated exfoliations attract broad attention to supersede the traditional scotch tape method as a means for high-quality materials. Gold proved to be suitably adhesive for the exfoliation of several 2D materials, including TMDCs. Previously reported methods rely on a simple press and peel mechanism. However, herein, a gold-mediated exfoliation enabled by low-temperature annealing is presented for the first time. This simple modification potentially increases the range of external conditions under which gold-mediated exfoliations operate in a robust manner. The exfoliation achieves scaling with parent crystal areas, rendering it on par with previously reported methods. On top of that, a unique gold-mediated transfer concept is introduced, where gold is repurposed as a metallic (polymer-free) transfer membrane. The transfer allows the deterministic and clean relocation of the exfoliated monolayers onto technologically relevant substrates like SiO2/Si. The process is benchmarked using MoS2 as the prototypical TMDC and monolayer areas up to ≈80 mm2 are successfully exfoliated and transferred.Peer Reviewe

A Porous Azatruxene Covalent Organic Framework as Positive Electrode Materials in Li- and Mg-based Batteries

Covalent-organic frameworks (COFs) containing well-defined redox-active groups have become competitive materials for next-generation batteries. Although a high rate performance can be expected, only few examples of p-type COFs have been reported for charge storage to date, with even fewer examples showing the use of COFs in multivalent ion batteries. Herein, we report the synthesis of an azatruxene-based COF and its application as positive electrode material in Li- and Mg-based batteries. Through solvothermal condensation a highly porous and crystalline COF was obtained, as confirmed by N2 adsorption and powder X-ray diffraction (PXRD). The electron-rich azatruxene monomer shows up to three reversible one-electron oxidations making it an attractive material for anion storage. When this material is utilized in Li-based cells as a COF/CNT electrode, an average discharge potential of 3.9 V is obtained with discharge capacities of up to 70 mA h g−1 at a 2C rate. In Mg batteries using a tetrakis(hexafluoroisopropyloxy) borate electrolyte cycling proceeds with an average discharge voltage of 2.9 V. Even at a fast current rate of 5C, the capacity retention amounts to 84% over 1000 cycles, and the cells deliver an energy density of 112 W h kg−1

Detection of a novel truncating Merkel cell polyomavirus large T antigen deletion in chronic lymphocytic leukemia cells

Merkel cell polyomavirus (MCPyV) is detected in approximately 80% of Merkel cell carcinomas (MCC). Yet, clonal integration and truncating mutations of the large T antigen (LTAg) of MCPyV are restricted to MCC. We tested the presence and mutations of MCPyV in highly purified leukemic cells of 70 chronic lymphocytic leukemia (CLL) patients. MCPyV was detected in 27.1% (n = 19) of these CLL cases. In contrast, MCPyV was detected only in 13.4% of normal controls (P < .036) in which no LTAg mutations were found. Mutational analyses revealed a novel 246bp LTAg deletion in the helicase gene in 6 of 19 MCPyV-positive CLL cases. 2 CLL cases showed concomitant mutated and wild-type MCPyV. Immunohistochemistry revealed protein expression of the LTAg in MCPyV-positive CLL cases. The detection of MCPyV, including LTAg deletions and LTAg expression in CLL cells argues for a potential role of MCPyV in a significant subset of CLL cases. (Blood. 2010;116(24):5280-5284

Inhibition of Protein Geranylgeranylation Specifically Interferes with CD40-Dependent B Cell Activation, Resulting in a Reduced Capacity To Induce T Cell Immunity

Ab-independent effector functions of B cells, such as Ag presentation and cytokine production, have been shown to play an important role in a variety of immune-mediated conditions such as autoimmune diseases, transplant rejection, and graft-versus-host disease. Most current immunosuppressive treatments target T cells, are relatively unspecific, and result in profound immunosuppression that places patients at an increased risk of developing severe infections and cancer. Therapeutic strategies, which interfere with B cell activation, could therefore be a useful addition to the current immunosuppressive armamentarium. Using a transcriptomic approach, we identified upregulation of genes that belong to the mevalonate pathway as a key molecular event following CD40-mediated activation of B cells. Inhibition of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme of the mevalonate pathway, by lipophilic statins such as simvastatin and atorvastatin resulted in a specific inhibition of B cell activation via CD40 and impaired their ability to act as stimulatory APCs for allospecific T cells. Mechanistically, the inhibitory effect resulted from the inhibition of protein geranylgeranylation subsequent to the depletion of mevalonate, the metabolic precursor for geranylgeranyl. Thus, inhibition of geranylgeranylation either directly through geranylgeranyl transferase inhibitors or indirectly through statins represents a promising therapeutic approach for the treatment of diseases in which Ag presentation by B cells plays a role

The scaffold protein NEDD9 is necessary for leukemia-cell migration and disease progression in a mouse model of chronic lymphocytic leukemia

The scaffold protein NEDD9 is frequently upregulated and hyperphosphorylated in cancers, and is associated with poor clinical outcome. NEDD9 promotes B-cell adhesion, migration and chemotaxis, pivotal processes for malignant development. We show that global or B-cell-specific deletion of Nedd9 in chronic lymphocytic leukemia (CLL) mouse models delayed CLL development, markedly reduced disease burden and resulted in significant survival benefit. NEDD9 was required for efficient CLL cell homing, chemotaxis, migration and adhesion. In CLL patients, peripheral NEDD9 expression was associated with adhesion and migration signatures as well as leukocyte count. Additionally, CLL lymph nodes frequently expressed high NEDD9 levels, with a subset of patients showing NEDD9 expression enriched in the CLL proliferation centers. Blocking activity of prominent NEDD9 effectors, including AURKA and HDAC6, effectively reduced CLL cell migration and chemotaxis. Collectively, our study provides evidence for a functional role of NEDD9 in CLL pathogenesis that involves intrinsic defects in adhesion, migration and homing

Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia

Deciphering the evolution of cancer cells under therapeutic pressure is a crucial step to understand the mechanisms that lead to treatment resistance. To this end, we analyzed whole-exome sequencing data of eight chronic lymphocytic leukemia (CLL) patients that developed resistance upon BCL2-inhibition by venetoclax. Here, we report recurrent mutations in BTG1 (2 patients) and homozygous deletions affecting CDKN2A/B (3 patients) that developed during treatment, as well as a mutation in BRAF and a high-level focal amplification of CD274 (PD-L1) that might pinpoint molecular aberrations offering structures for further therapeutic interventions