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The optical energy input during laser-based powder bed fusion of polymers (PBF-LB/P) is influenced by a variety of process parameters (e.g., energy density) and powder material properties (e.g. optical properties, additives). Qualification of newly developed and/or modified powder materials still requires extensive, empirical parameter studies to assess processibility and find suitable process strategies. For powder characterization, a double-integrating-sphere system with an intervening hot stage, which allows accurate sample heating during the measurement of the optical properties, is presented and described. For qualification of the system and the associated characterization method for the PBF-LB/P process, the interaction of a collimated CO2 laser beam with selected polyamide powder materials during heating and cooling is investigated. The obtained results illustrate the suitability of the presented thermo-optical characterization technique, i.e., the temperature-dependent measurement of radiation reflected by and transmitted through the samples, for the systematical investigation of material-related (i.e., additives) and process-related (i.e., preheating temperature, layer height) influences on the beam-matter interaction.

MALT1 plays a central role in immune cell activation by transducing NF-κB signaling, and its proteolytic activity represents a key node for therapeutic intervention. Two cycles of scaffold morphing of a high-throughput biochemical screening hit resulted in the discovery of MLT-231, which enabled the successful pharmacological validation of MALT1 allosteric inhibition in preclinical models of humoral immune responses and B-cell lymphomas. Herein, we report the structural activity relationships (SARs) and analysis of the physicochemical properties of a pyrazolopyrimidine-derived compound series. In human T-cells and B-cell lymphoma lines, MLT-231 potently and selectively inhibits the proteolytic activity of MALT1 in NF-κB-dependent assays. Both in vitro and in vivo profiling of MLT-231 support further optimization of this in vivo tool compound toward preclinical characterization.

Energy density, scanning strategy and laser spot size are some of the parameters influencing the optical energy input during laser-based powder bed fusion of polymers. For newly developed polymer powders, such parameters must still be determined empirically. Understanding the complex mechanisms underlying the beam-matter interaction, including absorption characteristics or multiple scattering behavior, is crucial to predict material processability and to improve interlayer fusion for enhanced final part properties. A measurement system based on two integrating spheres is employed to analyze the scattering processes during the interaction of a CO2 laser beam with polymeric powder materials. The setup is used to measure total reflection from the sample surface as well as unscattered and diffuse transmission through the sample. The resulting optical properties of polyamide 12 powder are evaluated and compared to those of thin films of the same base material. Thus, the influence of particle interfaces on the energy deposition characteristics can be analyzed qualitatively.

Arctic Ocean properties and processes are highly relevant to the regional and global coupled climate system, yet still scarcely observed, especially in winter. Team OCEAN conducted a full year of physical oceanography observations as part of the Multidisciplinary drifting Observatory for the Study of the Arctic Climate (MOSAiC), a drift with the Arctic sea ice from October 2019 to September 2020. An international team designed and implemented the program to characterize the Arctic Ocean system in unprecedented detail, from the seafloor to the air-sea ice-ocean interface, from sub-mesoscales to pan-Arctic. The oceanographic measurements were coordinated with the other teams to explore the ocean physics and linkages to the climate and ecosystem. This paper introduces the major components of the physical oceanography program and complements the other team overviews of the MOSAiC observational program. Team OCEAN’s sampling strategy was designed around hydrographic ship-, ice- and autonomous platform-based measurements to improve the understanding of regional circulation and mixing processes. Measurements were carried out both routinely, with a regular schedule, and in response to storms or opening leads. Here we present along-drift time series of hydrographic properties, allowing insights into the seasonal and regional evolution of the water column from winter in the Laptev Sea to early summer in Fram Strait: freshening of the surface, deepening of the mixed layer, increase in temperature and salinity of the Atlantic Water. We also highlight the presence of Canada Basin deep water intrusions and a surface meltwater layer in leads. MOSAiC most likely was the most comprehensive program ever conducted over the ice-covered Arctic Ocean. While data analysis and interpretation are ongoing, the acquired datasets will support a wide range of physical oceanography and multi-disciplinary research. They will provide a significant foundation for assessing and advancing modeling capabilities in the Arctic Ocean.

The development of acute thrombosis within the TIPS tract may be prevented by prophylactic anticoagulation; however, there is no evidence of the correct anticoagulation regimen after TIPS placement. The purpose of this single-center retrospective study was to evaluate the short-term occlusion rate of transjugular intrahepatic portosystemic shunts (TIPSs) with polytetrafluorethylene (PTFE)-coated stents under consequent periprocedural full heparinization (target partial thromboplastin time [PTT]: 60–80 s). We analyzed TIPS placements that were followed up over a six-month period by Doppler ultrasound in 94 patients and compared the study group of 54 patients who received intravenous periprocedural full heparinization (target PTT: 60–80 s) without any other anticoagulation to patients with prolonged anticoagulation medication. The primary endpoint was TIPS patency after six months. The primary patency rate was 88.3% overall, and in the study group, 90.7%, with an early thrombosis rate of 3.2% (study group: 1.9%) and a primary assisted patency rate of 95.7% (study group: 96.3%). In the study group, one case of TIPS thrombosis occurred on the 23rd day after TIPS placement. Two patients underwent reintervention because of stenosis or buckling. Moreover, the target PTT was not attained in 8 of the 54 patent TIPSs. Four patients had an increased portosystemic pressure gradient, without stenosis, and the flow rate was corrected by increasing the TIPS diameter by dilation. Two-day heparinization seems sufficient to avoid early TIPS thrombosis over a six-month period.

Die Steigerung der elektromagnetischen Ausnutzung elektrischer Maschinen ist im Wesentlichen durch eine Erhöhung des Strombelages möglich. Die Belastungsgrenze resultiert u. a. aus der maximal zulässigen Temperatur der Wicklungsisolation. Aus der geringen spezifischen thermischen Leitfähigkeit herkömmlicher Isolierwerkstoffe resultieren große Temperaturgradienten im Wicklungsquerschnitt und es kommt zur Bildung von Hotspots z. B. in den Wicklungsköpfen. Im Beitrag werden die Entwicklung und die Charakterisierung von Polysiloxan-Kompositen mit keramischen Füllstoffen vorgestellt. Im Vergleich zu herkömmlichen Isoliermaterialen kann die spezifische thermische Leitfähigkeit damit etwa um den Faktor fünf gesteigert werden. Die Materialien werden für die Herstellung der Hauptisolation des Elektroblechpaketes in einem Tauchprozess sowie die Vakuum-Imprägnierung der Wicklung eingesetzt. Für einen elektrischen Radnabenantrieb werden die erwartete Wicklungstemperaturreduzierung und die daraus resultierende mögliche Leistungsdichtesteigerung diskutiert. The increase of the electromagnetic utilisation of electrical machines is essentially achievable by increasing the electric load. The power limit results from the maximum permissible temperature of the winding insulation. The low specific thermal conductivity of conventional insulating materials results in large temperature gradients in the winding cross section and the appearance of hotspots in the end windings. The paper discusses the development and characterisation of polysiloxane composites with ceramic fillers. Compared to conventional insulating materials, therewith the specific thermal conductivity can be increased by a factor of five. The materials are used for the production of the main insulation of the laminated core in a dipping process and the vacuum impregnation of the winding. For an electric wheel hub motor, the expected winding temperature reduction and the possible power density increase are discussed.

During the past years additive manufacturing (AM) has revolutionized the manufacturing world by enabling rapid generation of geometrically-intricate designs. However, up to now in laser and beam-based AM of polymers only single powder materials whether filled or pure plastics can be processed. One aim of the Collaborative Research Center 814 (CRC 814) – Additive Manufacturing is to establish new process technologies to produce multi-material polymer parts in AM. Therefore, two different strategies basing on Laser Sintering (LS) will be explored: On the one side, selective powder deposition technologies like vibrating nozzles or electrophotography are investigated, which enable to lay down different powders beside each other in one process. On the other side, a liquid reactive UV-curing thermoset is implemented into the LS process chamber. After curing of the UV-curing thermoset the powder beside the cured thermoset is molten by the use of the CO2 laser. Both strategies allow the generation of multi-material parts consisting of material regions with different functional properties.

Social cohesion plays a key role in processes of peacebuilding and sustainable development. Fostering social cohesion might present a potential to enhance the connection of natural resource management and peacebuilding and better functioning of sustainable land use systems. This contribution explores the nexus between social cohesion, natural resource management, and peacebuilding. We do so by (1) reviewing literature on the three concepts and (2) studying four different key action areas in the context of sustainable cocoa production for their potential to enhance social cohesion, namely (a) agroforestry; (b) cooperatives; (c) certification schemes; and (d) trade policies. Research is based on experience from cocoa production in two post-conflict countries, C��te d���Ivoire and Colombia. Our findings show that by fostering environmentally sustainable agricultural practices, these key action areas have a clear potential to foster social cohesion among cocoa producers and thus provide a valuable contribution to post-conflict peacebuilding in both countries. However, the actual effects strongly depend on a multitude of local factors which need to be carefully taken into consideration. Further, the focus in implementation of some of these approaches tends to be on increasing agricultural productivity and not directly on fostering cocoa farmers��� wellbeing and societal relations, and hence a shift toward social objectives is needed in order to strengthen these approaches as a part of overall peacebuilding strategies.

In this paper, calculation models and measurement results of squirrel-cage induction machines with copper cage and axially segmented end rings produced by an optimized manufacturing process are presented. The design of the copper-bar rotor winding is based on an analytical calculation approach that takes into account the technologically and electrically interconnection between rotor bars and segmented short-circuit rings according to the applied laser and electron beam welding process. Rotors with aluminum and copper short-circuit cages manufactured by die-casting serve as a basis for comparison. Based on the separation of losses as well as no-load, load and short-circuit measurements, the influences of the optimized production process using laser welding and the cage material on the efficiency and the operating behavior are discussed. In addition, aspects of mechanical high-speed performance for application in electric mobility are considered by means of overspeed tests of prototype rotors. Moreover, numerical models are derived to describe the electromagnetic behavior of segmented rotor cages. Using numerical 3D field calculation, the current and loss densities, which are particularly important in the interconnection between rotor bars and short-circuit end rings, are determined. With the aim of increasing the accuracy of the design process, analytical calculation approaches for the most accurate consideration of the welded joint in the short circuit ring are presented.

International audience; Already in the middle of the last century, concepts were described which show that electrostatic transducers come closest to the ideal of distortion-free audio reproduction. Only years later - with the availability of the appropriate materials and manufacturing techniques - could these concepts be put into practice and enjoy great popularity in high-quality audiophile loudspeakers and headphones. In this paper, a MEMS actuator is presented which, due to its symmetrical design, opens up these advantageous properties for electrostatically actuated MEMS speakers: The actuator consists of an elastic beam with several electrostatically actuated cells. By the application of an electrostatic field a bending moment is generated, which leads to a bending of the beam by a suitable beam design and a suitable number of electrostatic cells. This so-called NED principle (NED: Nanoscopic Electrostatic Drive) enables deflections which are many times higher than the usable deflection of the individual electrodes limited by the pull-in to approx. 1/3 of the electrode gap. Compared to asymmetrical actuators, the proportion of second harmonics can be significantly reduced by a symmetrical actuator design. A micro speaker based on a large number of symmetrically designed NED actuators is presented in this paper and results of electrical, optical and acoustic measurements are discussed.

MALT1 plays a central role in immune cell activation by transducing NF-κB signaling, and its proteolytic activity represents a key node for therapeutic intervention. Two cycles of scaffold morphing of a high-throughput biochemical screening hit resulted in the discovery of MLT-231, which enabled the successful pharmacological validation of MALT1 allosteric inhibition in preclinical models of humoral immune responses and B-cell lymphomas. Herein, we report the structural activity relationships (SARs) and analysis of the physicochemical properties of a pyrazolopyrimidine-derived compound series. In human T-cells and B-cell lymphoma lines, MLT-231 potently and selectively inhibits the proteolytic activity of MALT1 in NF-κB-dependent assays. Both

This article summarizes the evolution of the screening deck at the Novartis Institutes for BioMedical Research (NIBR). Historically, the screening deck was an assembly of all available compounds. In 2015, we designed a first deck to facilitate access to diverse subsets with optimized properties. We allocated the compounds as plated subsets on a 2D grid with property based ranking in one dimension and increasing structural redundancy in the other. The learnings from the 2015 screening deck were applied to the design of a next generation in 2019. We found that using traditional leadlikeness criteria (mainly MW, clogP) reduces the hit rates of attractive chemical starting points in subset screening. Consequently, the 2019 deck relies on solubility and permeability to select preferred compounds. The 2019 design also uses NIBR's experimental assay data and inferred biological activity profiles in addition to structural diversity to define redundancy across the compound sets.

Additive manufacturing promises high flexibility and customized product design. Powder bed fusion processes use a laser to melt a polymer powder at predefined locations and iterate the scheme to build 3D objects. The design of flowable powders is a critical parameter for a successful fabrication process that currently limits the choice of available materials. Here, a bottom-up process is introduced to fabricate tailored polymer- and composite supraparticles for powder-based additive manufacturing processes by controlled aggregation of colloidal primary particles. These supraparticles exhibit a near-spherical shape and tailored composition, morphology, and surface roughness. These parameters can be precisely controlled by the mixing and size ratio of the primary particles. Polystyrene/silica composite particles are chosen as a model system to establish structure-property relations connecting shape, morphology, and surface roughness to the adhesion within the powder, which is accessed by tensile strength measurements. The adhesive properties are then connected to powder flowability and it is shown that the resulting powders allow the formation of dense powder films with uniform coverage. Finally, successful powder bed fusion is demonstrated by producing macroscopic single layer specimens with uniform distribution of nanoscale silica additives.

Multiplexed gene-signature-based phenotypic assays are increasingly used for the identification and profiling of small molecule-tool compounds and drugs. Here we introduce a method (provided as R-package) for the quantification of the dose-response potency of a gene-signature as EC50 and IC50 values. Two signaling pathways were used as models to validate our methods: beta-adrenergic agonistic activity on cAMP generation (dedicated dataset generated for this study) and EGFR inhibitory effect on cancer cell viability. In both cases, potencies derived from multi-gene expression data were highly correlated with orthogonal potencies derived from cAMP and cell growth readouts, and superior to potencies derived from single individual genes. Based on our results we propose gene-signature potencies as a novel valid alternative for the quantitative prioritization, optimization and development of novel drugs.

Chemogenetic libraries, collections of well-defined chemical probes, provide tremendous value to biomedical research but require substantial effort to ensure diversity as well as quality of the contents. We have assembled a chemogenetic library by data mining and crowdsourcing institutional expertise. We are sharing our approach, lessons learned, and disclosing our current collection of 4,185 compounds with their primary annotated gene targets (https://github.com/Novartis/MoaBox). This physical collection is regularly updated and used broadly both within Novartis and in collaboration with external partners.

Insulating sheets, impregnants and encapsulation materials commonly used for winding insulation offer low thermal conductivities. This leads to an increased heating of the winding of electrical machines and to the existence of hotspots. The electromagnetical utilization of the machine has to be reduced with respect to the allowed maximum winding temperature. In this paper, the development and experimental investigation of novel polysiloxane composites with ceramic fillers are presented. The materials are tested by means of impregnated and encapsulated samples of a round-wire winding as well as the main insulation of electrical steel sheets and laminated cores. Numerical models are implemented for determining the equivalent thermal conductivity of the winding compound comprising the enameled wire and the impregnant. Based on the example of a permanent-magnet synchronous machine with outer-rotor in modular construction, the potential for increasing the electromagnetical utilization is shown.

As Additive Manufacturing (AM) is fast-growing, properties adaption of feedstock materials for AM is becoming more and more relevant due to high quality standards in industrial applications. Compared to traditional manufacturing techniques like injection molding, laser powder bed fusion (PBF-LB) of polymers has a very limited variety of processable materials, which is a major obstacle for future growth. Nanocomposites are an established material class for addressing the limitations in PBF-LB but often show poor dispersion of the nanomaterial in/on the polymer powder. Especially in the context of plasmonic nanomaterials and composites, where the state of aggregation considerably influences the optical properties, dispersion plays an important role. Our study presents a deeper understanding of the colloidal surface additivation of polyamide 12 (PA12) powders with laser-generated plasmonic silver nanoparticles, leading to high dispersion of the nanoparticles on the micropowder surface with good reproducibility. The additivation is ruled by colloidal stability and control of electrostatic forces between particles and resulted in powders that could successfully be processed on a PBF-LB machine to generate plasmonic-functionalized parts. Finally, we introduce the surface specific nanoparticle dose (surf%) as scaling key parameter complementary to the commonly used mass specific dose (wt%) to appropriately describe nanoparticle load, proving the effect of such surface additivation on the recrystallization behavior of PA12. Via flash calorimetry, already at 0.01 vol% silver load, significant nanoparticle-induced heterogeneous nucleation effects are evident, whereas the thermal properties analyzed by conventional calorimetry remain unaffected.

In this study, we present dissolved oxygen (DO) concentration data collected during an observational program conducted in the central Baltic Sea, six months after a Major Baltic Inflow (MBI) event from December 2014 has ended a long period of stagnation. The main working area was the Eastern Gotland Basin (EGB). The spatial distribution of DO was obtained by two ship based CTD-systems (classical CTD probe, towed undulating CTD probe) and by using a glider (Slocum), while the temporal variability of DO concentrations was revealed by a profiling mooring (GODESS - Gotland Deep Environmental Sampling Station). In this paper, we compare the performance of all platforms used and show that integrating modern oceanographic tools into an existing observation network can help to enhance the capability of the network to capture the spatiotemporal variability of DO in the Baltic Sea on both a large (seasonal; 10–500 km) and a small (diurnal; 1–10 km) scale. It was found that in comparison to a classical standard CTD system, a towed undulating CTD system (ScanFish) is better suited to resolve the meso- and submeso-scale distribution patterns of DO concentrations. In particular, in the sub-halocline layers where the variability of DO concentrations was consistently high (1–70 µM). The highly dynamic post-inflow situation was also observed by the glider and the profiling mooring. For comparison purposes four different sub-halocline layers in a depth range from 80 m to 180 m depth were defined and the mean oxygen content of these layers was calculated for both platforms. It turned out, that the mean DO concentrations for the different layers, which were determined from glider and mooring measurements, differ only slightly from each other. Differences were greatest (up to 7 µM) below the halocline (80–120m) and could be explained by the spatial and temporal variability of DO concentrations in this area and by the large response time of the gliders oxygen optode. However, the temporal development of inflow events could be determined and investigated in more detail by using autonomous platforms. The frequency and size of smaller inflows, for instance, that move along the halocline or in deeper layers thus could be evaluated.