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Simulation and X-ray experiments indicate confinement induce orientational ordering of the non-polar molecules in the vicinity of the interfaces.

Multiple Sclerosis is a chronic autoimmune neurodegenerative disorder of the central nervous system (CNS) that is characterized by inflammation, demyelination, and axonal injury leading to permeant disability. In the early stage of MS, inflammation is the primary driver of the disease progression. There remains an unmet need to develop high efficacy therapies with superior safety profiles to prevent the inflammation processes leading to disability. Herein, we describe the discovery of BIIB091, a structurally distinct orthosteric ATP competitive, reversible inhibitor that binds the BTK protein in a DFG-in confirmation designed to sequester Tyr-551, an important phosphorylation site on BTK, into an inactive conformation with excellent affinity. Preclinical studies demonstrated BIB091 to be a high potency molecule with good drug-like properties and a safety/tolerability profile suitable for clinical development as a highly selective, reversible BTKi for treating autoimmune diseases such as MS.

In order to reduce operating costs and increase the operational stability, the aviation industry is continuously introducing digital technologies to automate the state detection of their assets and derive maintenance decisions. Thus, many industry efforts and research activities have focused on an early state fault detection and the prediction of system failures. Since research has mainly been limited to the calculation of remaining useful lifetimes (RUL) and has neglected the impact on surrounding processes, changes on the objectives of the involved stakeholders, resulting from these technologies, have hardly been addressed in existing work. However, to comprehensibly evaluate the potential of a fault diagnosis and failure prognosis system, including its effects on adjacent maintenance processes, the condition monitoring system’s maturity level needs to be taken into account, expressed for example through the technology’s automation degree or the prognostic horizon (PH) for reliable failure projections. In this paper, we present key features of an automatic condition monitoring architecture for the example of a Tire Pressure Indication System (TPIS). Furthermore, we develop a prescriptive maintenance strategy by modeling the involved stakeholders of aircraft and line maintenance operations with their functional dependencies. Subsequently, we estimate the expected implications for a small aircraft fleet with the introduction of such a monitoring system with various levels of technological maturity. Additionally, we calculate the maintenance cost savings potential for different measurement strategies and compare these results to the current state-of-the-art maintenance approach. To estimate the effects of implementing an automated condition monitoring system, we use a discrete-event, agentbased simulation setup with an exemplary flight schedule and a simulated time span of 30 calendar days. The obtained results allow a comprehensive estimation of the maintenance related implications on airline operation and provide key aspects in the development of an airline’s prescriptive maintenance strategy.

A combination of several manufacturing process steps in a simultaneous manner allows to save energy costs, reduce investment and economic logistical efforts. This paper provides the contribution reports on particular research work performed by the Institute for Metal Forming Technology, which deals with gearwheel bodies manufactured by lateral extrusion (forging). The scope of this paper focuses on the joining process and achievement of desired properties for forged wheel bodies. At the beginning of the forming process, a blank is placed in a ring having an axial and tangential profile. Due to a force application on the face surface, the material flows into the ring radially and in the following, the joint provides both a form and press fit. Since the forming and joining process is conducted in one step, the lubricant for the forming process must fulfil two requirements. First, low friction for the manufacturing process is advised. On the contrary, the joint gearwheel needs to transmit the applied load during use. In order to determine the influences of two different lubricants onto both the manufacturing processes and static torque application, experimental investigations were performed

The hierarchical organization of properly sized blood vessels ensures the correct distribution of blood to all organs of the body, and is controlled via haemodynamic cues. In current concepts, an endothelium-dependent shear stress set point causes blood vessel enlargement in response to higher flow rates, while lower flow would lead to blood vessel narrowing, thereby establishing homeostasis. We show that during zebrafish embryonic development increases in flow, after an initial expansion of blood vessel diameters, eventually lead to vessel contraction. This is mediated via endothelial cell shape changes. We identify the transforming growth factor beta co-receptor endoglin as an important player in this process. Endoglin mutant cells and blood vessels continue to enlarge in response to flow increases, thus exacerbating pre-existing embryonic arterial-venous shunts. Together, our data suggest that cell shape changes in response to biophysical cues act as an underlying principle allowing for the ordered patterning of tubular organs.

The ongoing digitalization allows operators and manufacturers to constantly gain new insights about their asset’s performance and degradation status. This information could potentially help to reduce operating and maintenance costs. Although significant amount of research has been spent in determining Remaining Useful Lifetimes (RUL) of various systems, these efforts often implicitly assume an unrestricted availability of measurement data. However, the amount of acquired data significantly drives the necessary investment cost or is sometimes even impossible to obtain in required frequencies in reality. In this paper, we will investigate the changes of the precision for the RUL prognosis on the example of a Tire Pressure Indication System (TPIS). After a possible layout with sensor requirements for a fully automated condition monitoring system has been developed in theory, we describe necessary data cleansing steps to account for environmental impacts on the system’s performance and to derive the system’s health status. With the help of a Monte Carlo (MC) simulation, we evaluate the system’s sensitivity towards changes in precision of the RUL for different measurement frequencies, prognostic models, and parameter settings. The results allow an estimation of the minimum pressure measurement frequency for a fully automated TPIS in order to obtain the required prognostic performance and to maximize cost efficiency.

BACKGROUND: Non-small cell lung cancer (NSCLC) represents 80% of lung cancers, the second leading cause of cancer deaths globally. Mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are genomic drivers in a molecular sub-type of NSCLC that is sensitive to tyrosine kinase inhibitors (TKIs). Third-generation, irreversible TKIs, such as osimertinib and lazertinib, have become standard of care and are now widely used as first-line therapy in EGFR-driven metastatic NSCLC. However, resistance invariably arises during treatment. The C797S mutation is the most frequent on-target resistance mechanism in response to third-generation TKIs when used in the first-line setting. There are currently no approved therapies for patients who progress with a C797S mutation. Although first-generation TKIs inhibit EGFR with a C797S mutation, they carry liabilities of 1) insufficient selectivity over wild-type (WT) EGFR, which precludes maximal target coverage and results in dose-limiting adverse events; and 2) limited brain penetration. METHODS: BLU-701 activity was tested in biochemical assays for EGFR mutants and EGFR WT. Cellular activity was evaluated by a phosphorylation specific EGFR AlphaLisa assay in WT cell lines or those expressing EGFR mutations. The in vivo antitumor activity of BLU-701 was assessed in a PC9 ex19del cell line-derived tumor xenograft (CDX) model. RESULTS: We have developed an orally available, single-digit nanomolar, brain-penetrant, WT-sparing, reversible EGFR inhibitor that is active against the C797S resistance mutation. BLU-701 is equally potent against both the sensitizing mutations ex19del and L858R, and the resistance double mutants ex19del/C797S and L858R/C797S. BLU-701 is brain penetrant (Kpu,u >0.9) and demonstrates a selectivity over WT EGFR that compares favorably with osimertinib. Oral administration of BLU-701 to PC9 ex19del tumor-bearing mice resulted in strong and prolonged pathway suppression and tumor regression at tolerated doses. CONCLUSION: Due to its potent pharmacological activity and selectivity for mutant EGFR, BLU-701 has the potential to demonstrate activity in first-line and resistance settings as a single agent and in combination therapy, addressing potential tumor heterogeneity. The pre-clinical data described here supports the clinical development of BLU-701 in EGFR-driven NSCLC. Citation Format: Chiara Conti, John Campbell, Rich Woessner, Jian Guo, Yoav Timsit, Maria Iliou, Scott Wardwell, Alison Davis, Sharon Chicklas, John Hsieh, Meredith Eno, Omar Ahmad, Dilinie Fernando, Kevin Barvian, Joseph Kim, Steven Kazmirski, Emanuele Perola, Tom Dineen, Victoria Brown, Timothy Guzi, Ayşegül Özen, Faith Stevison, Caitlin Utt, Clare Medendorp, Robert Meissner, Marion Dorsch, Klaus Hoeflich. BLU-701 is a highly potent, brain-penetrant and WT-sparing next-generation EGFR TKI for the treatment of sensitizing (ex19del, L858R) and C797S resistance mutations in metastatic NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1262.

Today, electric mobility, weight of vehicles and costs of powertrain components continue to play an essential role. Therefore, material consumption and the type of production have a significant influence. Gears have an essential significance in mobile powertrains. In the past few years, recent developments have shown the technological potential of shaft-hub connections produced by joining by forming. In order to improve manufacturing time and costs while saving material waste, a representative two-piece design consisting of a gear ring and a gearwheelbody offers a wide variety of possibilities for individual design of the shaft-hub connection and a suitable material combination. Therefore, two process strategies have been investigated at the Institute for Metal Forming Technology in Stuttgart. First, a shaft is joined with a hub by lateral extrusion. For the second manufacturing process, a blank is placed between a gear ring and a shaft and is joined by cold forming. In order to manufacture two-piece shaft-hub-connections, a gear ring needs to be produced prior to joining. Thus, a new cold forming process has been developed to enhance the economic efficiency and material usage for manufacturing of radial gears. In this context, gear rings offering the required tolerances can be produced for the described joining process without additional machining. In this process, a sequential forming of the tooth geometry is performed, which results into a reduction of the forming force and tool load. This contribution describes the combination of both processes in order. The novel manufacturing method for an exemplary gearwheel is presented and the required forming process steps are numerically examined considering their applicability.

All higher developed organisms contain complex hierarchical networks of arteries, veins and capillaries. These constitute the cardiovascular system responsible for supplying nutrients, gas and waste exchange. Diseases related to the cardiovascular system are among the main causes for death worldwide. In order to understand the processes leading to arteriovenous malformation, we studied hereditary hemorrhagic telangiectasia (HHT), which has a prevalence of 1:5000 worldwide and causes internal bleeding. In zebrafish, HHT is induced by mutation of the endoglin gene involved in HHT and observed to reduce red blood cell (RBC) flow to intersegmental vessels (ISVs) in the tail due to malformations of the dorsal aorta (DA) and posterior cardinal vein (PCV). However, these capillaries are still functional. Changes in the blood flow pattern are observed from in vivo data from zebrafish embryos through particle image velocimetry (PIV). Wall shear rates (WSRs) and blood flow velocities are obtained non-invasively with millisecond resolution. We observe significant increases of blood flow velocity in the DA for endoglin-deficient zebrafish embryos (mutants) at 3 days post fertilization. In the PCV, this increase is even more pronounced. We identified an increased similarity between the DA and the PCV of mutant fish compared to siblings, i.e., unaffected fish. To counteract the reduced RBC flow to ISVs we implement optical tweezers (OT). RBCs are steered into previously unperfused ISVs showing a significant increase of RBC count per minute. We discuss limitations with respect to biocompatibility of optical tweezers in vivo and determination of in vivo wall shear stress (WSS) connected to normal and endoglin-deficicent zebrafish embryos.

Estimating the free energy of adsorption of materials-binding peptides is fundamental to quantify their interactions across bio/inorganic interfaces, but is difficult to achieve both experimentally and theoretically. We employ a combination of molecular dynamics (MD) simulations and dynamical force-spectroscopy experiments based on atomic force microscopy (AFM) to estimate the free energy of adsorption ΔGads of a (GCRL) tetrapeptide on amorphous SiO2 in pure water. The results of both equilibrium, advanced sampling MD and non-equilibrium, steered MD are compared with those of two different approaches used to extract ΔGads from the dependence of experimentally measured adhesion forces on the applied AFM loading rates. In order to obtain unambiguous peak forces and bond loading rates from steered MD trajectories, we have developed a novel numerical protocol based on a piecewise-harmonic fit of the adhesion work profile along each trajectory. The interpretation of the experiments has required a thorough quantitative characterization of the elastic properties of polyethylene glycol linker molecules used to tether (GCRL)15 polypeptides to AFM cantilevers, and of the polypeptide itself. All obtained ΔGads values fall within a relatively narrow window between -5 and -9 kcal mol(-1), but can be associated with large relative error bars of more than 50%. Among the different approaches compared, Replica Exchange with Solute Tempering simulations augmented with MetaDynamics (RESTMetaD) and fitting of dynamic force spectroscopy experiments with the model of Friddle and De Yoreo lead to the most reliable ΔGads estimates.

In this work we demonstrate microfabricated thin alumina nanopore membranes as a platform for impedance sensing of DNA immobilization and hybridization. We develop a wafer-scale fabrication of free-standing alumina nanopore membranes with well controlled thickness, pore diameter and overall pore density. One 1 cm x 1 cm single chip contains an array of 69 membranes. Each membrane is 100 mu m x 100 mu m large and 2 mu m thick, with pore diameter of 120 nm. With low pore density of similar to 6 pores/mu m(2), nanopore resistance and membrane capacitance can be recognized clearly in the electrochemical impedance spectrum from 100 to 1 MHz. The total surface area can be further increased by the coating of silica nanoparticles with similar to 20 nm in diameter. During the immobilization of probe ssDNA to (3-glycidoxypropyl) trimethoxysilane functionalized surface, the nanopore resistance drops significantly by 80%, whereas the membrane capacitance increases less than 2%. After hybridization with complementary DNA, the nanopore resistance increases up to 10%. Non-complementary ssDNA has no obvious effect. The detection limit is 12.5 nM in phosphate-buffered saline (PBS) solution. (C) 2015 Elsevier B.V. All rights reserved.

Shaft-hub connections, which are joined by plastic deformation of at least one component (e.g. joining by lateral extrusion), can meet today's contradictory requirements for high power densities with low manufacturing costs. As opposed to classical manufacturing methods, the tight manufacturing tolerances of shafts and hubs are not required here since the shaft is formed in the hub during the process to generate a combined frictional and positive-locking connection. However, plastic deformation generally results in an uneven distribution of contact stress, which causes negative effects such as increased hub stress and deformation, as well as the reduced transmission capacity of the connection. To overcome this effect, an iterative design approach for plastically stressed shaft-hub connections was developed in Ulrich et al. (2019)[1], in which the contact-stress distribution is influenced by contouring of the hub contact surface. Nonetheless, one major challenge in this process is the high sensitivity of the stress distribution to contour changes, particularly in the edge area of the connection, meaning that a dependency on tight manufacturing tolerances is present here, too. Therefore, an investigation is conducted to determine the extent to which deviations in the manufacturing process of the components, in the tool quality and during joining by lateral extrusion influence the resulting contact stress. In order to achieve this goal, numerical investigations are carried out, and the effects on the resulting contact-stress distribution are analysed. Finally, recommendations for manufacturing accuracy and process limits are derived in order to ensure manufacturability and enable the transfer of technology to industrial applications involving shaft-hub connections joined by lateral extrusion.

Understanding embryonic development requires the characterization of the forces and the mechanical features that shape cells and tissues within the organism. In addition, experimental application of forces on cells and altering cell and organelle shape allows determining the role such forces play in morphogenesis. Here, we present a holographic optical tweezers-based new microscopic platform for in vivo applications in the context of a developing vertebrate embryo that unlike currently used setups allows simultaneous trapping of multiple objects and rapid comparisons of viscoelastic properties in different locations. This non-invasive technique facilitates a dynamic analysis of mechanical properties of cells and tissues without intervening with embryonic development. We demonstrate the application of this platform for manipulating organelle shape and for characterizing the mechanobiological properties of cells in live zebrafish embryos. The method of holographic optical tweezers as described here is of general interest and can be easily transferred to studying a range of developmental processes in zebrafish, thereby establishing a versatile platform for similar investigations in other organisms. Fluorescent beads injected into zebrafish embryos at 1-cell stage are maintained within the embryos and do not affect their development as observed in the presented 1-day old embryo.

Being a key enabling technology, optofluidics allows precise light-based manipulation of liquids and solid particles on micrometer scales in fluidic environments and covers high potential to fabricate efficient integrated lab-on-a-chip devices. In many of these devices, the ability to control and to manipulate particles by light is of utmost importance. This comprises an all-optical treatment of particles, viable cells, or droplets to be moved or trapped for analytical purposes. Such an all-optical control can be realized either by direct exposure in optical tweezers or indirectly by activating electric, thermal or mechanical properties by nonlinear light-matter interaction. Beneath particle manipulation, we demonstrate control of cells by holographic optical tweezers as well as droplet manipulation based on dielectrophoretic optical tweezers.

On interannual to decadal times scales, model simulations suggest a strong relationship between anomalies in the deep water formation rate, the strength of the subpolar gyre, and the meridional overturning circulation in the North Atlantic. Whether this is valid, can only be confirmed by continuous, long observational time series. Several measurement components are already in place, but crucial arrays to obtain time series of the meridional volume and heat transport in the subpolar North Atlantic are still missing. Here we summarize the recent developments of the deep water formation rates and the subpolar gyre transports. We discuss how existing observational components in the subpolar North Atlantic could be supplemented to provide long-term monitoring of the meridional heat and volume transport. Through a combined analysis of observations and model results the temporal and spatial scales that had to be covered with instruments are discussed, together with the key regions with the highest variability in the velocity and temperature fields.

This communication presents a novel experi- mental model for Alzheimer studies, where connected pri- mary neurons were set into subtend, co-pathological states. Cortical neurons were cultured in two separated cell com- partments in a microfluidic device. A neurite network was generated in a main channel through the neurite outgrowth from both cell compartments. A gradient of okadaic acid (OA) is generated over this neurite network by perfusion. OA is a phosphatase inhibitor that induces hyperphosphor- ylation of Tau proteins, a major hallmark in Alzheimer disease. The local OA treatment resulted in a connected ‘‘diseased’’ and ‘‘healthy’’ cell population. Anti-phosphory- lated tau (Ser262) staining confirmed different states of phosphorylated Tau proteins, and synapthophysin staining the connection of ‘‘healthy’’ and ‘‘diseased’’ cells. Here, we present a novel in vitro model that opens the possibility to study cellular and molecular propagation mechanisms in neurodegeneration, in Tauopathies (as e.g., in Alzheimer), as well as simultaneous drug effects on connected healthy and diseased cell populations.

Multicomponent processes for production of high performance gearwheels combines both high power density and high lightweight potential. In this paper, the focus is on manufacturing an assembled gearwheel using cold forging and simultaneously joining the gearwheel body and a gear ring. In this study, FEA results regarding the joining process of two different materials for assembled gearwheels are presented. The aim of the numerical investigation is to achieve a robust forging process and define appropriate tool parameters.

Alzheimer's disease (AD) affects more than 35 million people worldwide and no treatment is currently available to stop neuronal decline in the brain. Microfluidics represents a promising approach to overcome limitations of conventional cell culture (1) for the establishment of in vivo-like ordered and polarized three-dimensional cell cultures and (2) for their use as alternatives to animals to study the disease progression from one part of the neuronal network to another. This chapter highlights how microtechnology-based neuroscience research opens new avenues to a thorough understanding of AD and how it may help to find answers to fundamental AD-related questions such as why pathological proteins (Tau, Aβ) spread all over the brain in a predictable pattern. Those insights potentially provide us with the necessary knowledge for the development of drug targets that counteract the dreadful consequences of this disease.

The influence of adhesion on molecular conformations—besides solely molecule orientation—and vice versa was rarely considered in adhesion science due to the difficult analysis of conformational equilibria, in general, and the high number of possible conformations in classical polymers, in particular. Fortunately, some insight is available from the interphase chemistry of proteins due to the importance regarding their biological function in heterogeneous systems. Peptides and proteins are, thus, ideal model systems for the experimental and theoretical investigation of conformational changes in interphases. The conformational equilibrium of any kind of compound or, more specifically, a polymer interacting with a surface must differ in the interphase when compared with the bulk. This is also the case for common adhesives. Therefore, we define that the interphase of an adhesive bond is the area in which the chemical composition or the conformational equilibrium differs from that of the bulk phase.

We present a novel study on label-free recognition and distinction of drug resistant breast cancer cells (MCF-7 DOX) from their parental cells (MCF-7 WT) via impedimetric measurements. Drug resistant cells exhibited significant differences in their dielectric properties compared to wild-type cells, exerting much higher extracellular resistance (Rextra ). Immunostaining revealed that MCF-7 DOX cells gained a much denser F-actin network upon acquiring drug resistance indicating that remodeling of actin cytoskeleton is probably the reason behind higher Rextra , providing stronger cell architecture. Moreover, having exposed both cell types to doxorubicin, we were able to distinguish these two phenotypes based on their substantially different drug response. Interestingly, impedimetric measurements identified a concentration-dependent and reversible increase in cell stiffness in the presence of low non-lethal drug doses. Combined with a profound frequency analysis, these findings enabled distinguishing distinct cellular responses during drug exposure within four concentration ranges without using any labeling. Overall, this study highlights the possibility to differentiate drug resistant phenotypes from their parental cells and to assess their drug response by using microelectrodes, offering direct, real-time and noninvasive measurements of cell dependent parameters under drug exposure, hence providing a promising step for personalized medicine applications such as evaluation of the disease progress and optimization of the drug treatment of a patient during chemotherapy.

We present a novel technology for the simultaneous and simple impedimetric screening of multiple microfluidic channels with only one electrode pair. We have exploited the frequency dimension to distinguish between up to three channels. Each ‘sub-sensor’ possesses its corresponding measurement frequency where the sample-specific dielectric properties can be probed. We have shown the validity of our frequency-multiplexing impedance sensor (FMIS) by comparison with conventional ‘single sensors’. Our highly sensitive FMIS was proven suitable for life science applications through usage as a cell-based toxicology platform. We are confident that our technology might find great utility in parallelized cell-based analysis systems as well as in biomedical devices where size limitations and spatially distributed probing are important parameters.

We present a novel perfusion-based microfluidic platform for label-free drug toxicity screening which can single out non-lethal morphological changes from cellular death using electrical impedance spectroscopy. Minor cellular changes such as cell-cell contacts and major cell injury were identified via impedance phase angle analysis and follow-up of impedance magnitude at different frequencies. Having exposed HepG2/C3A cells to acetaminophen (AP), we showed that continuous drug perfusion caused a time and concentration-dependent impedance decrease. Moreover, perfusion of repeated doses revealed altered dielectric properties of the cell culture after recovery from AP exposure. This study highlights the possibility to sense cellular changes long before cellular death takes place, pointing out the remarkable sensitivity advantage of this technique over standard endpoint viability tests and its interest for toxicology.

Variations in calcium ion (Ca^(2+)) concentrations play a crucial role in cell–cell communication; periodic changes act as cellular signals. In this study, we developed a solid-state calcium ion-selective electrode (Ca^(2+) ISE) integrated in a microchannel to measure extracellular Ca^(2+) variations; an ISE has a high detection sensitivity (as low as 10^(−9) M) and selectivity against potassium ions (K^+). The sensor was used to monitor the cellular activities of HepG2/C3As cultured in a microchannel. We measured a periodically oscillating extracellular Ca^(2+) concentration that was superimposed on a gradual increase in the Ca^(2+) concentration after potassium chloride (KCl) stimulation. The oscillation period was in the range of 30–50 s, which was in good agreement with the literature.

We report an alternative technique to perform a direct and local measurement of electrical resistivities in a layered retinal tissue. Information on resistivity changes along the depth in a retina is important for modelling retinal stimulation by retinal prostheses. Existing techniques for resistivity-depth profiling have the drawbacks of a complicated experimental setup, a less localised resistivity probing and/or lower stability for measurements. We employed a flexible microprobe to measure local resistivity with bipolar impedance spectroscopy at various depths in isolated rat and chick embryo retinas for the first time. Small electrode spacing permitted high resolution measurements and the probe flexibility contributed to stable resistivity profiling. The resistivity was directly calculated based on the resistive part of the impedance measured with the Peak Resistance Frequency (PRF) methodology. The resistivity-depth profiles for both rat and chick embryo models are in accordance with previous mammalian and avian studies in literature. We demonstrate that the measured resistivity at each depth has its own PRF signature. Resistivity profiles obtained with our setup provide the basis for the construction of an electric model of the retina. This model can be used to predict variations in parameters related to retinal stimulation and especially in the design and optimisation of efficient retinal implants.