System identification of a hysteresis-controlled pump system using SINDy

Hysteresis-controlled devices are widely used in industrial applications. For example, cooling devices usually contain a two-point controller, resulting in a nonlinear hybrid system with two discrete states. Dynamic models of systems are essential for optimizing such industrial supply technology. However, conventional system identification approaches can hardly handle hysteresis-controlled devices. Thus, the new identification method Sparse Identification of Nonlinear Dynamics (SINDy) is extended to consider hybrid systems. SINDy composes models from basis functions out of a customized library in a data-driven manner. For modeling systems that behave dependent on their own past as in the case of natural hysteresis, Ferenc Preisach introduced the relay hysteron as an elementary mathematical description. In this new method (SINDyHybrid), tailored basis functions in form of relay hysterons are added to the library which is used by SINDy. Experiments with a hysteresis controlled water basin show that this approach correctly identifies state transitions of hybrid systems and also succeeds in modeling the dynamics of the discrete system states. A novel proximity hysteron achieves the robustness of this method. The impacts of the sampling rate and the signal noise ratio of the measurement data are examined accordingly

System identification of a hysteresis-controlled pump system using SINDy

Hysteresis-controlled devices are widely used in industrial applications. For example, cooling devices usually contain a two-point controller, resulting in a nonlinear hybrid system with two discrete states. Dynamic models of systems are essential for optimizing such industrial supply technology. However, conventional system identification approaches can hardly handle hysteresis-controlled devices. Thus, the new identification method Sparse Identification of Nonlinear Dynamics (SINDy) is extended to consider hybrid systems. SINDy composes models from basis functions out of a customized library in a data-driven manner. For modeling systems that behave dependent on their own past as in the case of natural hysteresis, Ferenc Preisach introduced the relay hysteron as an elementary mathematical description. In this new method (SINDyHybrid), tailored basis functions in form of relay hysterons are added to the library which is used by SINDy. Experiments with a hysteresis controlled water basin show that this approach correctly identifies state transitions of hybrid systems and also succeeds in modeling the dynamics of the discrete system states. A novel proximity hysteron achieves the robustness of this method. The impacts of the sampling rate and the signal noise ratio of the measurement data are examined accordingly

ADME Profiling in Drug Discovery and a New Path Paved on Silica

The drug discovery and development pipeline have more and more relied on in vitro testing and in silico predictions to reduce investments and optimize lead compounds. A comprehensive set of in vitro assays is available to determine key parameters of absorption, distribution, metabolism, and excretion, for example, lipophilicity, solubility, and plasma stability. Such test systems aid the evaluation of the pharmacological properties of a compound and serve as surrogates before entering in vivo testing and clinical trials. Nowadays, computer-aided techniques are employed not just in the discovery of new lead compounds but embedded as part of the entire drug development process where the ADME profiling and big data analyses add a new layer of complexity to those systems. Herein, we give a short overview of the history of the drug development pipeline presenting state-of-the-art ADME in vitro assays as established in academia and industry. We will further introduce the underlying good practices and give an example of the compound development pipeline. In the next step, recent advances at in silico techniques will be highlighted with special emphasis on how pharmacogenomics and in silico PK profiling can enhance drug monitoring and individualization of drug therapy

In for a penny, in for a pound: methylphenidate reduces the inhibitory effect of high stakes on persistent risky choice

Methylphenidate (MPH) is a stimulant that increases extracellular levels of dopamine and noradrenaline. It can diminish risky decision-making tendencies in certain clinical populations. MPH is also used, without license, by healthy adults, but the impact on their decision-making is not well established. Previous work has found that dopamine receptor activity of healthy adults can modulate the influence of stake magnitude on decisions to persistently gamble after incurring a loss. In this study, we tested for modulation of this effect by MPH in 40 healthy human adults. In a double-blind experiment, 20 subjects received 20 mg of MPH, while 20 matched controls received a placebo. All were provided with 30 rounds of opportunities to accept an incurred loss from their assets or opt for a "double-or-nothing" gamble that would either avoid or double it. Rounds began with a variable loss that would double with every failed gamble until it was accepted, recovered, or reached a specified maximum. Probability of recovery on any gamble was low and ambiguous. Subjects receiving placebo gambled less as the magnitude of the stake was raised and as the magnitude of accumulated loss escalated over the course of the task. In contrast, subjects treated with MPH gambled at a consistent rate, well above chance, across all stakes and trials. Trait reward responsiveness also reduced the impact of high stakes. The findings suggest that elevated catecholamine activity by MPH can disrupt inhibitory influences on persistent risky choice in healthy adults

Novel Highlight in Malarial Drug Discovery:Aspartate Transcarbamoylase

Malaria remains one of the most prominent and dangerous tropical diseases. While artemisinin and analogs have been used as first-line drugs for the past decades, due to the high mutational rate and rapid adaptation to the environment of the parasite, it remains urgent to develop new antimalarials. The pyrimidine biosynthesis pathway plays an important role in cell growth and proliferation. Unlike human host cells, the malarial parasite lacks a functional pyrimidine salvage pathway, meaning that RNA and DNA synthesis is highly dependent on the de novo synthesis pathway. Thus, direct or indirect blockage of the pyrimidine biosynthesis pathway can be lethal to the parasite. Aspartate transcarbamoylase (ATCase), catalyzes the second step of the pyrimidine biosynthesis pathway, the condensation of L-aspartate and carbamoyl phosphate to form N-carbamoyl aspartate and inorganic phosphate, and has been demonstrated to be a promising target both for anti-malaria and anti-cancer drug development. This is highlighted by the discovery that at least one of the targets of Torin2 – a potent, yet unselective, antimalarial – is the activity of the parasite transcarbamoylase. Additionally, the recent discovery of an allosteric pocket of the human homology raises the intriguing possibility of species selective ATCase inhibitors. We recently exploited the available crystal structures of the malarial aspartate transcarbamoylase to perform a fragment-based screening to identify hits. In this review, we summarize studies on the structure of Plasmodium falciparum ATCase by focusing on an allosteric pocket that supports the catalytic mechanisms

Discovery of Small-Molecule Allosteric Inhibitors of PfATC as Antimalarials

The discovery and development of new drugs against malaria remain urgent. Aspartate transcarbamoylase (ATC) has been suggested to be a promising target for antimalarial drug development. Here, we describe a series of small-molecule inhibitors of P. falciparum ATC with low nanomolar binding affinities that selectively bind to a previously unreported allosteric pocket, thereby inhibiting ATC activation. We demonstrate that the buried allosteric pocket is located close to the traditional ATC active site and that reported compounds maintain the active site of PfATC in its low substrate affinity/low activity conformation. These compounds inhibit parasite growth in blood stage cultures at single digit micromolar concentrations, whereas limited effects were seen against human normal lymphocytes. To our knowledge, this series represent the first PfATC-specific allosteric inhibitors

Standardised data reporting from pre-hospital advanced airway management - a nominal group technique update of the Utstein-style airway template

Background Pre-hospital advanced airway management with oxygenation and ventilation may be vital for managing critically ill or injured patients. To improve pre-hospital critical care and develop evidence-based guidelines, research on standardised high-quality data is important. We aimed to identify which airway data were most important to report today and to revise and update a previously reported Utstein-style airway management dataset. Methods We recruited sixteen international experts in pre-hospital airway management from Australia, United States of America, and Europe. We used a five-step modified nominal group technique to revise the dataset, and clinical study results from the original template were used to guide the process. Results The experts agreed on a key dataset of thirty-two operational variables with six additional system variables, organised in time, patient, airway management and system sections. Of the original variables, one remained unchanged, while nineteen were modified in name, category, definition or value. Sixteen new variables were added. The updated dataset covers risk factors for difficult intubation, checklist and standard operating procedure use, pre-oxygenation strategies, the use of drugs in airway management, airway currency training, developments in airway devices, airway management strategies, and patient safety issues not previously described. Conclusions Using a modified nominal group technique with international airway management experts, we have updated the Utstein-style dataset to report standardised data from pre-hospital advanced airway management. The dataset enables future airway management research to produce comparable high-quality data across emergency medical systems. We believe this approach will promote research and improve treatment strategies and outcomes for patients receiving pre-hospital advanced airway management.publishedVersio

Estimating health adjusted age at death (HAAD)

Objectives: At any point in time, a person’s lifetime health is the number of healthy life years they are expected to experience during their lifetime. In this article we propose an equity-relevant health metric, Health Adjusted Age at Death (HAAD), that facilitates comparison of lifetime health for individuals at the onset of different medical conditions, and allows for the assessment of which patient groups are worse off. A method for estimating HAAD is presented, and we use this method to rank four conditions in six countries according to several criteria of “worse off” as a proof of concept. Methods: For individuals with specific conditions HAAD consists of two components: past health (before disease onset) and future expected health (after disease onset). Four conditions (acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), schizophrenia, and epilepsy) are analysed in six countries (Ethiopia, Haiti, China, Mexico, United States and Japan). Data from 2017 for all countries and for all diseases were obtained from the Global Burden of Disease Study database. In order to assess who are the worse off, we focus on four measures: the proportion of affected individuals who are expected to have HAAD<20 (T20), the 25th and 75th percentiles of HAAD for affected individuals (Q1 and Q3, respectively), and the average HAAD (aHAAD) across all affected individuals. Results: Even in settings where aHAAD is similar for two conditions, other measures may vary. One example is AML (aHAAD = 59.3, T20 = 2.0%, Q3-Q1 = 14.8) and ALL (58.4, T20 = 4.6%, Q3-Q1 = 21.8) in the US. Many illnesses, such as epilepsy, are associated with more lifetime health in high-income settings (Q1 in Japan = 59.2) than in low-income settings (Q1 in Ethiopia = 26.3). Conclusion: Using HAAD we may estimate the distribution of lifetime health of all individuals in a population, and this distribution can be incorporated as an equity consideration in setting priorities for health interventions.publishedVersio

The Flexible Ocean and Climate Infrastructure Version 1 (FOCI1): Mean State and Variability

A new Earth system model, the Flexible Ocean and Climate Infrastructure (FOCI), is introduced. A first version of FOCI consists of a global high-top atmosphere (ECHAM6.3) and an ocean model (NEMO3.6) as well as sea ice (LIM2) and land surface model components (JSBACH), which are coupled through the OASIS3-MCT software package. FOCI includes a number of optional modules which can be activated depending on the scientific question of interest. In the atmosphere, interactive stratospheric chemistry can be used (ECHAM6-HAMMOZ) to study, for example, the effects of the ozone hole on the climate system. In the ocean, a biogeochemistry model (MOPS) is available to study the global carbon cycle. A unique feature of FOCI is the ability to explicitly resolve mesoscale ocean eddies in specific regions. This is realized in the ocean through nesting; first examples for the Agulhas Current and the Gulf Stream systems are described here. FOCI therefore bridges the gap between coarse-resolution climate models and global high-resolution weather prediction and ocean-only models. It allows to study the evolution of the climate system on regional and seasonal to (multi-) decadal scales. The development of FOCI resulted from a combination of the long-standing expertise in ocean and climate modeling in several research units and divisions at GEOMAR. FOCI will thus be used to complement and interpret long-term observations in the Atlantic, enhance the process understanding of the role of mesoscale oceanic eddies for large-scale oceanic and atmospheric circulation patterns, study feedback mechanisms with stratospheric processes, estimate future ocean acidification, improve the simulation of the Atlantic Meridional Overturning Circulation changes and their influence on climate, ocean chemistry and biology. In this paper we present both the scientific vision for the development of FOCI as well as some technical details. This includes a first validation of the different model components using several configurations of FOCI. Results show that the model in its basic configuration runs stably under pre-industrial control as well as under historical forcing, and produces a mean climate and variability which compares well with observations, reanalysis products and other climate models. The nested configurations reduce some long-standing biases in climate models and are an important step forward to include the atmospheric response in multi-decadal eddy-rich configurations

Wind tunnel testing and modal validation of TU-Flex's high aspect-ratio wings

High aspect ratio flexible wing aircraft present very complex and coupled structural and flight dynamics. This research describes a bottom-to-top validation process for this type of wing. This procedure starts with static, followed by ground vibration and wind tunnel tests. The concept of this approach is to first validate the structural and aeroelastic models before addressing the full flying vehicle. The experimental data was used to tune the structural model of a flexible flying demonstrator called TU-Flex. This aircraft was designed as a flying lab capable of recording coupled flight dynamic data of a flexible aircraft with a transport/airliner configuration. Three software were used to design the wing and to define the experimental test cases: NASTRAN, Loads Kernel, and ModSiG. The gathered data permitted tuning and showing the accuracy of the structural model. It also allows for finding inaccuracies in the aerodynamic and aeroelastic models for further tuning. The models are capable of capturing the overall aeroelastic trend nevertheless, fine tuning is now necessary. Therefore, the proposed process seems adequate to collect all necessary data to tune aeroelastic models within the process to prepare the models for the full flying vehicle